Edwards Syndrome (Trisomy 18)

Edwards syndrome, or trisomy 18, is a genetic syndrome caused by the presence of an extra chromosome 18. The extra chromosome is either from 3 full copies of chromosome 18 or an additional segment of chromosome 18. As the 2nd most common trisomy, Edwards syndrome is seen in 1 out of every 5,500 live births and increases with maternal age. Many cases are detected prenatally with maternal screening and ultrasound findings. Abnormalities include intrauterine growth restriction (IUGR), overlapping fingers, typical craniofacial features, rocker-bottom feet, and congenital heart defects. Trisomy 18 frequently results in fetal loss. For term pregnancies, most deaths occur during the 1st 6 months of life. Delivery in a specialized center is recommended for full-term pregnancies and intervention is based on associated abnormalities.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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Overview

Definition

Edwards syndrome, or trisomy 18, is defined as the presence of 3 copies of chromosome 18.

Epidemiology

  • 2nd most common trisomy (1 per 5,500 live births)
  • Affects girls more than boys
  • In utero death rate: 90%
  • If full-term pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-hCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care survival, the death rate is 50% within the first 2 weeks of life (most within the first year of life).
  • Incidence increases with advanced maternal age.

Etiology

  • In 90% of trisomy 18 cases, the presence of 3 copies of the 18th chromosome is due to nondisjunction.
  • Types:
    • Trisomy 18 due to nondisjunction
    • Translocation involving chromosome 18
    • Trisomy 18 mosaicism

Mnemonic

Mnemonic for Edwards syndrome (trisomy 18): “At 18 you can vote in an election.”

Pathophysiology

Genetics Genetics Genetics is the study of genes and their functions and behaviors. Basic Terms of Genetics

  • Chromosomes contain genetic material.
  • Human cells:
    • 46 chromosomes: 23 pairs with 1 homolog from the mother/egg and 1 from the father/sperm
    • Chromosomes 1–22: autosomes
    • Chromosome 23: 2 sex chromosomes 
      • Female: X, X
      • Male: X, Y
  • Meiosis Meiosis The creation of eukaryotic gametes involves a DNA replication phase followed by 2 cellular division stages: meiosis I and meiosis II. Meiosis I separates homologous chromosomes into separate cells (1n, 2c), while meiosis II separates sister chromatids into gametes (1n, 1c). Meiosis
    • DNA replication DNA replication The entire DNA of a cell is replicated during the S (synthesis) phase of the cell cycle. The principle of replication is based on complementary nucleotide base pairing: adenine forms hydrogen bonds with thymine (or uracil in RNA) and guanine forms hydrogen bonds with cytosine. DNA Replication is followed by reproductive cell division (cells separate chromosomes before reproduction from 46 → 23 chromosomes).
    • Diploid (2 sets of chromosomes) cells divide into an egg or sperm gamete and become a haploid (1 set of chromosomes) cell.
  • In fertilization Fertilization To undergo fertilization, the sperm enters the uterus, travels towards the ampulla of the fallopian tube, and encounters the oocyte. The zona pellucida (the outer layer of the oocyte) deteriorates along with the zygote, which travels towards the uterus and eventually forms a blastocyst, allowing for implantation to occur. Fertilization and First Week, a diploid zygote forms when a haploid egg and sperm unite.

Nondisjunction

  • Most common mechanism
  • In nondisjunction:
    • Failure of proper separation of 2 homologous chromosomes or sister chromatids
    • A diploid cell with a pair of chromosomes divides → 1 gamete ends up with 2 chromosomes while the other cell has none (not viable)
    • Results in aneuploidy (a state of chromosomal imbalance)
  • Trisomy 18:
    • Chromosome 18 is present 3 times (or has 3 copies).
    • Occurrence:
      • The egg with a chromosome 18 pair is fertilized by a normal haploid cell (2 from the egg and 1 from the sperm = 3).
      • The sperm with a chromosome 18 pair fertilizes a normal haploid cell (2 from the sperm and 1 from the egg = 3).

