Edwards Syndrome (Trisomy 18)

1. Clinical Overview

Summary

Edwards Syndrome (Trisomy 18) is the second most common autosomal trisomy after Down syndrome, characterized by the presence of an extra copy of chromosome 18. First described by John Hilton Edwards in 1960, this severe chromosomal disorder presents with a distinctive phenotype including severe intrauterine growth restriction (IUGR), craniofacial dysmorphism, characteristic limb abnormalities (overlapping fingers, rocker-bottom feet), and multiple congenital malformations affecting particularly the cardiovascular, renal, and central nervous systems. [1]

The condition carries a grave prognosis, with an estimated 50-95% of affected fetuses dying in utero, and median survival of liveborn infants ranging from 3-15 days depending on the study population. However, the historical characterization of trisomy 18 as "incompatible with life" or "lethal" has been challenged by contemporary data showing that 5-10% of infants survive beyond the first year, particularly those with mosaic forms or those receiving intensive care. [2,3] The preferred terminology has evolved to "life-limiting" rather than "lethal," acknowledging both the severity of the condition and the spectrum of outcomes. [4]

The prognosis remains poor overall, with survivors experiencing profound neurodevelopmental disability, requiring lifelong multidisciplinary support. Modern management emphasizes individualized, family-centered care that respects parental values and goals while providing accurate, balanced prognostic information. [5]

Key Facts

• Incidence: Approximately 1 in 6,000 live births, with conception rates much higher (estimated 1 in 2,500) due to high fetal loss rates. [1]
• The Pathognomonic "Overlapping Fingers": The index finger crosses over the middle finger, and the fifth finger crosses over the fourth finger, creating a distinctive clenched fist posture (camptodactyly).
• Rocker Bottom Feet: Convex plantar surface with prominent calcaneus, resembling the rocker of a rocking chair (vertical talus).
• Cardiac Defects: Present in > 90% of cases; most commonly ventricular septal defect (VSD), atrial septal defect (ASD), patent ductus arteriosus (PDA), and polyvalvular dysplasia. [6]
• Female Predominance: Live births show a 3:1 female-to-male ratio, reflecting higher in utero male fetal loss.
• Mosaic Forms: Approximately 5% of cases represent mosaic trisomy 18, with variable phenotype severity and improved survival compared to full trisomy. [7]

Clinical Pearls

The "Small" Baby with Polyhydramnios: Edwards babies are invariably small for gestational age (SGA/IUGR). The combination of severe IUGR with polyhydramnios (due to impaired fetal swallowing from neuromuscular dysfunction) should immediately raise suspicion for trisomy 18 or 13.

Prominent Occiput: Unlike Patau syndrome (trisomy 13) characterized by midline defects (holoprosencephaly, cleft lip/palate), Edwards syndrome features a petite face with severe micrognathia but a markedly prominent occiput where the posterior skull projects posteriorly.

Screening Biochemistry: The "triple low" pattern on second-trimester maternal serum screening distinguishes trisomy 18 from trisomy 21. All markers (AFP, uE3, hCG) are low in trisomy 18, whereas hCG is typically elevated in Down syndrome.

Mosaicism Matters: Approximately 5% of trisomy 18 cases are mosaic, where only a proportion of cells carry the extra chromosome 18. These individuals may have significantly milder phenotypes, better neurodevelopmental outcomes, and prolonged survival, emphasizing the importance of detailed karyotype analysis. [7]

Central Apnoea: The leading cause of death in trisomy 18 is central apnoea resulting from brainstem dysfunction. Unlike obstructive apnoea, central apnoea does not respond to airway positioning or CPAP.

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2. Epidemiology

Incidence and Prevalence

Conception and Prenatal Loss

• Estimated conception rate: 1 in 2,500 pregnancies
• Approximately 50-95% of affected conceptuses are lost through spontaneous miscarriage or stillbirth
• Second-trimester loss rates are particularly high, contributing to the discrepancy between prenatal detection and live birth rates [1,8]

Live Birth Incidence

• Overall: 1 in 6,000 live births
• Geographic and ethnic variations exist but are less pronounced than for trisomy 21
• Temporal trends show relatively stable incidence rates, though prenatal diagnosis has increased detection with subsequent pregnancy termination affecting live birth rates [9]

Sex Ratio

• Live births demonstrate a marked 3:1 female-to-male ratio
• Male fetuses experience higher rates of in utero demise
• The sex difference may reflect X-linked protective or Y-linked deleterious modifying factors [1]

Risk Factors

Maternal Age

• Strong association with advanced maternal age (> 35 years), similar to other autosomal trisomies
• Risk increases exponentially with maternal age due to age-related meiotic nondisjunction errors in oocytes
• At age 35: approximately 1 in 2,500 live births
• At age 40: approximately 1 in 650 live births
• Unlike trisomy 21, paternal age shows minimal association [8]

Genetic Factors

• 95% of cases result from de novo nondisjunction events (sporadic)
• Recurrence risk for full trisomy 18 is approximately 1% (slightly above population baseline)
• Translocation forms (rare, less than 5%) may have significantly higher recurrence risks (up to 100% for certain translocation carriers)
• Parental karyotyping is indicated for translocation cases to assess recurrence risk and offer genetic counseling [10]

Other Associations

• No strong environmental risk factors have been consistently identified
• Assisted reproductive technology may be associated with slightly increased risk, though data are conflicting
• Prior affected pregnancy: recurrence risk approximately 1% for full trisomy 18

Geographic and Temporal Trends

Studies from multiple countries show relatively consistent incidence rates, with live birth prevalence ranging from 1 in 3,000 to 1 in 8,000. Temporal studies demonstrate stable conception rates but declining live birth rates in regions with widespread prenatal screening and high pregnancy termination rates following prenatal diagnosis. [9]

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3. Pathophysiology

Molecular Genetics

Chromosomal Basis Edwards syndrome results from the presence of three copies of chromosome 18 (trisomy 18) instead of the normal two copies. Three distinct cytogenetic forms exist:

1. Full Trisomy 18 (90-95% of cases)

   • Complete extra copy of chromosome 18 in all cells
   • Results from meiotic nondisjunction, most commonly maternal meiosis II error
   • Most severe phenotype with poorest prognosis

2. Mosaic Trisomy 18 (5% of cases)

   • Mixture of trisomic and normal cell lines
   • Results from postzygotic mitotic error
   • Phenotype severity correlates with proportion of trisomic cells
   • Generally milder features and improved survival compared to full trisomy [7]

3. Partial Trisomy 18 (less than 5% of cases)

   • Only a portion of chromosome 18 is present in triplicate
   • Usually results from unbalanced translocation
   • Phenotype depends on which regions are duplicated
   • May have recurrence risk if parent carries balanced translocation [10]

Mechanisms of Nondisjunction

• Meiotic nondisjunction: failure of chromosome 18 homologs (meiosis I) or sister chromatids (meiosis II) to separate properly during gamete formation
• Approximately 90% of cases arise from maternal meiosis II errors
• Advanced maternal age increases nondisjunction risk due to:
  • Prolonged oocyte arrest in meiosis I (from fetal life until ovulation)
  • Age-related deterioration of spindle checkpoint proteins
  • Declining cohesin protein function maintaining sister chromatid cohesion

Critical Regions and Genotype-Phenotype Correlations Molecular mapping studies have identified two noncontiguous critical regions on chromosome 18 associated with the Edwards syndrome phenotype: 18q11-12 and 18q21-23. Patients with partial duplications of these regions may manifest the characteristic features, while duplications of other chromosome 18 regions may produce different phenotypes. [11]

Developmental Pathophysiology

Organogenesis Disruption The extra genetic material from chromosome 18 disrupts normal developmental pathways during critical embryonic periods (weeks 3-8 of gestation):

Cardiovascular Development (Weeks 3-8)

• Disruption of neural crest cell migration affecting outflow tract septation
• Abnormal endocardial cushion development leading to septal defects
• Impaired valve formation causing polyvalvular dysplasia
• Results in: VSD, ASD, PDA, bicuspid aortic valve, coarctation of aorta [6]

Craniofacial Development (Weeks 4-8)

• Abnormal cranial neural crest cell development
• Disrupted branchial arch derivatives affecting facial structures
• Results in: micrognathia, low-set malformed ears, microcephaly, prominent occiput

Limb Development (Weeks 4-8)

• Abnormal apical ectodermal ridge (AER) signaling
• Disrupted digit patterning and joint formation
• Results in: overlapping fingers, rocker-bottom feet, radial aplasia, clubfoot

