Continuing Education Activity

Edwards syndrome was first reported by Edwards et al in 1960 in a neonate with multiple congenital malformations and cognitive deficits. Trisomy 18 is an autosomal chromosomal aneuploidy caused by an extra chromosome 18, leading to various congenital malformations, and is the second most common autosomal trisomy after trisomy 21. Traditionally, infants diagnosed with trisomy 18 are offered comfort care as the condition is deemed lethal. Recent literature suggests a shift in the management of the condition. Technological interventions are now being offered, with more parents choosing these interventions. Comprehensive care requires a multidisciplinary approach and empathetic support for families to navigate complex medical and ethical decisions. This activity reviews the clinical presentation, evaluation, and management of Edwards syndrome, highlighting key information useful for the interprofessional team in identifying, assessing, and approaching patients with this condition and their families.

Objectives:

• Identify the etiology and epidemiology of Edwards syndrome.
• Apply appropriate diagnostic methods for evaluating Edwards syndrome.
• Implement the available treatment options for patients with Edwards syndrome.
• Collaborate with interprofessional team to provide comprehensive care for patients with Edwards syndrome.

Introduction

Edwards syndrome, also called trisomy 18, is an autosomal chromosomal disorder caused by an extra copy of chromosome 18. This disorder is one of the autosomal trisomy syndromes, second in frequency only to trisomy 21. Edwards syndrome was first reported by Edwards et al in 1960, who reported a neonate with multiple congenital malformations and cognitive deficits.[1] Smith et al confirmed the extra copy of chromosome 18 as an underlying cause of Edwards syndrome.[2]

Etiology

Edwards syndrome typically results from an extra copy of chromosome 18q. There are 3 types of Edwards syndrome—complete trisomy 18, partial trisomy 18, and mosaic trisomy 18.

• Complete trisomy 18 is the most common form (94%). In this type, every cell contains 3 complete copies of chromosome 18. The extra chromosome is due to nondisjunction, mostly during meiosis II. The extra chromosome is most often of maternal origin. The frequency of nondisjunction errors increases with advancing maternal age.[3] 
• Mosaic trisomy 18 is the second most common type (<5%). In this type, both a complete trisomy 18 and a normal cell line exist. Thus, the phenotype can range from a complete trisomy 18 phenotype with early mortality to a normal phenotype.
• Partial trisomy 18 accounts for 2% of Edwards syndrome. In this type, only a partial segment of chromosome 18q is present in triplicate. The partial triplicate often results from a balanced translocation or inversion carried by 1 of the parents. The phenotype of partial trisomy 18 is variable based on the location and extent of the triplicated segment.

The prevalence of Edwards syndrome is positively correlated with advancing maternal age. The recurrence risk for complete trisomy 18 is 0.5% to 1% for subsequent pregnancies.[4] If 1 parent is found to be a carrier of a balanced translocation leading to an unbalanced translocation in the child, as observed in partial trisomy 18, the recurrence risk can be higher, up to 20%, for subsequent pregnancies.

Epidemiology

The live birth prevalence of Edwards syndrome ranges from 1 in 3600 to 1 in 10,000. In the past 2 decades, the prevalence of trisomy 18 has increased due to an increase in the average maternal age. The prevalence of Edwards syndrome varies by country and termination policies. In the United States, the overall prevalence of Edwards syndrome is approximately 1 in 2500, and the liveborn prevalence is 1 in 8600.[5][6] The prevalence is higher in females compared to males, with a ratio of 3:2. However, fetal loss is higher in males compared to females, and females have better survival rates compared to males.

Pathophysiology

The phenotype of Edwards syndrome appears to be associated with 3 copies of 2 critical regions on the long arm of chromosome 18, specifically from 18q12.1 to 18q21.2 and 18q22.3 to 18qter.[7] Severe mental retardation in Edwards syndrome may be associated with trisomy of 18q12.1 to 18q21.2. The trisomy of the short arm of chromosome 18 (18p) does not seem to cause any of the major features of Edwards syndrome.

History and Physical

Edwards syndrome is characterized by variable clinical manifestations. More than 125 anomalies have been reported as features of Edwards syndrome. However, none of the clinical features are pathognomonic for Edwards syndrome.

Most cases of Edwards syndrome are diagnosed prenatally, often through antenatal screening with maternal age, maternal serum markers, or ultrasound findings during the second trimester. Antenatally, Edwards syndrome can reveal intrauterine growth restriction, polyhydramnios, agenesis of the corpus callosum, choroid plexus cyst, nuchal thickening, brachycephaly, clenched hands with overriding index fingers, cardiac defects, omphalocele, and a single umbilical artery.[8] Edwards syndrome has a high risk of fetal loss and stillbirth.