Translocation

  • Translocation occurs when a part of the chromosome either attaches to or interchanges with a segment of another chromosome.
  • Translocation trisomy 18 or partial trisomy 18:
    • 2% of cases
    • A piece of chromosome 18 attaches to another chromosome.
    • Symptoms are less severe as only a segment of chromosome 18 long or short arm Arm The arm, or "upper arm" in common usage, is the region of the upper limb that extends from the shoulder to the elbow joint and connects inferiorly to the forearm through the cubital fossa. It is divided into 2 fascial compartments (anterior and posterior). Arm is present in the 3 copies.
Unbalanced translocation

Unbalanced translocation:
Extra chromosome 18 material (long arm Arm The arm, or "upper arm" in common usage, is the region of the upper limb that extends from the shoulder to the elbow joint and connects inferiorly to the forearm through the cubital fossa. It is divided into 2 fascial compartments (anterior and posterior). Arm) attached to chromosome 15 (on the left) and
partial trisomy 18 from 2 sets of chromosome 18 + extra long arm Arm The arm, or "upper arm" in common usage, is the region of the upper limb that extends from the shoulder to the elbow joint and connects inferiorly to the forearm through the cubital fossa. It is divided into 2 fascial compartments (anterior and posterior). Arm chromosome 18 (on the right)

Image by Lecturio.

Mosaicism

  • Occurrence < 5% 
  • Extra chromosome 18 is not carried by all cells.
  • Less severe clinical manifestations

Related videos

Clinical Presentation

  • Major findings:
    • Intrauterine growth restriction (IUGR) with polyhydramnios Polyhydramnios Polyhydramnios is a pathological excess of amniotic fluid. Common causes of polyhydramnios include fetal anomalies, gestational diabetes, multiple gestations, and congenital infections. Patients are often asymptomatic but may present with dyspnea, extremity swelling, or abdominal distention. Polyhydramnios on ultrasound
    • Prominent occiput
    • Micrognathia
    • Microcephaly
    • Low-set, pointy ears
    • Cleft lip Cleft lip The embryological development of craniofacial structures is an intricate sequential process involving tissue growth and directed cell apoptosis. Disruption of any step in this process may result in the formation of a cleft lip alone or in combination with a cleft palate. As the most common craniofacial malformation of the newborn, the diagnosis of a cleft is clinical and usually apparent at birth. Cleft Lip and Cleft Palate and palate Palate The palate is the structure that forms the roof of the mouth and floor of the nasal cavity. This structure is divided into soft and hard palates. Oral Cavity: Palate
    • Short sternum
    • Horseshoe kidney
    • Rocker-bottom feet and clenched, overlapping fingers
  • Cardiac malformations in > 50% of patients: 
    • Most common: ventricular septal defect (VSD)
    • Patent ductus arteriosus Patent ductus arteriosus The ductus arteriosus (DA) allows blood to bypass pulmonary circulation. After birth, the DA remains open for up to 72 hours and then constricts and involutes, becoming the ligamentum arteriosum. Failure of this process to occur results in patent ductus arteriosus (PDA), a condition that causes up to 10% of congenital heart defects. Patent Ductus Arteriosus (PDA) ( PDA PDA The ductus arteriosus (DA) allows blood to bypass pulmonary circulation. After birth, the DA remains open for up to 72 hours and then constricts and involutes, becoming the ligamentum arteriosum. Failure of this process to occur results in patent ductus arteriosus (PDA), a condition that causes up to 10% of congenital heart defects. Patent Ductus Arteriosus (PDA))
    • Pulmonary stenosis Pulmonary stenosis Valvular disorders can arise from the pulmonary valve, located between the right ventricle (RV) and the pulmonary artery (PA). Valvular disorders are diagnosed by echocardiography. Pulmonary stenosis (PS) is valvular narrowing causing RV outflow tract obstruction. Pulmonary Stenosis
    • Atrial septal defect Atrial Septal Defect Atrial septal defects (ASDs) are benign acyanotic congenital heart defects characterized by an opening in the interatrial septum that causes blood to flow from the left atrium (LA) to the right atrium (RA) (left-to-right shunt). Atrial Septal Defect (ASD)
  • GI involvement in approximately 75% of cases:
    • Meckel diverticulum and malrotation
    • Omphalocele Omphalocele Omphalocele is a congenital anterior abdominal wall defect in which the intestines are covered by peritoneum and amniotic membranes. The condition results from the failure of the midgut to return to the abdominal cavity by 10 weeks' gestation. Omphalocele is common prenatally.
  • Severe intellectual disability in survivors