Central Nervous System (Weeks 3-8 and beyond)

• Impaired neurulation and neural tube closure
• Abnormal neuronal migration and cortical development
• Brainstem and cerebellar hypoplasia
• Results in: microcephaly, cerebellar hypoplasia, corpus callosum agenesis, neural tube defects [12]

Renal and Genitourinary (Weeks 5-12)

• Abnormal nephrogenesis and ureteric bud development
• Impaired kidney fusion and ascent
• Results in: horseshoe kidney, hydronephrosis, renal agenesis/dysplasia, cryptorchidism

Pathophysiology of Clinical Features

Growth Restriction Severe IUGR (virtually universal) results from:

• Placental insufficiency with abnormal placental development
• Reduced insulin-like growth factor signaling
• Cellular metabolic dysfunction from gene dosage imbalance
• Mean birth weight typically 1.5-2 standard deviations below mean for gestational age

Neurological Dysfunction

• Brainstem hypoplasia → central apnoea (leading cause of death)
• Cortical malformations → seizures, profound developmental delay
• Hypotonia (early) progressing to hypertonia (later)
• Poor feeding coordination due to bulbar dysfunction

Polyhydramnios Present in 25-30% of cases, resulting from:

• Impaired fetal swallowing (neuromuscular dysfunction)
• Esophageal atresia (when present)
• Paradoxically coexists with IUGR

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4. Clinical Presentation

Prenatal Presentation

First Trimester (11-14 weeks)

• Increased nuchal translucency (NT > 95th percentile)
• Absent or hypoplastic nasal bone
• Tricuspid regurgitation
• Abnormal ductus venosus flow
• Cystic hygroma
• Early-onset IUGR [13]

Second and Third Trimester

• Severe, persistent IUGR (often less than 3rd percentile)
• Polyhydramnios (25-30% of cases)
• Decreased fetal movements
• Abnormal fetal posture ("fixed" limb positions)
• Congenital heart defects on fetal echocardiography
• Choroid plexus cysts (present in 30-50% but non-specific)
• Strawberry-shaped skull (frontal bossing with narrow biparietal diameter)
• Single umbilical artery (30% of cases)
• Omphalocele, diaphragmatic hernia (less common)
• Oligohydramnios in late gestation (may follow earlier polyhydramnios)

Neonatal Presentation

General Appearance

• Severe IUGR: birth weight typically 1,500-2,500g at term
• Weak, feeble cry
• Hypertonia or hypotonia
• Poor Apgar scores
• Respiratory distress from birth

Craniofacial Features

• Skull: Microcephaly, prominent occiput, bitemporal narrowing (strawberry-shaped skull)
• Face: Triangular face, small features, micrognathia
• Eyes: Hypertelorism, epicanthic folds, short palpebral fissures, microphthalmia
• Ears: Low-set, posteriorly rotated, malformed pinnae ("fawn-like" appearance), often lacking cartilage
• Mouth: Narrow palate, occasionally cleft lip/palate (less common than trisomy 13)

Limbs and Skeleton

• Hands: The pathognomonic clenched fists with overlapping fingers
  • Index finger overlaps third finger
  • Fifth finger overlaps fourth finger
  • Camptodactyly (flexion contractures)
  • Single palmar crease (25-50%)
  • Hypoplastic nails
  • Limited finger extension
• Feet: Rocker-bottom feet (vertical talus) with convex sole and prominent calcaneus
• Other: Short sternum, narrow pelvis, limited hip abduction, radial aplasia, clubfoot (talipes equinovarus)

Systemic Features

Cardiovascular (> 90% of cases) [6]

• Ventricular septal defect (VSD) - most common
• Atrial septal defect (ASD)
• Patent ductus arteriosus (PDA)
• Polyvalvular disease (pulmonary, aortic, mitral)
• Coarctation of aorta
• Tetralogy of Fallot (less common)
• Double outlet right ventricle
• Coronary artery anomalies
• Clinical signs: murmur (pansystolic or continuous), cyanosis, heart failure

Respiratory

• Apnoea (central and obstructive)
• Weak respiratory effort
• Recurrent aspiration (from swallowing dysfunction)
• Respiratory distress syndrome
• Tracheoesophageal fistula (rare)

Gastrointestinal

• Omphalocele (10-20%)
• Esophageal atresia ± tracheoesophageal fistula
• Pyloric stenosis
• Meckel diverticulum
• Malrotation
• Feeding difficulties: poor suck, unsafe swallow, gastroesophageal reflux

Genitourinary (60% of cases)

• Horseshoe kidney (most common renal anomaly)
• Renal agenesis/hypoplasia/dysplasia
• Hydronephrosis
• Vesicoureteral reflux
• Cryptorchidism (males)
• Hypoplastic external genitalia

Central Nervous System [12]

• Structural anomalies:
  • Cerebellar hypoplasia
  • Corpus callosum agenesis/hypoplasia
  • Neural tube defects (less common)
  • Holoprosencephaly (rare; more common in trisomy 13)
• Functional:
  • Profound developmental delay
  • Seizures (10-20%)
  • Hypertonia progressing from early hypotonia
  • Poor visual and auditory responsiveness

Infant and Childhood Presentation (Long-term Survivors)

For the 5-10% who survive beyond the first year: [2,3]

Growth and Development

• Severe failure to thrive despite nutritional support
• Height and weight persistently less than 3rd percentile
• Profound global developmental delay
• Minimal or no achievement of developmental milestones
• Non-verbal or severely limited speech
• Dependent for all activities of daily living

Medical Complications

• Recurrent aspiration pneumonia
• Chronic respiratory insufficiency
• Progressive scoliosis and orthopedic complications
• Feeding difficulties requiring gastrostomy
• Increased malignancy risk: Wilms tumor, hepatoblastoma (screening recommended)
• Seizure disorders
• Hearing and vision impairment
• Constipation and gastrointestinal dysmotility

Mosaic Trisomy 18 [7]

• Phenotype varies with percentage of trisomic cells
• May have milder dysmorphic features
• Better neurodevelopmental outcomes (though still significantly delayed)
• Longer survival (many reach school age or adulthood)
• Some achieve developmental milestones (sitting, walking with support)
• Diagnosis requires karyotype analysis on multiple tissue types

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5. Clinical Examination

Neonatal Examination Approach

General Observation

• Document general appearance: weak, hypotonic/hypertonic, poor activity
• Assess respiratory effort, color, perfusion
• Note any respiratory distress or apnoeic episodes
• Observe posture and spontaneous movements

Anthropometry

• Weight: Plot on growth chart (expect less than 3rd percentile, often less than 1st)
• Length: Typically reduced for gestational age
• Head circumference: Microcephaly common (plot for gestational age)
• Proportions: Short stature with relatively preserved head-to-body ratio

Head and Face

• Skull shape: View from above to assess strawberry skull (bitemporal narrowing)
  • Profile view to assess prominent occiput
  • Measure and plot head circumference
• Face: Assess for triangular face, micrognathia, small features
  • Check for cleft lip/palate (open mouth, palpate palate)
• Eyes: Assess spacing (hypertelorism), epicanthic folds, palpebral fissure length
  • Fundoscopy if indicated (cataracts, colobomas rare)
• Ears: Position (draw horizontal line from outer canthus to ear; low-set if insertion below this line)
  • Assess shape, cartilage development, rotation
  • Check hearing response (if stable enough for testing)

Cardiovascular Examination

• Inspection: Cyanosis, respiratory distress, precordial activity
• Palpation: Apex beat location and character, heaves, thrills, femoral pulses
• Auscultation:
  • Pansystolic murmur (VSD) - left lower sternal border
  • Continuous machinery murmur (PDA) - left upper sternal border
  • Ejection systolic murmur (pulmonary stenosis, ASD)
  • Assess heart rate, rhythm, additional sounds (S3, S4)
• Signs of heart failure: Tachypnoea, hepatomegaly, poor feeding, gallop rhythm

Respiratory Examination

• Pattern: Tachypnoea, apnoeic episodes, irregular breathing
• Work of breathing: Intercostal/subcostal recession, nasal flaring, grunting
• Auscultation: Air entry, crackles (aspiration), wheeze

Abdominal Examination

• Inspection: Omphalocele (covered defect with visible organs), scaphoid abdomen
• Palpation: Hepatomegaly (heart failure), masses (hydronephrosis, tumors)
  • "Kidneys: palpate for horseshoe kidney (midline mass)"
• Genitalia: Assess for cryptorchidism (males), hypoplastic external genitalia
  • Document Tanner staging if older child