Postnatally, Edwards syndrome is characterized by a cluster of phenotypes, including the following:

• Neurologic findings
• • Neonatal hypotonia followed by hypertonia
  • Apnea
  • Seizures
  • Poor sucking
  • Delayed psychomotor development and mental retardation

• Craniofacial findings
• • Skull: Microcephaly, bitemporal narrowing, and prominent occiput
  • Face: Triangular and asymmetrical face with facial paralysis
  • Eyes: Microphthalmia, hypertelorism, epicanthus, short palpebral fissures, coloboma of the iris, cataract, corneal clouding, hypoplastic supraorbital ridge, upward or downward slanting palpebral fissures, and abnormal retinal pigmentation. 
  • Nose: Prominent nasal bridge with hypoplastic nasal root, upturned nares, and choanal atresia
  • Oral cavity: Micro-retrognathia, microstomia, narrow arched palate, cleft lip, and cleft palate
  • Ears: Microtia, preauricular appendages, low-set or retroverted ears, and dysplastic ears [9]

• Skeletal 
• • Severe growth retardation
  • Short neck
  • Short sternum
  • Broad chest, with or without widely spaced small nipples
  • Incomplete ossification of the clavicle
  • Hemivertebrae or fused vertebrae and scoliosis
  • Pectus excavatum 
  • Narrow pelvis and limitation of the hip abduction 
  • Hip dislocation
  • Arthrogryposis
  • Clenched hands with overriding fingers, camptodactyly, syndactyly, single palmar crease and clinodactyly of the fifth fingers, radial or thumb hypoplasia, and hypoplastic nails
  • Rocker-bottom feet with prominent calcanei, talipes equinovarus, and dorsiflexed great toes [10]

• Cardiovascular 

  • Cardiac defects in 90% of patients with Edwards syndrome
  • Ventricular or atrial septal defect, patent ductus arteriosus, tetralogy of Fallot, overriding aorta, coarctation of the aorta, and hypoplastic left heart syndrome
  • Polyvalvular heart disease (involving 2 or more valves, most commonly the aortic and pulmonary valves)

• Pulmonary 

  • Pulmonary hypoplasia
  • Tracheobronchomalacia, laryngomalacia
  • Obstructive and central apnea 
  • Early-onset pulmonary hypertension

• Gastrointestinal

  • Omphalocele
  • Esophageal atresia with tracheoesophageal fistula 
  • Pyloric stenosis
  • Ileal atresia
  • Malrotation
  • Meckel diverticulum
  • Diastasis recti 
  • Umbilical hernia

• Genitourinary

  • Cryptorchidism, hypospadias, and micropenis
  • Clitoral hypertrophy, hypoplasia of the labia majora, ovarian dysgenesis, and bifid uterus 
  • Horseshoe kidney, renal agenesis, and hydronephrosis

• Central nervous system malformations (occur in 30% of cases)

  • Cerebellar hypoplasia 
  • Meningoencephalocele
  • Anencephaly
  • Hydrocephalus
  • Holoprosencephaly
  • Arnold-Chiari malformation
  • Hypoplasia of the corpus callosum

Evaluation

The evaluation and diagnosis of trisomy 18 begin in the antenatal period. Maternal serum screening can show low levels of alpha-fetoprotein, human chorionic gonadotropin, and unconjugated estriol.[11] Serum and genetic markers are more useful when combined with classic ultrasound findings, such as increased nuchal translucency. For example, noninvasive prenatal testing using cell-free fetal DNA in maternal plasma has a role in diagnosing trisomy 18 but has a positive predictive value of only 60.7% when used alone. Combined with ultrasound, noninvasive prenatal testing has a positive predictive value of 100% and a negative predictive value of up to 100% by the second trimester.[12] Amniocentesis or chorionic villus sampling is recommended if the antenatal screening suggests a high risk for fetal aneuploidy.[13]

Postnatally, phenotypic variation and clinical presentation guide the evaluation. Diagnostic imaging studies, such as ultrasonography, can assess intracranial, cardiac (echocardiogram), intra-abdominal, and renal abnormalities; however, circumstances dictate the study of choice.[14] Screening is essential in these patients, as anomalies often involve multiple organ systems. Although the diagnosis is typically clinical, karyotyping can confirm trisomy, and microarray testing provides more detailed information about mosaicism.

