Trisomy 18 – Key Findings, Prenatal Screening and Prognosis
WHAT IS IT?
Trisomy 18 (47,XX,+18 or 47,XY,+18) is also referred to as Edwards syndrome
Second most common trisomy after Down syndrome
Present in approximately 1/5000 live births
Prevalence during pregnancy is considerably higher: 1/2500-1/2600 due to the high frequency of fetal loss and pregnancy termination after prenatal diagnosis
Approximately 72% of trisomy 18 pregnancies result in loss between 12 weeks to term
50% survive longer than one week
5% to 10% of infants will survive past the first year
There are individuals who have survived into adulthood but require significant care
Intellectual disability is profound and overall, the developmental age in older children is 6-8 months
May affect almost every organ system but the following findings are particularly common and may be identified on prenatal ultrasound. Most affected fetuses have multiple findings:
Prenatal/postnatal growth deficiency
Cleft lip and palate
Congenital heart defects (80-100%), most commonly one of the following:
Ventricular septal defect (VSD)
Atrial septal defect (ASD)
Patent ductus arteriosis (PDA)
Polyvalvular disease
Major limb malformations (5-10%): radial ray anomalies and other preaxial limb defects
Hydrocephalus with or without an open neural tube defect
Other findings may not be apparent until postnatal life, such as feeding difficulties
SYNOPSIS:
Trisomy 18 (Edwards syndrome) is a condition caused by an extra chromosome 18 that is present at the time of conception. Most cases (90%) are the result of nondisjunction during meiosis, which is typically a sporadic occurrence. In some affected individuals a chromosomal imbalance is the cause, inherited from a parent who has a balanced karyotype (i.e. Robertsonian translocation). There is also a small portion of affected individuals that have partial Trisomy 18 which may be the result of a parental translocation. A small proportion of affected individuals are diagnosed with mosaic Trisomy 18.
KEY POINTS:
Risk increases with maternal age
ACOG requires all women be offered prenatal screening (biochemical/ cfDNA) or invasive testing (amniocentesis / CVS)
Screening tests used to detect fetal Down syndrome also include risk assessment for Trisomy 18
Offer confirmatory testing following a positive screening test for Trisomy 18 due to the potential for false positive results
Strongly consider a false positive screening test if the prenatal ultrasound is normal as most affected fetuses will have multiple anomalies
If there is a family history or previous Trisomy 18 pregnancy, refer for genetic counseling
Note:ACMG provides healthcare professionals with open access ‘ACT Sheets’ to guide next steps following a positive NIPS report for trisomy 18 (see ‘Learn More – Primary Sources’ below)
Trisomy 13 – An Overview of Prenatal Findings and Outcomes
WHAT IS IT?
Trisomy 13 (47,XY,+13 or 47,XX,+13) is also referred to as Patau syndrome
Most affected individuals do not survive fetal/newborn life
Approximately 50% of Trisomy 13 pregnancies end in loss between 12 weeks to term
More than 80% of newborns will not survive past the first month of life
Approximately 5-8% of infants may survive the first year, but with high acuity intensive care
May affect almost every organ system but the following findings are particularly common and may be identified on prenatal ultrasound
Significant, symmetrical growth restriction
Midline cleft lip and palate
Occular anomalies: hypotelorism is most commonly seen; cylcopia may be present in severe cases
Proboscis
Congenital heart defects (90%)
Renal anomalies
Postaxial polydactyly
Omphalocele
Abnormal hand and foot posturing
CNS structural defects
Holoprosencephaly
Complications for survivors are severe and include:
breathing and feeding difficulties
Heart failure
Seizures
Deafness and visual impairment
Severe intellectual disability and developmental delay
SYNOPSIS:
Trisomy 13 is a condition caused by the presence of an extra chromosome (#13) that is present at the time of conception. In approximately 75% of cases, it is the result of nondisjunction during meiosis (Trisomy 13), which is usually a random occurrence. In 20% of affected individuals, chromosomal imbalance is the cause, inherited from a parent who has a balanced karyotype (i.e. Robertsonian translocation). A small proportion of affected individuals are diagnosed with mosaic Trisomy 13.