Limb Examination - Critical Diagnostic Features

• Hands:

  • "Posture: Observe spontaneous clenched fist position"
  • "Overlapping fingers: Attempt passive extension"
    • Index finger overlaps third finger (medially)
    • Fifth finger overlaps fourth finger (medially)
  • "Palmar creases: Single transverse palmar crease in 25-50%"
  • "Nails: Hypoplastic, small"
  • "Thumbs: May be hypoplastic or absent (radial aplasia)"
  • "Range of motion: Limited finger extension (camptodactyly)"

• Feet:

  • "Rocker-bottom feet: Convex sole, prominent calcaneus"
    • Lateral view shows vertical talus deformity
  • Clubfoot (talipes equinovarus) may coexist
  • "Toes: Assess for syndactyly, hyperconvex nails"

• Other skeletal:

  • Palpate sternum (short sternum)
  • Hip examination (developmental dysplasia risk)
  • Spine (scoliosis in survivors)

Neurological Examination

• Tone: Hypertonia or hypotonia (often evolves from hypotonia to hypertonia)
• Reflexes: Primitive reflexes (Moro, grasp, rooting) - may be weak or absent
  • Deep tendon reflexes (may be brisk if hypertonic)
• Fontanelle: Size, tension (usually not enlarged)
• Cry: Weak, high-pitched, or absent
• Feeding: Assess suck reflex, coordination of suck-swallow-breathe
• Seizure activity: Observe for subtle seizures

Serial Examination in Survivors

For infants surviving beyond the neonatal period:

Growth Monitoring

• Plot weight, length, head circumference on trisomy 18-specific growth charts if available
• Monitor for failure to thrive
• Assess nutritional status and feeding method efficacy

Developmental Assessment

• Document achievement (or non-achievement) of milestones
• Assess vision and hearing responses
• Evaluate for emerging seizure activity
• Monitor tone evolution (typically hypotonia → hypertonia)

Cardiovascular Follow-up

• Monitor for heart failure progression
• Assess need for medical management or surgical intervention

Orthopedic Surveillance

• Scoliosis screening (common in survivors)
• Hip surveillance for dysplasia
• Contracture development

Tumor Screening

• Abdominal ultrasound every 3 months until age 4 years (Wilms tumor risk)
• Alpha-fetoprotein levels (hepatoblastoma risk)

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6. Investigations

Antenatal Screening and Diagnosis

First-Trimester Combined Screening (11-14 weeks) [13]

Ultrasound Markers

• Increased nuchal translucency (NT ≥95th percentile)
• Absent or hypoplastic nasal bone
• Tricuspid regurgitation
• Abnormal ductus venosus flow (reversed a-wave)
• Detection rate: 90% with 5% false positive rate when combined with biochemistry

Biochemical Markers

• Pregnancy-associated plasma protein A (PAPP-A): Decreased
• Free β-hCG: Decreased
• Combined with NT measurement: detection rate 85-90%

Second-Trimester Serum Screening (15-20 weeks)

Quadruple Test - Characteristic "Triple Low" Pattern

• Alpha-fetoprotein (AFP): Low
• Unconjugated estriol (uE3): Low
• Human chorionic gonadotropin (hCG): Low
• Inhibin A: Variable (may be low or normal)

Key Distinguishing Feature:

• Trisomy 18: All markers LOW ("triple low")
• Trisomy 21: hCG HIGH, AFP low, uE3 low (different pattern)
• Detection rate: 60-70% with 5% false positive rate

Second-Trimester Ultrasound (18-22 weeks)

Common Findings (in order of frequency):

• Severe IUGR (less than 5th percentile for gestational age)
• Congenital heart defects (VSD, ASD, PDA) - > 90%
• Choroid plexus cysts (30-50% but NON-SPECIFIC - common in normal fetuses)
• Clenched hands with overlapping fingers
• Rocker-bottom feet
• Strawberry-shaped skull
• Single umbilical artery
• Omphalocele (10-20%)
• Renal anomalies (horseshoe kidney, hydronephrosis)
• Polyhydramnios (25-30%)
• Micrognathia

Cell-Free Fetal DNA Testing (NIPT) [13]

• Non-invasive prenatal testing from maternal blood (from 10 weeks gestation)
• Sensitivity: > 99% for trisomy 18
• Specificity: > 99.9%
• Positive Predictive Value: 80-90% (lower in low-risk populations)
• Key Point: Screening test, NOT diagnostic - positive results require confirmatory diagnostic testing
• Lower PPV than for trisomy 21 due to lower prevalence
• False positives may occur with confined placental mosaicism

Diagnostic Testing

Chorionic Villus Sampling (CVS) (11-14 weeks)

• Indications: Abnormal first-trimester screening, previous affected pregnancy
• Provides tissue for rapid and full karyotype
• Miscarriage risk: 0.5-1%

Amniocentesis (from 15 weeks)

• Indications: Abnormal screening results, ultrasound anomalies
• Amniotic fluid provides fetal cells for karyotype
• Miscarriage risk: 0.1-0.3%

Rapid Aneuploidy Detection (QF-PCR/FISH)

• Quantitative fluorescent polymerase chain reaction (QF-PCR)
• Results in 24-48 hours
• Detects trisomy 18, 21, 13, and sex chromosome aneuploidies
• Does NOT detect translocations or mosaicism - follow-up full karyotype essential

Full Karyotype

• Gold standard for prenatal and postnatal diagnosis
• G-banded chromosome analysis
• Results in 10-14 days
• Essential for:
  • Distinguishing full trisomy from mosaic or partial trisomy
  • Detecting translocations (important for recurrence risk counseling)
  • Providing accurate prognostic information
• Should be performed on multiple tissue types if mosaicism suspected

Postnatal Investigations

Immediate Postnatal (First 24-48 hours)

Rapid Genetic Confirmation

• QF-PCR: From blood sample, results in 24-48 hours
  • Allows rapid confirmation for counseling and decision-making
  • Follow with full karyotype (see below)

Full Karyotype (Essential)

• Blood lymphocyte culture for G-banded karyotype
• Results in 7-14 days
• Critical for:
  • Confirming diagnosis
  • Distinguishing full trisomy (47,XX,+18 or 47,XY,+18) from mosaic or partial
  • Detecting balanced translocations in parents (rare but important for recurrence risk)
• If mosaicism suspected: analyze multiple tissues (blood, skin fibroblasts)

Cardiac Assessment

• Echocardiography: Comprehensive structural and functional assessment
  • Perform within first 24-48 hours
  • Identifies VSD, ASD, PDA, valve abnormalities
  • Assesses ventricular function and pulmonary pressures
  • Guides management decisions (medical vs. surgical)
• ECG: Arrhythmia screening

Renal Assessment

• Renal ultrasound: Within first week
  • Assess for horseshoe kidney, hydronephrosis, dysplasia, agenesis
  • Guide further investigations if abnormalities detected

Basic Metabolic and Organ Function

• Full blood count: Baseline hematological parameters
• Urea and electrolytes: Renal function
• Liver function tests: Hepatic function
• Glucose: Hypoglycemia risk
• Blood gas: If respiratory distress present

Neuroimaging (if clinically indicated)

• Cranial ultrasound (through anterior fontanelle): Quick screening for major structural anomalies
• MRI brain: More detailed assessment if survival anticipated
  • Cerebellar hypoplasia, corpus callosum abnormalities, cortical malformations
  • Not typically performed if palliative care pathway chosen

Investigations for Long-term Survivors

Ongoing Cardiac Surveillance

• Serial echocardiography (frequency based on lesion severity)
• Assessment for heart failure progression
• Evaluation for surgical candidacy if appropriate

Renal Monitoring

• Serial renal ultrasounds (6-12 monthly)
• Urea, electrolytes, creatinine monitoring
• Blood pressure monitoring
• Urine analysis

Tumor Surveillance (Increased Wilms tumor and hepatoblastoma risk) [14]

• Abdominal ultrasound: Every 3 months until age 4 years
• Serum alpha-fetoprotein (AFP): Every 3 months (hepatoblastoma marker)
• Prompt investigation of any abdominal mass or unexplained symptoms

Neurodevelopmental Assessment

• Developmental milestone tracking
• EEG if seizures suspected
• Vision and hearing assessment
• Neuroimaging if new neurological signs

Orthopedic Surveillance

• Scoliosis screening (clinical and radiographic)
• Hip ultrasound/radiography for dysplasia
• Assessment of contractures

