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AUTHOR AND EDITOR INFORMATION
Section 1 of 11  
Author: Harold Chen, MD, MS, FAAP, FACMG, Professor, Departments of Pediatrics, Obstetrics and Gynecology, Pathology, Director of Perinatal Genetics and Genetic Laboratory Services, Louisiana State University Medical Center; Laboratory Director, Hema-Con Cancer Cytogenetics Laboratory, Gainesville, Florida
Harold Chen is a member of the following medical societies: American Academy of Pediatrics, American Medical Association, American Society of Human Genetics, and Teratology Society
Editors: Michael Fasullo, PhD, Associate Professor, Center for Immunology and Microbial Disease, Albany Medical College; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; David Flannery, MD, FAAP, FACMG, Vice Chair of Education, Chief, Section of Medical Genetics, Professor, Department of Pediatrics, Medical College of Georgia; Paul D Petry, DO, FACOP, FAAP, Consulting Staff, Freeman Pediatric Care, Freeman Health System; Bruce Buehler, MD, Professor, Department of Pediatrics, Pathology and Microbiology, Executive Director, Hattie B Munroe Center for Human Genetics and Rehabilitation, University of Nebraska Medical Center
Author and Editor Disclosure
Synonyms and related keywords:
Edwards syndrome, Edwards' syndrome, trisomy 18 syndrome, trisomy E syndrome, severe psychomotor retardation, severe growth retardation, microcephaly, microphthalmia, malformed ears, micrognathia, retrognathia, microstomia, clenched fingers, congenital malformations, cardiac malformations, renal malformations, polyhydramnios, oligohydramnios, small placenta, single umbilical artery, intrauterine growth retardation, weak fetal activity, fetal distress, delayed psychomotor development, mental retardation, neonatal hypotonia, cerebellar hypoplasia, meningoencephalocele, anencephaly, hydrocephaly, holoprosencephaly, Arnold-Chiari malformation, hypoplasia of corpus callosum, aplasia of corpus callosum, defective falx cerebri, frontal lobe defect, migration defect, arachnoid cyst, myelomeningocele, ocular hypertelorism, epicanthal folds, short palpebral fissures, iris coloboma, cataract, corneal clouding, abnormal retinal pigmentation, short nose with upturned nares, choanal atresia, narrow palatal arch, cleft lip, cleft palate, preauricular tags, camptodactyly, limited hip abduction, narrow pelvis, short sternum, short neck with excessive skin folds, dorsiflexed great toes, hypoplastic nails, radial aplasia, radial hypoplasia, thumb aplasia, syndactyly of the second and third digits, arthrogryposis, rocker-bottom feet with prominent calcanei, talipes equinovarus, ventricular septal defects, poly-valvular heart disease, pulmonary valve defects, aortic valve defects, atrial septal defects, patent ductus arteriosus, overriding aorta, coarctation of aorta, hypoplastic left heart syndrome, tetralogy of Fallot, transposition of great arteries, pulmonary hypoplasia, abnormal lobation of lung, omphalocele, malrotation of the intestine, ileal atresia, common mesentery, Meckel diverticulum, esophageal atresia, tracheoesophageal fistula, diaphragmatic eventration, prune belly anomaly, diastasis recti, absent gallbladder, absent appendix, accessory spleens, exstrophy of Cloaca, pyloric stenosis, imperforate anus, malpositioned anus, pilonidal sinus, hernias, micro multicystic kidneys, double ureters, megaloureters, hydroureters, hydronephrosis, horseshoe kidneys, unilateral renal agenesis, cryptorchidism, hypospadias, micropenis, hypoplasia of labia, hypoplasia of ovaries, hypoplastic ovaries, clitoral hypertrophy, bifid uterus, thymic hypoplasia, thyroid hypoplasia, adrenal hypoplasia, clinodactyly of the fifth fingers, single flexion crease, transverse palmar crease, increased atd angle, postzygotic mitotic errors
Background
Trisomy 18 was independently described by Edwards et al and Smith et al in 1960.1, 2 Among liveborn children, trisomy 18 is the second most common autosomal trisomy after trisomy 21. The disorder is characterized by severe psychomotor and growth retardation, microcephaly, microphthalmia, malformed ears, micrognathia or retrognathia, microstomia, distinctively clenched fingers, and other congenital malformations.
Pathophysiology
Trisomy 18 severely affects all organ systems. In translocations that result in partial trisomy or in cases of mosaic trisomy 18, clinical expression is less severe, and survival is usually longer.
Frequency
United States
Prevalence is approximately 1 in 6000-8000 live births.
Mortality/Morbidity
- Approximately 95% of conceptuses with trisomy 18 die as embryos or fetuses; 5-10% of affected children survive beyond the first year of life.