KEY POINTS:
Overall, this condition is present in approximately 1/16,000 live births
Risk increases with maternal age
ACOG requires all women be offered prenatal screening (biochemical/ cfDNA) or invasive testing (amniocentesis / CVS)
Screening tests used to detect fetal Down syndrome may also include risk assessment for Trisomy 13
Offer confirmatory testing following a positive screening test for Trisomy 13 due to the potential for false positive results
Strongly consider a false positive screening test if the prenatal ultrasound is normal as most affected fetuses will have multiple anomalies
If there is a family history or previous Trisomy 13 pregnancy, refer for genetic counseling
Note: ACMG provides healthcare professionals with open access ‘ACT Sheets’ to guide next steps following a positive NIPS report for trisomy 13 (see ‘Learn More – Primary Sources’ below)
Should Amniocentesis or Chorionic Villus Sampling Be Offered to All Pregnant Women?
CLINICAL ACTIONS:
Invasive prenatal diagnostic testing usually refers to amniocentesis (analysis of amniotic fluid cells) or chorionic villus sampling (placental cells). Prenatal healthcare providers should
Offer all patients the option of prenatal invasive testing or prenatal screening
Counsel patients that unlike invasive tests which cover all chromosomal abnormalities, traditional screening tests or even the newer cfDNA (NIPS / NIPT) tests will only screen for specific and limited chromosomal abnormalities
although cfDNA has superior detection for Down syndrome, traditional first-trimester combined screening can detect additional structural and anatomical anomalies because of the ultrasound component of the test
Identify the following risk factors for fetal aneuploidy and consider referral to genetic counseling and high risk OB services if patient requires more in depth counseling or has additional concerns
Maternal age of 35 or older at EDD: the risk for chromosomal aneuploidy increases throughout the reproductive lifespan, not just after age 35
If either parent of the fetus has an unusual chromosome makeup or aneuploidy, such as an additional X or Y chromosome
ACOG states
A patient’s baseline risk for chromosomal abnormalities should not limit testing options; serum screening with or without NT ultrasound or cell-free DNA screening and diagnostic testing (CVS or amniocentesis) should be discussed and offered to all patients regardless of maternal age or risk for chromosomal abnormality
ACMG recommends
Allowing patients to select diagnostic or screening approaches for the detection of fetal aneuploidy and/or genomic changes that are consistent with their personal goals and preferences
Informing all pregnant women that diagnostic testing (CVS or amniocentesis) is an option for the detection of chromosome abnormalities and clinically significant CNVs
SYNOPSIS:
The cells obtained from amniocentesis or CVS are analyzed to determine if the number of chromosomes are correct (46) and whether there are structural changes such as deletions or duplications. Routine karyotyping is done using light microscopy. If changes are smaller than the resolution of a microscope, then molecular techniques are required and these small alterations are called microduplications or microdeletions (see ‘Related ObG Topics’ below). Presently, despite major advances in screening technologies, diagnosis of fetal aneuploidy still requires an invasive test.
KEY POINTS:
Miscarriage Risks
In expert hands, there is a 0.1 to 0.3% chance of miscarriage associated with invasive prenatal testing
Cochrane Review (Alfirevic et al., 2017) has released its review on amnio/CVS safety
2nd trimester amnio increased risk of pregnancy loss, but it was not possible to quantify the loss rate, based on one study that is now over 30 years old
Early amnio (11w0d-12w6d) is associated with pregnancy loss and clubfoot compared to 2nd trimester amnio (15w0d-16w6d)
Transcervical CVS may be associated with higher loss rate compared to 2nd trimester amnio but the quality of the evidence was downgraded due to heterogeneity between studies
Wulff et al. (Ultrasound Obstet Gynecol, 2016)
Using propensity scoring on a nationwide database of approximately 150,000 women, did not find an increased risk of miscarriage or stillbirth due to amnio or CVS when indications for the procedures were taken in to account (see Related OBG Topics below for review of this paper and other recent papers on this subject of procedure related fetal loss)
Salomon et al. (Ultrasound Obstet Gynecol, 2019)
Estimated procedure-related risk of miscarriage after amniocentesis and chorionic villus sampling (CVS)
Performed a systematic review and meta-analysis, covering 20 controlled studies
The authors concluded
…amniocentesis is associated with a procedure-related risk of 1:300 at most, or more likely, no significant increase in risk
With regard to CVS, our results demonstrate that, there is no significant procedure-related risk associated with undertaking this procedure
Routine Karyotyping or Microarray?