Nutritional Assessment

• Growth monitoring (weight, length, head circumference)
• Swallow assessment (videofluoroscopy if aspiration suspected)
• Nutritional status evaluation
• Gastrostomy consideration for chronic feeding difficulties

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7. Management

Management Algorithm

            SUSPECTED TRISOMY 18
   (Prenatal diagnosis OR Neonatal dysmorphism)
                     ↓
         CONFIRM DIAGNOSIS
       (Rapid QF-PCR + Full Karyotype)
                     ↓
    ┌────────────────┴────────────────┐
PRENATAL                           POSTNATAL
    ↓                                  ↓
COUNSELING                    FAMILY COUNSELING
(Balanced, accurate)          (Multidisciplinary)
    ↓                                  ↓
PARENTAL DECISION            GOALS OF CARE DISCUSSION
    ↓                                  ↓
┌───┴───┐                    ┌─────────┴─────────┐
│       │                    │                   │
TOP   CONTINUE          COMFORT CARE      ACTIVE TREATMENT
      PREGNANCY         (Palliative)      (Individualized)
          ↓                  ↓                   ↓
    DELIVERY PLAN      NO ESCALATION      FULL SUPPORT
    (Palliative vs.    Symptom focus      (Including
    Active care)       Hospice support    surgery if
          ↓                  ↓             appropriate)
    ┌─────┴─────┐           ↓                   ↓
    │           │     END-OF-LIFE         ONGOING CARE
COMFORT      ACTIVE        CARE          (Multidisciplinary)
CARE      TREATMENT         ↓                   ↓
    ↓           ↓      Bereavement         HOME SUPPORT
SUPPORT    NICU CARE       support        Palliative input
             ↓                            Developmental care
    SURVIVORSHIP CARE                     Tumor surveillance
    (If > 1 year survival)                      ↓
             ↓                          SURVIVORSHIP
    Developmental support                    CARE
    Tumor surveillance
    Multidisciplinary input

Prenatal Management and Counseling

Diagnosis Confirmation and Communication [5]

When trisomy 18 is suspected or confirmed prenatally:

1. Confirmatory Testing

   • Offer diagnostic testing (CVS or amniocentesis) if screening suggests trisomy 18
   • Rapid aneuploidy detection (QF-PCR) for quick confirmation
   • Full karyotype essential for distinguishing full vs. mosaic vs. partial trisomy

2. Multidisciplinary Counseling

   • Clinical genetics
   • Maternal-fetal medicine
   • Neonatology
   • Palliative care
   • Pediatric cardiology (if continuing pregnancy)

3. Information Provision (Balanced and Accurate) [4,5]

   • Natural history: high fetal loss rate, poor median survival, but spectrum of outcomes
   • Avoid terms like "incompatible with life" or "lethal"

• use "life-limiting"
  • Discuss survival statistics:
    • 50-95% fetal loss
    • Median survival if liveborn: 3-15 days
    • 5-10% survive to 1 year
    • Mosaic forms have better prognosis
  • Neurodevelopmental outcomes: profound disability in survivors
  • Management options: continuation vs. termination of pregnancy
  • Postnatal care options: comfort care vs. intensive care

4. Parental Decision-Making
   • Respect parental autonomy and values
   • Provide time for decision-making (avoid rushed decisions)
   • Offer psychological support and counseling
   • Connect with support organizations (e.g., SOFT - Support Organization for Trisomy)

Options After Prenatal Diagnosis

Termination of Pregnancy (TOP)

• Available in many jurisdictions for severe fetal anomaly
• Timing depends on gestational age and local laws
• Offer post-mortem examination (genetic confirmation, additional anomalies)
• Provide bereavement support

Continuation of Pregnancy

• Plan delivery and postnatal management
• Serial ultrasound monitoring (growth, polyhydramnios, fetal well-being)
• Develop goals-of-care plan BEFORE delivery (essential)
• Involve neonatal team in prenatal counseling

Delivery Planning

• Timing: Await spontaneous labor (unless maternal/fetal indication for earlier delivery)
  • Risk of stillbirth increases in third trimester
• Mode: Vaginal delivery preferred unless obstetric indication for cesarean section
  • Cesarean section solely for fetal benefit is controversial and should be discussed
• Location: Hospital with neonatal facilities if active care considered
• Resuscitation plan: Document clearly BEFORE delivery
  • Full resuscitation
  • Limited resuscitation (e.g., PPV but no intubation)
  • Comfort care only (no resuscitation)

Neonatal Management

Delivery Room Management [4,5]

Comfort Care/Palliative Approach

• Most families historically chose this pathway
• Principles:
  • No resuscitation or intensive care interventions
  • "Focus on comfort: warmth, holding, skin-to-skin contact"
  • "Symptom management: secretion management, pain relief if needed"
  • Family bonding time
  • Memory-making (photographs, handprints, chaplaincy if desired)
  • Withdrawal of support when death imminent

Active Care Approach

• Increasingly offered in some centers following parental advocacy [5]
• Standard neonatal resuscitation as per NLS guidelines
• Admission to neonatal intensive care unit
• Supportive care: respiratory support, cardiovascular support, feeding
• Investigations as outlined above
• Individualized approach based on infant's clinical status and parental wishes

Key Considerations

• No "one-size-fits-all" approach
• Decisions should be individualized, respecting parental values
• Guidelines from AAP and other bodies recommend avoiding blanket "do not resuscitate" policies
• Trial of therapy approach: intensive care with ongoing reassessment
• Clear communication and shared decision-making throughout

Neonatal Intensive Care (if Active Care Chosen)

Respiratory Support

• Oxygen therapy for hypoxemia
• CPAP for respiratory distress
• Mechanical ventilation if severe respiratory failure (controversial - discuss with family)
• Monitor for central apnoea (leading cause of death)

Cardiovascular Management

• Medical management of heart failure:
  • Diuretics (furosemide)
  • ACE inhibitors (controversial in neonates)
  • Digoxin (if indicated)
• Management of PDA:
  • Conservative approach often appropriate
  • Medical closure (NSAIDs) controversial
  • Surgical ligation rarely performed
• Echocardiographic monitoring

Feeding and Nutrition

• Most infants have unsafe swallow and poor oral intake
• Nasogastric tube feeding commonly required
• Gastrostomy tube for long-term survivors with persistent feeding difficulties
• Anti-reflux measures (positioning, thickened feeds, medications)
• Nutritional support to optimize growth (though growth remains poor)

Infection Prevention and Management

• Standard infection control measures
• Prompt treatment of infections (antibiotics as indicated)
• Immunizations as per standard schedule (if surviving)

Seizure Management

• Anti-epileptic drugs if seizures present (phenobarbital first-line)
• EEG monitoring if seizures suspected

Palliative Care Input

• Even with active care, palliative care involvement helpful
• Symptom management
• Family support
• Advance care planning
• Transition to home-based care

Surgical Management

Historical Approach

• Cardiac surgery traditionally withheld, considered "futile"
• Rationale: poor overall prognosis, profound neurodevelopmental impairment unchanged by surgery

Contemporary Approach [5,15]

• Some centers now offer cardiac surgery to selected patients
• Japanese and North American case series show surgery can prolong survival
• However, neurodevelopmental outcomes remain profoundly impaired

Evidence

• Cardiac surgery improves survival in selected cases (studies from Japan show 25-50% 1-year survival post-surgery vs. 5-10% without)
• Does NOT improve neurodevelopmental outcomes
• Significant perioperative risks
• Ethical debate: balancing prolongation of life vs. quality of life [15]

Current Recommendations

• Individualized decision-making
• Multidisciplinary discussion involving:
  • Cardiology, cardiac surgery
  • Neonatology, genetics
  • Palliative care
  • Ethics committee (if needed)
  • Family
• Consider:
  • Severity of cardiac lesion
  • Overall clinical status
  • Parental goals and values
  • Resource allocation considerations
• If surgery pursued: informed consent emphasizing outcomes and limitations

Other Surgical Interventions

• Omphalocele repair: may be performed if compatible with goals of care
• Gastrostomy tube placement: for long-term feeding in survivors
• Orthopedic procedures: scoliosis correction in older survivors (rare)

Management of Long-Term Survivors

For the 5-10% surviving beyond 1 year: [2,3]

Multidisciplinary Team

• Pediatrician (lead)
• Clinical genetics
• Cardiology
• Neurology
• Gastroenterology/nutrition
• Orthopedics
• Palliative care
• Developmental pediatrics
• Physiotherapy, occupational therapy, speech therapy
• Social work, psychology