Health Surveillance Guidelines for Edwards Syndrome

• The child with Edwards syndrome should be assessed for growth during each visit, and results should be plotted on specific growth charts.
• Sucking or swallowing difficulties can be assessed using a radiographic swallow study, which can be helpful when considering the ability of the child to protect the airway.
• Cognitive and motor development should be assessed at each visit, and referral to early intervention, if needed, is recommended. 
• An ophthalmologist referral is necessary at birth to rule out eye malformations and again in childhood to check for refractive errors and photophobia. An audiologist referral is essential at birth to rule out sensorineural hearing loss.
• A thorough neurologic examination should be performed at each visit to detect signs of hypertonia or seizures, and a referral to a neurologist is recommended.
• An echocardiogram at birth should be performed to evaluate for congenital heart disease and pulmonary hypertension.
• Abdominal ultrasound is recommended at birth to screen for renal malformations and should be repeated every 6 months until adolescence to monitor for neoplasms, such as Wilms tumor or hepatoblastoma. 
• An orthopedic examination should be performed at every visit to check for joint contractures or scoliosis.
• A pulmonologist referral and a sleep study are recommended if obstructive or central apnea is encountered.
• Referrals to a gastroenterologist and nutritionist are warranted if enteral nutrition or management of gastroesophageal reflux is needed.[15][16]

Treatment / Management

There is no definitive treatment for Edwards syndrome. Ethical issues exist around the treatment plan for newborns with Edwards syndrome due to the high mortality rate and difficulty predicting which infants survive beyond their first year of life. The major causes of sudden death in Edwards syndrome are neurological instability, cardiac failure, and respiratory failure. An individualized approach should be considered for each patient, giving the utmost importance to the parental choices in the child's best interests.

• Delivery room and neonatal intensive care unit management: Previously, trisomy 18 was considered lethal, and resuscitation at birth was not indicated. The American Academy of Pediatrics and the recent Neonatal Resuscitation Program guidelines no longer advocate withholding active management, including resuscitative efforts in the delivery room.[17]
• Feeding management: Nasogastric tube feeding and gastrostomy feeding are considered to address feeding issues. Gastroesophageal reflux can be initially managed with medical therapy and later with surgical options if refractory.
• Cardiac management: Diuretics and digoxin are used for heart failure. Palliative and corrective cardiac surgery is recommended for complex congenital heart defects.
• Infections: The standard approach to treating respiratory infections, pneumonia, urinary tract infections, and otitis media is recommended.
• Orthopedic management may be required, particularly for scoliosis due to hemivertebra.            
• Psychiatric management: The family should receive psychosocial support, including information on support organizations.

Differential Diagnosis

The differential diagnosis of Edwards syndrome is relatively broad and includes the following conditions:

• Fetal akinesia sequence (Pena-Shokeir syndrome type I): An autosomal recessive condition characterized by facial anomalies, including micrognathia; multiple joint contractures; intrauterine growth restriction; polyhydramnios; and pulmonary hypoplasia.[18]
• Patau syndrome (trisomy 13)
• Distal arthrogryposis type I with joint contractures
• CHARGE syndrome (coloboma, heart malformations, atresia of the nasal choanae, retardation of growth, genital abnormalities, and ear abnormalities)
• VACTERL association (vertebral defects, anal atresia, cardiovascular defects, tracheoesophageal fistula, esophageal atresia, renal anomalies, and limb defects)

Prognosis

Although trisomy 18 remains life-limiting, recent advances in medical care have significantly improved survival rates and outcomes. Approximately 50% of fetuses carried to term are born alive, although 40% die during labor, and one-third of surviving fetuses are delivered preterm. Among live-born infants with trisomy 18, 60% to 75% survive the first week, 20% to 40% survive the first month, and 10% to 19% survive the first year. More recent studies indicate that intensive medical interventions, such as advanced hospital care and cardiac surgeries, can increase 1-year survival rates to 30% to 50%.[19] 

Female infants with trisomy 18 have a higher likelihood of survival compared to males, and individuals with mosaic trisomy 18 often experience more prolonged survival compared to those with complete trisomy 18. The primary causes of mortality include cardiac failure due to congenital heart defects and respiratory complications, such as obstructive apnea, pulmonary hypertension, and central apnea.[20] Advancements, driven by increased hospitalizations, surgeries, and technological interventions, such as cardiac surgery, underscore the importance of revising outdated terminology. Although trisomy 18 remains life-limiting, it is vital to adopt language that accurately reflects the progress in care and honors the experiences of affected individuals and families.