- The high mortality rate is usually due to the presence of cardiac and renal malformations, feeding difficulties, sepsis, and apnea caused by CNS defects.
- Severe psychomotor and growth retardation are invariably present in those who survive beyond infancy.
Race
Trisomy 18 has no racial predilection.
Sex
Approximately 80% of cases occur in females. The preponderance of females with trisomy 18 among liveborn infants (sex ratio 0.63) compared with fetuses with prenatal diagnoses (sex ratio 0.90) indicates a prenatal selection against males with trisomy 18 after the time of amniocentesis.
Age
Trisomy 18 is detectable during the prenatal and newborn periods.
History
- Prenatal history
- Maternal polyhydramnios possibly related to defective sucking and swallowing reflexes in utero
- Oligohydramnios secondary to renal defects
- Disproportionately small placenta
- Single umbilical artery
- Intrauterine growth retardation
- Weak fetal activity
- Fetal distress
- Clinical history
- Apneic episodes
- Poor feeding
- Marked failure to thrive
Physical
- Neurological
- Delayed psychomotor development and mental retardation (100%)
- Neonatal hypotonia followed by hypertonia, jitteriness, apnea, and seizures
- Malformations (eg, microcephaly, cerebellar hypoplasia, meningoencephalocele, anencephaly, hydrocephaly, holoprosencephaly, Arnold-Chiari malformation, hypoplasia or aplasia of the corpus callosum, defective falx cerebri, frontal lobe defect, migration defect, arachnoid cyst, myelomeningocele)
- Cranial - Microcephaly, elongated skull, narrow bifrontal diameter, wide fontanels, and prominent occiput
- Facial - Microphthalmia, ocular hypertelorism, epicanthal folds, short palpebral fissures, iris coloboma, cataract, corneal clouding, abnormal retinal pigmentation, short nose with upturned nares, choanal atresia, micrognathia or retrognathia, microstomia, narrow palatal arch, infrequent cleft lip and cleft palate, preauricular tags and low-set, and malformed ears (faunlike with flat pinnae and a pointed upper helix)
- Skeletal - Severe growth retardation, characteristic hand posture (ie, clenched hands with the index finger overriding the middle finger and the fifth finger overriding the fourth finger), camptodactyly, radial hypoplasia or aplasia, thumb aplasia, syndactyly of the second and third digits, arthrogryposis, rocker-bottom feet with prominent calcanei, talipes equinovarus, hypoplastic nails, dorsiflexed great toes, short neck with excessive skin folds, short sternum, narrow pelvis, and limited hip abduction
- Cardiac
- More than 90% of infants with trisomy 18 have cardiac malformations.
- The most common abnormalities are ventricular septal defects with polyvalvular heart disease (pulmonary and aortic valve defects).
- Other cardiac malformations include atrial septal defects, patent ductus arteriosus, overriding aorta, coarctation of aorta, hypoplastic left heart syndrome, tetralogy of Fallot, and transposition of great arteries.
- Pulmonary - Pulmonary hypoplasia and abnormal lobation of the lung
- Gastrointestinal - Omphalocele, malrotation of the intestine, ileal atresia, common mesentery, Meckel diverticulum, esophageal atresia with or without tracheoesophageal fistula, diaphragmatic eventration, prune belly anomaly, diastasis recti, absent gallbladder, absent appendix, accessory spleens, exstrophy of Cloaca, pyloric stenosis, imperforate or malpositioned anus, pilonidal sinus, and hernias (ie, umbilical, inguinal, diaphragmatic)
- Genitourinary
- Micromulticystic kidneys, double ureters, megaloureters, hydroureters, hydronephrosis, horseshoe kidneys, and unilateral renal agenesis
- Cryptorchidism, hypospadias, and micropenis in males
- Hypoplasia of labia and ovaries, bifid uterus, hypoplastic ovaries, and clitoral hypertrophy in females
- Endocrine - Thymic hypoplasia, thyroid hypoplasia, and adrenal hypoplasia
- Dermal (ie, dermatoglyphics) - Increased number of simple arches on the fingertips, transverse palmar crease, increased atd angle, and clinodactyly of the fifth fingers with a single flexion crease
Causes
- Full trisomy 18 is responsible for 95% of Edwards syndrome cases. Mosaicism and translocations cause few cases. An extra chromosome 18 is responsible for the phenotype.
- The incidence rate increases with advanced maternal age. In approximately 90% of cases, the extra chromosome is maternal in origin, with meiosis II errors occurring twice as frequently as meiosis I errors. This is in contrast to other human trisomies, which exhibit a higher frequency of nondisjunction in maternal meiosis I. Among cases resulting from paternal nondisjunction, most are the result of postzygotic mitotic errors.