Diagnosis and Prognosis

Maternal screening

  • 1st-trimester combined test:
    • 11th–14th week of gestation
    • Maternal serum testing:
      • ↓ ꞵ-hCG
      • ↓ Pregnancy-associated plasma protein A
    • Fetal nuchal translucency:
      • On ultrasound: increased hypoechoic area in the posterior neck
      • 11th–13th week of gestation
  • 2nd-trimester triple test (triple screen):
    • 15th–20th week of gestation; ideally up to week 18
    • ↓ ?-fetoprotein, β-hCG, free estriol
  • 2nd-trimester quadruple test (quad screen):
    • 15th–21st week of gestation; ideally up to week 18
    • The best option if the mother is presenting for prenatal care Prenatal care Prenatal care is a systematic and periodic assessment of pregnant women during gestation to assure the best health outcome for the mother and her fetus. Prenatal care prevents and identifies maternal and fetal problems that adversely affect the pregnancy outcome. Prenatal Care in the 2nd trimester.
    • Findings:
      • Unchanged inhibin A
      • ↓ Free estriol, ?-fetoprotein, β-hCG
  • Full integrated test: 
    • Combination of 1st-trimester pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-hCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care-associated plasma protein A and 2nd-trimester quadruple test 
    • Ultrasound fetal nuchal translucency
  • Serum integrated test: full integrated test without ultrasound fetal nuchal translucency
  • Sequential screening:
    • 1st-trimester screening: The patient is informed of the results.
    • Above a specific threshold, counseling is provided and diagnostic testing (i.e., chorionic villus sampling) is offered.
  • Cell-free DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure test:
    • Noninvasive fetal procedure
    • Anytime after the 10th week of gestation
    • Fetal DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure is isolated from maternal blood and evaluated for chromosomal abnormalities.
    • More accurate and specific than a traditional screening test
    • Tests for fetal sex
Table: Maternal screening 1st and 2nd trimesters
1st trimester 2nd trimester
NT PAPP-A hCG AFP Estriol hCG Inhibin A
Trisomy 13 Trisomy 13 Trisomy 13, or Patau syndrome, is a genetic syndrome caused by the presence of 3 copies of chromosome 13. As the 3rd most common trisomy, Patau syndrome has an incidence of 1 in 10,000 live births. Most cases of Patau syndrome are diagnosed prenatally by maternal screening and ultrasound. More than half of the pregnancies result in spontaneous abortions. Patau Syndrome (Trisomy 13) ↓↓ Unchanged Unchanged Unchanged Unchanged
Trisomy 18 ↑↑ ↓↓ ↓↓ ↓↓ ↓↓ Unchanged
Trisomy 21 ↑↑ ↓↓
NT: nuchal translucency
PAPP-A: pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-hCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care-associated plasma protein A
hCG: human chorionic gonadotropin
AFP: ?-fetoprotein

Diagnostic tests Diagnostic tests Diagnostic tests are important aspects in making a diagnosis. Some of the most important epidemiological values of diagnostic tests include sensitivity and specificity, false positives and false negatives, positive and negative predictive values, likelihood ratios, and pre-test and post-test probabilities. Epidemiological Values of Diagnostic Tests

  • Diagnostic invasive tests:
    • Indications:
      • Positive screening test
      • Prior pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-hCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care with a child with trisomy
      • Known chromosomal translocation or aberration in the parent
    • Risks include bleeding, infection, fetal injury, and fetal loss (rare)
    • Procedures:
      • Chorionic villus sampling: sample of the placenta Placenta The placenta consists of a fetal side and a maternal side, and it provides a vascular communication between the mother and the fetus. This communication allows the mother to provide nutrients to the fetus and allows for removal of waste products from fetal blood. Placenta, Umbilical Cord, and Amniotic Cavity for testing (10th–13th week of gestation)
      • Amniocentesis: sample of the amniotic fluid for testing (15th–20th week of gestation)
      • Percutaneous umbilical blood sampling: blood sample from the umbilical cord for testing (18th–22nd week of gestation); fetal loss rate of 2%
  • Fetal karyotyping: a prenatal and postnatal confirmatory test
Karyotype trisomy 18

Karyotype showing trisomy of the 18th chromosome
(notice the pairs of chromosomes 16 and 17 and the extra 18th chromosome)

Image: “12508” by Allan J. Ebbin. License: Public Domain

Management and Prognosis

Management

  • Delivery in a specialized center with a neonatologist
  • Supportive management:
    • Intervention: dependent on the type of abnormalities
    • Hospice care
  • Genetic counseling and chromosome studies for parents (especially if planning future pregnancies)
  • Supportive resources (e.g., Support Organization for Trisomy, or SOFT)

Prognosis

  • The majority of babies will die in utero.
  • Of the babies born alive, 50% will die in the firsts 2 weeks of life, and 80%–90% will die in the first 6 months of life.
  • Death is usually due to central apnea and congestive heart failure Congestive heart failure Congestive heart failure refers to the inability of the heart to supply the body with normal cardiac output to meet metabolic needs. Echocardiography can confirm the diagnosis and give information about the ejection fraction. Congestive Heart Failure.