Ongoing Medical Management

• Cardiac: Medical management of heart failure, arrhythmia surveillance
• Respiratory: Management of recurrent aspiration, chest physiotherapy, consider home oxygen
• Feeding: Gastrostomy feeding, anti-reflux measures, nutritional optimization
• Seizures: Anti-epileptic drugs as needed
• Constipation: Laxatives, bowel regimen
• Orthopedic: Scoliosis surveillance and management, contracture prevention

Developmental Support

• Early intervention programs
• Physiotherapy: Gross motor skills, positioning, contracture prevention
• Occupational therapy: Fine motor skills, activities of daily living
• Speech therapy: Communication (often non-verbal, may use assistive devices)
• Special education: Individualized education plans

Tumor Surveillance [14]

• Increased risk of Wilms tumor and hepatoblastoma
• Protocol:
  • Abdominal ultrasound every 3 months until age 4 years
  • Serum AFP every 3 months
• Prompt investigation and referral if tumor detected

Palliative Care

• Ongoing involvement for symptom management
• Advance care planning (what to do if deterioration)
• Family support
• Respite care
• End-of-life planning when appropriate

Family Support

• Genetic counseling: Recurrence risk (~1% for full trisomy)
• Psychological support for parents and siblings
• Support groups (SOFT - Support Organization for Trisomy 18, 13, and related disorders)
• Financial and social support (benefits, adaptations)
• Respite care

Transition Planning

• For rare survivors reaching adolescence/adulthood:
  • Transition to adult services
  • Ongoing multidisciplinary care
  • Residential care considerations
  • Advance directives and healthcare decision-making

---

8. Complications

Immediate Life-Threatening Complications

Central Apnoea [2]

• Pathophysiology: Brainstem hypoplasia → impaired respiratory drive
• Clinical features: Prolonged apnoeic episodes (> 20 seconds), bradycardia, desaturation
• Management:
  • Monitoring with apnoea alarms
  • Stimulation during episodes
  • Caffeine citrate (respiratory stimulant) - limited efficacy
  • Mechanical ventilation if severe and consistent with goals of care
• Prognosis: Leading cause of death in first days-weeks of life

Cardiac Failure [6]

• Causes: Large left-to-right shunts (VSD, PDA), polyvalvular disease, cardiomyopathy
• Clinical features: Tachypnoea, tachycardia, hepatomegaly, poor feeding, failure to thrive
• Management:
  • Diuretics (furosemide)
  • ACE inhibitors (controversial in neonates)
  • Nutritional support
  • Surgical intervention (controversial, see above)
• Prognosis: Progressive deterioration common, major cause of early mortality

Aspiration Pneumonia

• Pathophysiology: Unsafe swallow, gastroesophageal reflux, impaired cough reflex
• Clinical features: Recurrent respiratory infections, increased oxygen requirements, feeding intolerance
• Management:
  • Aspiration precautions
  • Nasogastric or gastrostomy feeding
  • Anti-reflux measures (positioning, thickened feeds, medications)
  • Antibiotics for pneumonia
• Prognosis: Recurrent episodes common in survivors, major cause of morbidity and mortality

Hypoglycemia

• Causes: Poor feeding, low glycogen stores, hyperinsulinism (rare)
• Monitoring: Regular blood glucose checks in first 48 hours
• Management: IV dextrose, frequent NG feeds once feeding established

Complications in Survivors

Neurodevelopmental

• Profound global developmental delay (universal in full trisomy survivors)
• Epilepsy (10-20% of survivors)
• Severe intellectual disability
• Cortical visual impairment
• Sensorineural hearing loss

Growth and Nutrition

• Severe failure to thrive despite nutritional support
• Feeding difficulties and aspiration risk
• Gastroesophageal reflux disease
• Constipation

Musculoskeletal

• Progressive scoliosis: Common in survivors, may require bracing or surgery
• Hip dysplasia: Developmental dysplasia of the hip
• Joint contractures: Particularly hands and feet
• Osteoporosis: Due to immobility and nutritional deficiencies

Cardiovascular

• Progressive heart failure
• Pulmonary hypertension (Eisenmenger syndrome if large unrepaired shunts)
• Arrhythmias

Respiratory

• Recurrent lower respiratory tract infections
• Chronic aspiration
• Restrictive lung disease (scoliosis, chest wall deformity)
• Obstructive sleep apnoea

Renal

• Chronic kidney disease (if significant structural anomalies)
• Urinary tract infections (if vesicoureteral reflux, hydronephrosis)
• Hypertension

Oncological [14]

• Wilms Tumor (Nephroblastoma): Increased risk (approximately 1-2% vs. 0.01% general population)
  • Peak incidence age 2-3 years
  • "Surveillance: Abdominal ultrasound every 3 months until age 4 years"
  • "Prognosis: Good if detected early and treated"
• Hepatoblastoma: Increased risk
  • "Surveillance: AFP every 3 months, liver ultrasound"
  • Presents with abdominal mass, elevated AFP

Gastrointestinal

• Gastroesophageal reflux
• Constipation (chronic)
• Feeding intolerance

Other

• Recurrent infections (not primarily immunodeficiency, but multifactorial)
• Dental problems
• Skin breakdown (poor nutrition, immobility)

Psychosocial Complications

Family Impact

• Parental grief and bereavement (ongoing, even for survivors)
• Stress and mental health problems (depression, anxiety, PTSD)
• Relationship strain
• Financial burden (medical costs, lost work, adaptations)
• Impact on siblings

Healthcare System

• High healthcare utilization
• Complex care coordination needs
• Ethical dilemmas regarding intensity of treatment

---

9. Prognosis and Outcomes

Survival Statistics [2,3]

Fetal and Perinatal Survival

• From conception to live birth: Only 5-50% of conceptuses survive to live birth (50-95% fetal loss)
• Stillbirth rate: Approximately 30-50% of pregnancies diagnosed in second trimester

Postnatal Survival - Full Trisomy 18

Overall Live Birth Cohorts

• Median survival: 3-15 days (varies by study, presence of life-limiting anomalies)
• Survival to 1 week: 40-60%
• Survival to 1 month: 30-40%
• Survival to 1 year: 5-10%
• Survival to 5 years: 1-3%
• Survival to 10 years: less than 1%

Survival by Intervention Level

Comfort Care/Palliative Approach

• Median survival: 3-5 days
• 1-year survival: less than 5%

Active Care/Intensive Treatment Approach

• Median survival: 14-60 days (varies by study)
• 1-year survival: 10-25% (studies from centers offering intensive care)
• Improved survival does NOT equate to improved neurodevelopmental outcomes

Cardiac Surgery Recipients

• Japanese studies: 25-50% 1-year survival post-surgery [15]
• North American studies: 30-40% 1-year survival post-surgery
• Long-term outcomes still limited by profound neurodevelopmental disability

Mosaic Trisomy 18 [7]

• Significantly better survival than full trisomy
• Many survive to school age, adolescence, or adulthood
• Prognosis depends on percentage of trisomic cells
• Neurodevelopmental outcomes still significantly impaired but better than full trisomy

Partial Trisomy 18

• Variable prognosis depending on which chromosomal regions are duplicated
• May have milder phenotype and better survival

Causes of Death [2,3,16]

Neonatal/Early Infant Period

1. Central apnoea (most common) - brainstem dysfunction
2. Cardiac failure - from structural heart disease
3. Aspiration pneumonia
4. Sepsis
5. Sudden unexpected death (mechanism unclear, possibly arrhythmia or apnoea)

After First Year of Life (in survivors) [16]

1. Respiratory complications: Aspiration pneumonia, respiratory infections
2. Cardiac complications: Progressive heart failure, arrhythmias
3. Neurological complications: Seizures, brainstem dysfunction
4. Sudden unexpected death

Neurodevelopmental Outcomes in Survivors

Full Trisomy 18 Survivors [2,3]

• Intellectual Disability: Profound (universal)
• Motor Development:
  • Majority never achieve independent sitting
  • Very few achieve independent walking (anecdotal cases only)
  • Significant hypotonia or hypertonia
• Communication:
  • Majority remain non-verbal
  • Some develop limited communication (eye gaze, sounds)
  • Rarely achieve word use
• Social Interaction:
  • May show social smiling, recognition of family
  • Limited but present social engagement in many
• Activities of Daily Living: Dependent for all care

Mosaic Trisomy 18 [7]

• Variable outcomes depending on proportion of trisomic cells
• Motor Development: Some achieve sitting, standing, walking with support
• Communication: Better than full trisomy; some achieve words or short phrases
• Intellectual Disability: Moderate to profound (still significant)
• Activities of Daily Living: Require significant support, though some achieve partial independence in some areas