Abnormal prenatal ultrasound with structural abnormality
A chromosomal microarray analysis that can detect submicroscopic changes is recommended
Standard karyotype may miss 6% of important chromosome changes
Normal prenatal ultrasound
A chromosomal microarray can be offered because 1.7% of significant chromosome changes will not be detected on a standard karyotype approach
Microarray limitations to discuss with patients (see ‘Related ObG Topics’ below for more on the benefits and limitations of microarray analysis)
In a small number of cases, the laboratory may identify copy number variants of uncertain significance (VUS), also referred to as variants of uncertain significance (VOUS)
Over time, as databases grow, VUSs can be re-categorized as benign or pathogenic
Microarrays cannot detect low levels of mosaicism (more than one cell line) or balanced translocations
Small risk that while overall DNA appears balanced on a microarray, the breaks involved in the translocation may have disrupted a gene and lead to abnormal protein production
Additional Considerations
A patient who would not terminate a pregnancy
Important information that may impact the management of a pregnancy may be obtained on invasive testing beyond termination of pregnancy
Therefore, all patients should be offered the option of screening or invasive testing and have the option of accepting or declining testing irrespective of future reproductive choices
Diagnosis code: diagnosis code will vary depending on indication
Procedure codes: amniocentesis- 59000; sono guidance for amniocentesis- 76946
Procedure codes: CVS- 59015; sono guidance for CVS-76945
cfDNA vs. Routine Screening – How Do They Compare?
FINDINGS:
Cell free DNA (cfDNA / NIPS / NIPT) screening tests for fetal Trisomy 21 (Down syndrome) are more sensitive, have lower false positive rates and higher positive predictive values regardless of maternal age, than standard first trimester screening
Despite improved performance compared to standard screening, cfDNA tests should be considered screening tests only. Further counseling and diagnostic confirmation should be sought prior to acting on a positive cfDNA screening test result
SYNOPSIS:
Norton and colleagues (NEJM, 2015) reported findings from the NEXT study comparing performance between new prenatal screening tests using cfDNA, compared to first trimester standard screening (serum pregnancy-associated plasma protein A, and total or free beta subunit of human chorionic gonadotropin measurements, with nuchal translucency).
KEY POINTS:
In a general population of women in the first trimester of pregnancy, cfDNA testing detected 38/38 fetuses affected with Trisomy 21 compared to 30/38 with standard screening
The positive predictive value (PPV) was 80.9% using cfDNA compared to 3.4% using standard screening
cfDNA screening did result in some false positives for Trisomy 21
confirmatory/diagnostic testing is therefore required before acting on cfDNA or standard screening tests
cfDNA screening is less ideal for obese patients as suggested in previous studies
“No results” cfDNA reports require additional follow-up to rule out fetal aneuploidy
This study was focused on Trisomy 21 detection only; however results for Trisomy 18 and Trisomy 13 suggest cfDNA provides more accurate screening for these disorders as well
22q11.2 deletion syndrome is referred to by other names in the literature, as well as in clinical reporting:
22q deletion syndrome, DiGeorge syndrome or Velocardiofacial (VCF) syndrome are alternate references
Most common microdeletion syndrome resulting from loss of a small segment of the long arm of chromosome 22
May affect almost every organ system, but the following findings are particularly common and may be identified on prenatal sonogram:
Congenital heart disease (74%): especially those disorders affecting the outflow tracts such as Tetralogy of Fallot (TOF), ventricular septal defect (VSD), interrupted aortic arch and truncus arteriosus
Cleft Palate: when associated with 22q deletion syndrome the roof of the mouth may appear intact
Look for submucosal cleft palate
May not be seen on prenatal ultrasound and may even be missed at birth without careful physical examination
Renal anomalies (31%)
Other findings may not be apparent until postnatal life and may require immediate attention:
Immune deficiency (77%)
Hypocalcemia (50%), which may lead to seizures
Feeding and swallowing problems
KEY POINTS:
In 93% of cases, it is a new occurrence
7% of individuals inherit the deleted chromosome from a parent.
Many cfDNA (NIPS/NIPT) tests may include 22q, but presently ACOG / SMFM do not recommend routine microdeletion screening
Prenatal diagnosis is available using prenatal chromosomal microarray technology
Offer microarray analysis to a patient with a fetus with one or more major structural abnormalities on ultrasound who is undergoing invasive prenatal diagnosis
Microarray analysis can be performed in a patient with a structurally normal fetus who is undergoing invasive prenatal diagnostic testing
Approximately 1/3000 to 1/6000 children are born with this disorder
Prenatal incidence may be higher at 1/1000 to 1/2000
While there may be noticeable characteristic facial features in some affected individuals, this syndrome may be missed at birth and can have life threatening consequences, if undiagnosed
Genetic consultation and multidisciplinary management is advised to maximize beneficial outcome
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