Edwards Syndrome (Trisomy 18)

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 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

• 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: 
  • 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, 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 is present in the 3 copies.

Mosaicism

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

Clinical Presentation

• Major findings:
  • Intrauterine growth restriction (IUGR) with polyhydramnios on ultrasound
  • Prominent occiput
  • Micrognathia
  • Microcephaly
  • Low-set, pointy ears
  • Cleft lip and 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 (PDA)
  • Pulmonary stenosis
  • Atrial septal defect (ASD)
• GI involvement in approximately 75% of cases:
  • Meckel diverticulum and malrotation
  • 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
  • ↓ 𝛼-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 in the 2nd trimester.
  • Findings:
    • Unchanged inhibin A
    • ↓ Free estriol, 𝛼-fetoprotein, β-hCG
• Full integrated test: 
  • Combination of 1st-trimester pregnancy-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 test:
  • Noninvasive fetal procedure
  • Anytime after the 10th week of gestation
  • Fetal DNA is isolated from maternal blood and evaluated for chromosomal abnormalities.
  • More accurate and specific than a traditional screening test
  • Tests for fetal sex

Diagnostic tests

• Diagnostic invasive tests:
  • Indications:
    • Positive screening test
    • Prior pregnancy 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 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

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.

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, coloboma of the iris, scalp defects, and polydactyly are more commonly seen in trisomy 13. Both trisomy 18 and 13 have poor prognoses.
• 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, 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. 
• 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 in the CHD7 gene is involved. No specific treatment is recommended as management is individualized based on the degree of major and minor abnormalities.