Prognostic Factors

Factors Associated with Better Survival

• Female sex (vs. male)
• Mosaic or partial trisomy (vs. full trisomy)
• Absence of severe cardiac defects
• Absence of renal anomalies
• Lower number of associated malformations
• Provision of intensive care and medical interventions
• Cardiac surgery (improves survival but not neurodevelopmental outcomes) [15]

Factors Associated with Poorer Survival

• Male sex
• Full trisomy 18
• Severe congenital heart disease (especially multiple lesions)
• Major renal anomalies
• Apnoeic episodes
• Lower birth weight
• Prematurity
• Multiple major malformations

Quality of Life Considerations

Parental Perspectives

• Studies of families with trisomy 18 children show diverse perspectives on quality of life
• Some parents report meaningful experiences and relationships with their child despite profound disability
• Others report significant burden and suffering
• Importance of individualized approach respecting parental values and perceptions [4,5]

Medical Perspectives

• Profound neurodevelopmental disability
• Recurrent medical complications and hospitalizations
• Significant caregiver burden
• Ethical debates about balancing prolongation of life vs. quality of life

Recurrence Risk [10]

Full Trisomy 18 (nondisjunction)

• Recurrence risk: Approximately 1% (slightly above general population risk)
• Risk increases with maternal age
• Not inherited from parents (de novo error)

Translocation Forms

• If parent carries balanced translocation: Recurrence risk up to 100% (depending on translocation type)
• Parental karyotyping essential if translocation detected in child
• Genetic counseling crucial for family planning

Mosaic Trisomy 18

• Very low recurrence risk (similar to full trisomy)
• Mosaicism arises post-fertilization (not inherited)

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10. Evidence and Guidelines

Key Guidelines

Landmark Studies and Systematic Reviews

Natural History and Survival

1. Cereda A, Carey JC. The trisomy 18 syndrome. Orphanet J Rare Dis. 2012;7:81. [1]

   • Comprehensive review of trisomy 18
   • Natural history, clinical features, management
   • Median survival 3-15 days; 5-10% 1-year survival
   • Most cited contemporary review article

2. Kosho T, Kuniba H, Tanikawa Y, et al. Natural history and parental experience in trisomy 18. Am J Med Genet A. 2013;161A(7):1531-42. [2]

   • Japanese parental support group survey (N=160)
   • Median survival 152.5 days (selected population receiving care)
   • 1-year survival 12.3%; 10-year survival 2.5%
   • Demonstrates importance of active care in selected cases
   • Parental perspectives on quality of life

3. Burke AL, Field K, Morrison JJ. Natural history of fetal trisomy 18 after prenatal diagnosis. Arch Dis Child Fetal Neonatal Ed. 2013;98(2):F140-4. [8]

   • Irish cohort (N=45) with prenatal diagnosis
   • Only 4% survived to live birth if diagnosed less than 24 weeks
   • High rate of intrauterine death
   • Informs prenatal counseling

4. Mehl JM, Gelfond J, Carey JC, et al. Causes of death in individuals with trisomy 18 after the first year of life. Am J Med Genet A. 2024;194(2):e63436. [16]

   • Recent study of causes of death in longer-term survivors
   • Respiratory complications most common cause after first year
   • Cardiac and neurological complications also important
   • Informs long-term care planning

Cardiac Surgery and Interventions

5. Maeda J, Yamagishi H, Furutani Y, et al. The impact of cardiac surgery in patients with trisomy 18 and trisomy 13 in Japan. Am J Med Genet A. 2011;155A(11):2641-6. [15]

   • Japanese cohort (N=36 with trisomy 18 receiving cardiac surgery)
   • 1-year survival 36.1% (vs. ~5% without surgery)
   • Surgery improves survival but NOT neurodevelopmental outcomes
   • Ethical considerations discussed

6. Kosho T, Nakamura T, Kawame H, et al. Neonatal management of trisomy 18: clinical details of 24 patients receiving intensive treatment. Am J Med Genet A. 2006;140(9):937-44. [17]

   • Japanese cohort receiving intensive neonatal care
   • 1-year survival 25% (vs. ~5% historical controls)
   • Demonstrates that intensive care can prolong survival
   • Does not change profound neurodevelopmental impairment

Prenatal Screening

7. Gil MM, Accurti V, Santacruz B, et al. Analysis of cell-free DNA in maternal blood in screening for aneuploidies: updated meta-analysis. Ultrasound Obstet Gynecol. 2017;50(3):302-14. [13]
   • Meta-analysis of cfDNA (NIPT) screening
   • Sensitivity 97.4%, specificity 99.9% for trisomy 18
   • Lower positive predictive value than trisomy 21 (due to lower prevalence)
   • Confirms NIPT as highly accurate screening test

Ethics and Parental Counseling

8. Janvier A, Farlow B, Wilfond BS. The experience of families with children with trisomy 13 and 18 in social networks. Pediatrics. 2012;130(2):293-8. [4]

   • Analysis of SOFT (Support Organization for Trisomy) community
   • Challenges historical "lethal" designation
   • Highlights parental experiences of meaningful relationships
   • Emphasizes need for balanced, individualized counseling

9. Russo FM, Pozzi E, Verderio M, et al. Parental counseling in trisomy 18: Novel insights in prenatal features and postnatal survival. Am J Med Genet A. 2016;170(2):302-8. [5]

   • Italian cohort (N=52)
   • Emphasizes importance of accurate, balanced prenatal counseling
   • Avoid "lethal" terminology; use "life-limiting"
   • Support parental decision-making with full information

Mosaic Trisomy 18

10. Tucker ME, Garringer HJ, Weaver DD. Phenotypic spectrum of mosaic trisomy 18: two new patients, a literature review, and counseling issues. Am J Med Genet A. 2007;143A(5):505-17. [7]
    • Review of mosaic trisomy 18 cases
    • Variable phenotype depending on mosaicism percentage
    • Better survival and developmental outcomes than full trisomy
    • Emphasizes importance of karyotype in multiple tissues

Molecular Genetics

11. Boghosian-Sell L, Mewar R, Harrison W, et al. Molecular mapping of the Edwards syndrome phenotype to two noncontiguous regions on chromosome 18. Am J Hum Genet. 1994;55(3):476-83. [11]
    • Identified critical regions on chromosome 18q11-12 and 18q21-23
    • Genotype-phenotype correlations
    • Partial trisomies of these regions produce Edwards syndrome features

Tumor Risk

12. Kaneko Y, Okita H, Haruta M, et al. A high incidence of WT1 abnormality in bilateral Wilms tumours in Japan, and the penetrance rates in children with WT1 germline mutation. Br J Cancer. 2015;112(6):1121-33. [14]
    • Confirms increased Wilms tumor risk in chromosomal disorders including trisomy 18
    • Supports tumor surveillance protocols

Evolution of Medical Practice

Historical Approach (pre-2000s)

• Trisomy 18 labeled "lethal" or "incompatible with life"
• Comfort care only, no resuscitation or intensive care offered
• Prenatal diagnosis often led to recommendation for termination
• Cardiac surgery uniformly withheld

Contemporary Approach (2000s-present) [4,5]

• Recognition of spectrum of outcomes (5-10% 1-year survival)
• Shift from "lethal" to "life-limiting" terminology
• Individualized, family-centered care models
• Offer of both palliative care AND active care options
• Some centers offering cardiac surgery on case-by-case basis
• Emphasis on shared decision-making and parental autonomy
• Recognition of parental experiences through advocacy groups (SOFT)

Ongoing Debates

• Appropriateness of intensive care and cardiac surgery
• Balancing prolongation of life vs. quality of life
• Resource allocation considerations
• Defining "meaningful survival" and quality of life
• Role of parental autonomy vs. medical beneficence/non-maleficence

---

11. Patient and Layperson Explanation

What is Edwards Syndrome?

Edwards syndrome, also called Trisomy 18, is a genetic condition that happens when a baby is born with an extra copy of chromosome number 18. Normally, we have 23 pairs of chromosomes (46 total), but babies with Edwards syndrome have three copies of chromosome 18 instead of two, giving them 47 chromosomes total.

This extra genetic material disrupts the baby's development, causing problems with many parts of the body including the heart, brain, kidneys, and skeleton.

How common is it?

Edwards syndrome affects about 1 in every 6,000 babies born. It actually happens more often during pregnancy (about 1 in 2,500 pregnancies), but sadly many affected babies do not survive to birth.

What causes Edwards syndrome?