Complications

Edwards syndrome is associated with a wide range of severe complications that affect multiple organ systems. These complications contribute to the high morbidity and mortality rates observed in affected individuals, often requiring multidisciplinary management to address the complex medical challenges. Major complications are as follows:

• Growth: Low birth weight followed by failure to thrive is common in Edwards syndrome. Patients with Edwards syndrome have feeding difficulties, gastroesophageal reflux, and recurrent aspiration. Edwards syndrome–specific growth curves are available for tracking development.[21][22] 
• Developmental delay: Severe to profound developmental delays are common. Cognitive and motor delays are noted in most surviving patients with Edwards syndrome. A few cases of Edwards syndrome, mosaic type, have been reported with normal intelligence.[23][24]
• Cardiorespiratory failure: This is the leading cause of death in Edwards syndrome, often due to congenital cardiac defects, hypoventilation, central apnea, and pulmonary hypoplasia.
• Neoplasm: Edwards syndrome increases the risk of neoplasms such as Wilms tumor/nephroblastoma, hepatoblastoma, and Hodgkin disease.[25]
• Endocrine: Thymic hypoplasia and adrenal hypoplasia are common in patients with Edwards syndrome.

Consultations

Prompt consultation with an interprofessional healthcare team can improve the outcome of Edwards syndrome. Clinical geneticists, developmental pediatricians, cardiologists, pulmonologists, ophthalmologists, audiologists, speech-language therapists, orthopedists, and psychologists may actively manage Edwards syndrome. Early childhood intervention and community nursing support can be recommended. The institution's ethics committee can be consulted to assist in palliative care versus intensive care decisions.

Deterrence and Patient Education

Deterrence and patient education in Edwards syndrome focus on providing families with comprehensive, empathetic counseling to facilitate informed decision-making. Although there is no definitive treatment for Edwards syndrome, healthcare professionals should educate parents about the condition's genetic basis, potential outcomes, and available treatment options. Parents of a child with Edwards syndrome often have to decide between palliative care (or comfort care) and prolonging life with intensive treatment or surgery. Emphasizing a shared decision-making approach ensures families feel supported while planning for the child's care.

Pearls and Other Issues

Prenatal counseling for parents with fetuses diagnosed with Edwards syndrome should be comprehensive, including the complexity of the varied presentations at birth, the unavoidable ethical issues due to the high fatality rate, and the significant developmental disability associated with the condition. When a prenatal diagnosis of trisomy 18 is made, the parents have difficulty making decisions regarding resuscitation, life support, intensive care, and surgical options. Clinicians must provide parents with accurate survival figures and comorbidity statistics. The expectant parents should be aware of all available management options during the neonatal period and beyond. Parents benefit by being in touch with family support groups. The parents should be counseled on the recurrence risk of 1% in subsequent pregnancies or as high as 20% in cases of partial trisomy due to unbalanced translocation.

Enhancing Healthcare Team Outcomes

Managing Edwards syndrome requires healthcare professionals to develop specialized skills in diagnosis, compassionate communication, and tailoring individualized care plans. Clinicians, advanced practitioners, and genetic counselors play critical roles in early identification and providing comprehensive counseling on prognosis and management options. Nurses and social workers support families by addressing emotional, educational, and logistical needs, whereas pharmacists ensure the safe and effective use of medications for symptom management.

Ethical responsibilities include respecting family values and preferences, avoiding stigmatizing language incompatible with life, and fostering shared decision-making. Patient-centered care focuses on improving the quality of life for both the patient and caregivers, emphasizing comfort, and considering palliative care when appropriate. Clear and consistent interprofessional communication ensures that care plans align across disciplines. Regular multidisciplinary team meetings shared electronic health records, and structured care protocols can reduce miscommunication and improve care coordination. Strategies such as family-centered care conferences encourage collaboration between providers and families, ensuring all voices are heard.

Effective care coordination involves synchronizing efforts among clinicians, advanced practitioners, pharmacists, and social workers to streamline interventions and minimize redundancies. This team-based approach improves patient safety, reduces medical errors, and ensures comprehensive support for complex needs. Continual education, simulation training, and feedback loops can further enhance team performance and patient outcomes in Edwards syndrome care.

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Disclosure: Palanikumar Balasundaram declares no relevant financial relationships with ineligible companies.

Disclosure: Indirapriya Darshini Avulakunta declares no relevant financial relationships with ineligible companies.