Differential Diagnosis

  • Patau’s syndrome (trisomy 13): the presence of 3 copies of the 13th chromosome. Many clinical findings of trisomy 18 and 13 overlap, but cleft lip and/or palate Palate The palate is the structure that forms the roof of the mouth and floor of the nasal cavity. This structure is divided into soft and hard palates. Oral Cavity: Palate, coloboma of the iris, scalp defects, and polydactyly are more commonly seen in trisomy 13. Both trisomy 18 and 13 have poor prognoses.
  • Thrombocytopenia Thrombocytopenia Thrombocytopenia occurs when the platelet count is < 150,000 per microliter. The normal range for platelets is usually 150,000-450,000/µL of whole blood. Thrombocytopenia can be a result of decreased production, increased destruction, or splenic sequestration of platelets. Patients are often asymptomatic until platelet counts are < 50,000/µL. Thrombocytopenia-absent radius syndrome: a microdeletion syndrome causing thrombocytopenia, congenital heart defects, and the absence of bilateral radii in the forearms. Bleeding may occur in the brain and other organs. Normal intellectual abilities can be expected in patients without bleeding issues. Children with trisomy 18 may present with absent radii and thrombocytopenia.
  • Fetal akinesia deformation sequence (also known as Pena-Shokeir syndrome type 1): Characteristics of fetal akinesia deformation sequence include fetal akinesia, pulmonary hypoplasia Pulmonary hypoplasia Pulmonary hypoplasia is the lack of normal fetal development of the pulmonary parenchyma. The condition is characterized by a decreased number of alveoli and bronchial generations. Oligohydramnios is a notable cause, but conditions that restrict lung development or lead to fetal lung compression can also result in pulmonary hypoplasia. Pulmonary Hypoplasia, IUGR, facial anomalies, other developmental abnormalities, and multiple joint contractures (arthrogryposis), including overlapping fingers. Approximately 30% of affected individuals are stillborn. Infants born alive have limited survival time due to complications of pulmonary hypoplasia Pulmonary hypoplasia Pulmonary hypoplasia is the lack of normal fetal development of the pulmonary parenchyma. The condition is characterized by a decreased number of alveoli and bronchial generations. Oligohydramnios is a notable cause, but conditions that restrict lung development or lead to fetal lung compression can also result in pulmonary hypoplasia. Pulmonary Hypoplasia
  • Colobomas, heart defects, atresia of the choanae, restriction of growth/developmental delay, genitourinary abnormalities, and ear anomalies (CHARGE) syndrome: In over 50% of cases, a genetic mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations in the CHD7 gene is involved. No specific treatment is recommended as management is individualized based on the degree of major and minor abnormalities.

References

  1. Cereda, A., Carey, J. C. (2012). The trisomy 18 syndrome. Orphanet journal of rare diseases. 7(81). https://doi.org/10.1186/1750-1172-7-81
  2. Edwards, J. H., et al. (1960). A New Trisomic Syndrome. Lancet. 1(7128), 787–790. https://pubmed.ncbi.nlm.nih.gov/13819419/
  3. Giersch, A. (2019). Congenital cytogenetic abnormalities. UpToDate. Retrieved March 23, 2021, from https://www.uptodate.com/contents/congenital-cytogenetic-abnormalities
  4. Jones, K. L., et al. (2013). Smith’s Recognizable Patterns of Human Malformation. Seventh edition, Elsevier Saunders.
  5. Meeks, N. J. L., et al. (2018). Genetics & Dysmorphology. In Hay William Jr., W., et al. Current Diagnosis & Treatment: Pediatrics. 24th ed., McGraw-Hill Education. accessmedicine.mhmedical.com/content.aspx?aid=1153315258
  6. Genetic and Rare Diseases Information Center (GARD). (2012). Fetal Akinesia Deformation Sequence. https://rarediseases.info.nih.gov/diseases/9634/fetal-akinesia-deformation-sequence
  7. National Organization for Rare Disorders (NORD). (2020). Trisomy 18. https://rarediseases.org/rare-diseases/trisomy-18-syndrome/

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