Edwards syndrome is usually a random event that occurs when the egg or sperm is being made, or very early in pregnancy. It is not caused by anything the parents did or didn't do. It is not inherited (passed down in families) in 95% of cases - it just happens by chance.

The risk of having a baby with Edwards syndrome increases slightly as mothers get older, especially after age 35.

Will it happen again if I have another baby?

For most families, the chance of having another baby with Edwards syndrome is very low - about 1% (1 in 100). This is only slightly higher than the general population risk. However, in rare cases where there is a chromosomal rearrangement (translocation), the risk may be higher. Your doctor can arrange genetic testing and counseling to give you specific information for your family.

How is it diagnosed?

During pregnancy:

• Screening tests (blood tests and ultrasound) can suggest Edwards syndrome, but don't diagnose it for certain
• A newer blood test called NIPT (non-invasive prenatal testing) is very accurate for screening
• Definitive diagnosis requires amniocentesis or CVS (chorionic villus sampling) - tests that analyze the baby's chromosomes directly

After birth:

• Doctors may suspect Edwards syndrome based on the baby's appearance and symptoms
• A blood test analyzing the chromosomes (karyotype) confirms the diagnosis

What are the signs of Edwards syndrome?

Babies with Edwards syndrome are usually very small and have distinctive features:

• Hands: Clenched fists with overlapping fingers (a key sign)
• Feet: "Rocker-bottom" feet with curved soles
• Face: Small chin, small head, prominent back of the head
• Ears: Low-set, unusual shape
• Heart problems: More than 90% have heart defects
• Other problems: Kidney problems, feeding difficulties, breathing problems

What is the outlook for my baby?

This is the hardest question, and we wish we had better news. Edwards syndrome is a very serious condition.

The reality:

• Many babies with Edwards syndrome die before birth or are stillborn
• Of those born alive, about half live less than a week
• About 5-10 out of every 100 babies (5-10%) live to their first birthday
• Very few children live beyond early childhood
• Those who do survive have severe disabilities and need lifelong care

But it's not all the same:

• Some babies (about 5%) have a "mosaic" form where only some cells have the extra chromosome - these children often live longer and may have milder problems
• With modern medical care, some babies are living longer than in the past
• Every baby is different, and it's hard to predict exactly what will happen for your individual child

What are the options?

During pregnancy (if diagnosed before birth):

1. Continue the pregnancy: Plan for the baby's birth and decide on the type of care you want your baby to receive
2. Terminate the pregnancy: In many places, this option is available if the diagnosis is made early enough

Both choices are deeply personal, and there is no "right" answer. Your healthcare team will support you whatever you decide.

After birth: You will be asked what level of medical care you want for your baby. Options include:

1. Comfort care (also called palliative care):

   • Focus on keeping the baby comfortable and allowing you to spend time together
   • No intensive medical treatments or machines
   • Many families choose this path

2. Active medical care:

   • Treating medical problems as they arise
   • May include intensive care, breathing support, feeding tubes, medications
   • Some babies may even have heart surgery
   • This can help some babies live longer, but doesn't change the underlying condition or developmental problems

Your doctors will discuss these options with you and help you make the decision that's right for your family and your baby.

Is there a cure?

Unfortunately, no. We cannot remove or "fix" the extra chromosome. All care focuses on:

• Keeping your baby comfortable
• Treating medical problems that arise
• Supporting your family
• Making the most of the time you have with your baby

What about my baby's suffering?

This is a major concern for all parents. Modern palliative care is very good at managing symptoms like:

• Pain
• Difficulty breathing
• Secretions
• Feeding problems

Whether you choose comfort care or active medical care, the medical team will work to ensure your baby is as comfortable as possible.

What support is available?

• Medical team: Doctors, nurses, genetic counselors, social workers
• Palliative care team: Specialists in comfort and family support
• Support groups: Organizations like SOFT (Support Organization for Trisomy 18, 13, and Related Disorders) connect you with other families who understand what you're going through
• Bereavement support: Help with grief and loss
• Practical support: Help with funeral arrangements, memory-making (photos, handprints), chaplaincy if you wish

What happens next?

Your healthcare team will:

• Give you time to absorb this information (it's overwhelming)
• Answer all your questions
• Connect you with specialists (geneticists, pediatricians, palliative care)
• Support you in making decisions about your baby's care
• Be there for you every step of the way

Remember: There is no rush to make decisions, and no "right" or "wrong" choice. What matters is what feels right for you, your baby, and your family.

Final thoughts

Receiving a diagnosis of Edwards syndrome is devastating. It's natural to feel shock, grief, anger, guilt, or numbness. All these feelings are valid.

What we can promise you:

• You are not alone
• Support is available
• Your baby will be cared for with compassion and respect
• Your wishes and values will be honored
• We will be with you throughout this journey

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12. References

Primary Sources

1. Cereda A, Carey JC. The trisomy 18 syndrome. Orphanet J Rare Dis. 2012;7:81. doi:10.1186/1750-1172-7-81

2. Kosho T, Kuniba H, Tanikawa Y, et al. Natural history and parental experience of children with trisomy 18 based on a questionnaire given to a Japanese trisomy 18 parental support group. Am J Med Genet A. 2013;161A(7):1531-1542. doi:10.1002/ajmg.a.35990

3. Imataka G, Nitta A, Suzumura H, Watanabe H, Yamanouchi H, Arisaka O. Survival of trisomy 18 cases in Japan. Genet Couns. 2007;18(3):303-308.

4. Janvier A, Farlow B, Wilfond BS. The experience of families with children with trisomy 13 and 18 in social networks. Pediatrics. 2012;130(2):293-298. doi:10.1542/peds.2012-0151

5. Russo FM, Pozzi E, Verderio M, et al. Parental counseling in trisomy 18: Novel insights in prenatal features and postnatal survival. Am J Med Genet A. 2016;170(2):302-308. doi:10.1002/ajmg.a.37424

6. Musewe NN, Alexander DJ, Teshima I, Smallhorn JF, Freedom RM. Echocardiographic evaluation of the spectrum of cardiac anomalies associated with trisomy 13 and trisomy 18. J Am Coll Cardiol. 1990;15(3):673-677. doi:10.1016/0735-1097(90)90644-5

7. Tucker ME, Garringer HJ, Weaver DD. Phenotypic spectrum of mosaic trisomy 18: two new patients, a literature review, and counseling issues. Am J Med Genet A. 2007;143A(5):505-517. doi:10.1002/ajmg.a.31562

8. Burke AL, Field K, Morrison JJ. Natural history of fetal trisomy 18 after prenatal diagnosis. Arch Dis Child Fetal Neonatal Ed. 2013;98(2):F140-F144. doi:10.1136/archdischild-2011-301589

9. Irving C, Richmond S, Wren C, Longster C, Embleton ND. Changes in fetal prevalence and outcome for trisomies 13 and 18: a population-based study over 23 years. J Matern Fetal Neonatal Med. 2011;24(1):137-141. doi:10.3109/14767051003758879

10. Hassold T, Chiu D, Yamane JA. Parental origin of autosomal trisomies. Ann Hum Genet. 1984;48(Pt 2):129-144. doi:10.1111/j.1469-1809.1984.tb00835.x

11. Boghosian-Sell L, Mewar R, Harrison W, et al. Molecular mapping of the Edwards syndrome phenotype to two noncontiguous regions on chromosome 18. Am J Hum Genet. 1994;55(3):476-483.

12. Kinoshita M, Nakamura Y, Nakano R, et al. Thirty-one autopsy cases of trisomy 18: clinical features and pathological findings. Pediatr Pathol. 1989;9(4):445-457. doi:10.3109/15513818909026936

13. Gil MM, Accurti V, Santacruz B, Plana MN, Nicolaides KH. Analysis of cell-free DNA in maternal blood in screening for aneuploidies: updated meta-analysis. Ultrasound Obstet Gynecol. 2017;50(3):302-314. doi:10.1002/uog.17484

14. Kaneko Y, Okita H, Haruta M, et al. A high incidence of WT1 abnormality in bilateral Wilms tumours in Japan, and the penetrance rates in children with WT1 germline mutation. Br J Cancer. 2015;112(6):1121-1128. doi:10.1038/bjc.2015.be 15

15. Maeda J, Yamagishi H, Furutani Y, et al. The impact of cardiac surgery in patients with trisomy 18 and trisomy 13 in Japan. Am J Med Genet A. 2011;155A(11):2641-2646. doi:10.1002/ajmg.a.34285

16. Mehl JM, Gelfond J, Carey JC, Rözelle AA, Proud MB, Martin GR. Causes of death in individuals with trisomy 18 after the first year of life. Am J Med Genet A. 2024;194(2):e63436. doi:10.1002/ajmg.a.63436

17. Kosho T, Nakamura T, Kawame H, Baba A, Tamura M, Fukushima Y. Neonatal management of trisomy 18: clinical details of 24 patients receiving intensive treatment. Am J Med Genet A. 2006;140(9):937-944. doi:10.1002/ajmg.a.31175

18. Visconti D, Esposito V, Brugnoli F, et al. Trisomy 18 and the possibility of choice: The importance of Perinatal Hospice's support. Eur J Pediatr. 2025;184(2):577. doi:10.1007/s00431-025-05970-8

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13. Examination Focus

Common Exam Questions

MCQ/SBA Format

1. Clinical Recognition Question

   • Question: A term neonate presents with severe IUGR, clenched fists with overlapping fingers, rocker-bottom feet, and a prominent occiput. Echocardiography reveals a large VSD. What is the most likely diagnosis?
   • Answer: Edwards syndrome (Trisomy 18)
   • Key: Pathognomonic overlapping fingers distinguish from other trisomies

2. Screening Biochemistry

   • Question: A 38-year-old woman undergoes second-trimester serum screening. Results show low AFP, low uE3, low hCG, and increased nuchal translucency. What is the most likely diagnosis?
   • Answer: Trisomy 18 (Edwards syndrome)
   • Key: "Triple low" pattern (vs. trisomy 21 which has HIGH hCG)

3. Genetics Question

   • Question: Parents of a child with full trisomy 18 ask about recurrence risk. What should you tell them?
   • Answer: Approximately 1% recurrence risk
   • Key: De novo nondisjunction; slightly above population baseline

4. Management Question

   • Question: A newborn is diagnosed with trisomy 18. The parents ask about options for care. What is the most appropriate approach?
   • Answer: Individualized, family-centered care with option of comfort care or active treatment based on parental values
   • Key: Modern approach avoids blanket DNR policies; offers both palliative and active care

5. Complications Question

   • Question: What is the leading cause of death in infants with trisomy 18?
   • Answer: Central apnoea from brainstem dysfunction
   • Key: Not primarily cardiac, though cardiac disease is common

6. Cardiac Question

   • Question: What is the most common cardiac defect in Edwards syndrome?
   • Answer: Ventricular septal defect (VSD)
   • Key: > 90% have cardiac defects; VSD most frequent

7. Long-term Complications

   • Question: A 3-year-old child with trisomy 18 requires tumor surveillance. What is the screening protocol?
   • Answer: Abdominal ultrasound every 3 months until age 4 years (Wilms tumor risk)
   • Key: Increased risk of Wilms tumor and hepatoblastoma

Data Interpretation Question

Scenario: Prenatal ultrasound at 20 weeks shows severe IUGR, large VSD, rocker-bottom feet, choroid plexus cysts, and polyhydramnios. Maternal serum screening shows AFP 0.4 MoM, uE3 0.3 MoM, hCG 0.5 MoM.

• Question: What is the most likely diagnosis and what test would you recommend?
• Answer: Trisomy 18; recommend amniocentesis for karyotype
• Explanation: Classic prenatal features + triple low biochemistry = trisomy 18; NIPT is screening only, karyotype diagnostic

OSCE/Clinical Examination Stations

Station: Neonatal Examination - Dysmorphic Infant

Task: Examine this newborn and present your findings

Expected Findings:

• Severe IUGR (weight less than 3rd percentile)
• Hands: Clenched fists, overlapping fingers (index over 3rd, 5th over 4th) - PATHOGNOMONIC
• Feet: Rocker-bottom feet (vertical talus)
• Head: Microcephaly, prominent occiput, strawberry-shaped skull
• Face: Micrognathia, low-set malformed ears
• Cardiac: Pansystolic murmur (VSD)
• Tone: Hypertonia or hypotonia

Diagnosis: Edwards syndrome (Trisomy 18)

Examiner Questions:

1. What is your differential diagnosis?

   • Edwards syndrome (trisomy 18) - most likely
   • Patau syndrome (trisomy 13) - but would have midline defects (cleft lip/palate, holoprosencephaly)
   • Pena-Shokeir syndrome - but neurogenic rather than chromosomal

2. What investigation would you perform?

   • Urgent karyotype (QF-PCR for rapid result + full karyotype)
   • Echocardiography
   • Renal ultrasound

3. The parents ask about prognosis. What would you tell them?

   • Life-limiting condition
   • Median survival 3-15 days
   • 5-10% survive to 1 year
   • Profound neurodevelopmental disability in survivors
   • Individualized care options available

Viva Voce Questions

Viva Topic 1: Distinguishing Trisomies

Question: How do you distinguish trisomy 18 from trisomy 13 and trisomy 21 clinically?

Model Answer:

Viva Topic 2: Ethics of Cardiac Surgery in Trisomy 18

Question: The parents of a neonate with trisomy 18 and a large VSD request cardiac surgery. How would you approach this?

Model Answer (Structured approach):

1. Acknowledge the request and parental emotions

• Validate their desire to do everything for their child
• Acknowledge this is a difficult and emotional decision

2. Provide balanced information

• Evidence: Japanese and North American studies show cardiac surgery can improve survival (25-50% 1-year survival vs. 5-10% without surgery)
• Limitations: Surgery does NOT improve neurodevelopmental outcomes; profound disability persists
• Prognosis: Even with surgery, long-term survival limited, and quality of life considerations significant

3. Explore goals of care

• What are the parents hoping to achieve?
  • Prolongation of life?
  • Quality of life?
  • Specific experiences or milestones?
• Clarify understanding of long-term prognosis and disability

4. Multidisciplinary discussion

• Involve: Neonatology, cardiology, cardiac surgery, genetics, palliative care, ethics committee (if needed)
• Case-by-case assessment of surgical candidacy

5. Ethical considerations

• Autonomy: Respect parental values and decision-making
• Beneficence: Will surgery benefit the child (survival) vs. burdens (operative risk, ICU care)
• Non-maleficence: Risk of prolonging suffering?
• Justice: Resource allocation (controversial but relevant in systems with limited resources)

6. Possible outcomes

• If surgery offered: Informed consent emphasizing realistic outcomes, ongoing reassessment
• If surgery not offered: Clearly explain rationale, offer second opinion, continue supportive care
• Ongoing support: Regardless of decision, ensure palliative care involvement and family support

Key Point: No "right" answer; individualized approach respecting parental autonomy while ensuring realistic expectations and child's best interests.

Viva Topic 3: Prenatal Counseling

Question: A couple attends clinic following prenatal diagnosis of trisomy 18 at 18 weeks. How would you counsel them?

Model Answer:

1. Confirm diagnosis

• Ensure definitive karyotype (not just screening)
• Distinguish full vs. mosaic vs. partial trisomy

2. Provide accurate, balanced information

• What is trisomy 18: Extra copy of chromosome 18, severe condition
• Prognosis:
  • Avoid "lethal" or "incompatible with life"
• use "life-limiting"
  • High fetal loss rate (30-50% stillbirth)
  • "If liveborn: median survival 3-15 days, 5-10% survive to 1 year"
  • Profound neurodevelopmental disability in survivors
• Clinical features: IUGR, dysmorphism, cardiac/renal anomalies
• Mosaic forms: Better prognosis (if mosaic detected)

3. Discuss options

• Continue pregnancy:
  • Plan delivery and postnatal care
  • Options for comfort care vs. active treatment after birth
  • Connect with support organizations (SOFT)
• Terminate pregnancy:
  • Available options depending on gestation and local laws
  • Post-mortem examination offered
  • Bereavement support

4. Recurrence risk

• Approximately 1% for full trisomy (de novo)
• Offer parental karyotyping if translocation suspected

5. Ongoing support

• Give time for decision-making (not rushed)
• Provide written information and resources
• Arrange follow-up with genetics, maternal-fetal medicine
• Offer psychological support

6. Address common questions

• "Did I cause this?"
• NO, random event
• "Will it happen again?"
• Low risk (~1%)
• "Can we do anything?"
• No cure, supportive care only

Key: Balanced, empathetic counseling; respect parental autonomy; avoid directive advice.

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Medical Disclaimer: MedVellum content is for educational purposes and clinical reference. Clinical decisions should account for individual patient circumstances. Always consult appropriate specialists and involve multidisciplinary teams in complex cases such as trisomy 18 management. Parental wishes and values should be central to all decision-making processes.