- Although full trisomy results from meiotic nondisjunction, mosaic trisomy is due to postzygotic mitotic nondisjunction. Mosaic trisomy 18 occurs when both a trisomy 18 cell line and a normal cell line are present in the same individual. Mosaic trisomy 18 accounts for approximately 5% of trisomy 18 cases. The clinical phenotype varies depending on the level of mosaicism and the tissue involved and ranges from the complete trisomy 18 phenotype to no dysmorphic features and normal intelligence.
- Translocation trisomy gives rise to partial trisomy 18 syndrome. Partial trisomy 18 occurs when a segment of chromosome 18 is present in triplicate, often resulting from a balanced translocation carried by one parent. It accounts for approximately 2% of trisomy 18 cases.
- The smallest extra region necessary for expression of serious anomalies of trisomy 18 appears to be 18q11-12.
Arthrogryposis
Other Problems to be Considered
Fetal akinesia sequence
Mental retardation syndromes
Multiple congenital anomalies
Other autosomal trisomies and monosomies
Pseudo–trisomy 19 syndrome
Lab Studies
- Conventional cytogenetic studies
- Full trisomy 18 (about 95% of cases)
- Trisomy 18 mosaicism (about 5% of cases)
- Translocation type trisomy 18 syndrome (very rare)
Imaging Studies
- Echocardiography for cardiac anomalies
- Barium swallow for gastrointestinal anomalies
- Ultrasonography for genitourinary anomalies
- Skeletal radiography to discern phocomelia, absent radius, tight flexion of the fingers with the second over the third and the fifth over the fourth, talipes equinovarus, short sternum, hemivertebrae, fused vertebrae, short neck, scoliosis, rib anomaly, and dislocated hip
Medical Care
- Medical care is supportive.
- Treat infections as appropriate. These are usually secondary to otitis media, upper respiratory tract infections (eg, bronchitis, pneumonia), and urinary tract infection.
- Sepsis is a continuous concern.
- Provide nasogastric and gastrostomy supplementation for feeding problems.
- Orthopedic management of scoliosis may be needed secondary to hemivertebrae.
- Cardiac management is primarily medical. Most of these children require a diuretic and digoxin for congestive heart failure.
- Genetic counseling
- Recurrence risk is 1% or less for full trisomy 18.
- If a parent is a balanced carrier of a structural rearrangement, the risk is substantially high. Risk should be assessed based on the type of structural rearrangement and its segregation pattern.
- Psychosocial management
- During the neonatal period, issues of diagnosis and survival are paramount. Parents need information about the syndrome, including its cause, implications, and possible outcomes.
- Support services within the hospital and in the community should be made available to the family.
- The presence of a disabled child in any family is a source of stress and anxiety.
- Families also undergo a complex grieving process that combines both the reactive grief predominant in chronic illness and the preparatory grief associated with impending death.
Surgical Care
Because of the extremely poor prognosis, surgical repair of severe congenital anomalies such as esophageal atresia or congenital heart defects is not likely to improve the survival rate of infants and should be discussed with families.
Consultations
- Clinical geneticist
- Developmental pediatrician
- Cardiologist
- Ophthalmologist
- Orthopedist
- Psychologist
- Speech language pathologist
- Audiologist
- Early childhood educational programs
Diet
No special diet is required.
Activity
Activities are limited because of profound mental retardation and physical handicaps.
Drug therapy currently is not a component of the standard of care for this disorder. See Treatment section.
Further Inpatient Care
- Cardiac management is primarily medical.
- Provide gastrostomy for feeding problems.
Further Outpatient Care
- Nasogastric or gastrostomy feeding
- Orthopedic care of scoliosis
- Audiologic evaluation for hearing loss
- Apnea monitoring
In/Out Patient Meds
- Diuretics and digoxin may be used for management of congestive heart failure secondary to congenital heart defect.
Complications
- Infection is an ongoing medical concern. Infections are usually secondary to otitis media, upper respiratory tract infections, and urinary tract infections.
- Scoliosis secondary to hemivertebra is a common finding.
- Feeding problems are a major management issue.
- Congenital heart defect with congestive heart failure is a frequent cause of death.
- Wilms tumor may develop in long-term survivors with trisomy 18.
Prognosis
- A small number of children with trisomy 18 survive beyond the first year, and few live into their teens and twenties. Survival rates for Edwards syndrome are as follows:
- Newborns have a 40% chance of surviving to age 1 month.
- Infants have a 5% chance of surviving to age 1 year.
- Children have a 1% chance of surviving to age 10 years.
- The high mortality rate is due to congenital heart malformations, gastrointestinal and genitourinary anomalies, feeding difficulties, and associated CNS defects that produce central apnea.
- Although they function with severe handicaps, all older children with trisomy 18 smile, laugh, interact, relate to their families, and achieve some psychomotor maturation.
- Mosaic cases may show milder phenotypic expression and prolonged survival.
Patient Education
- The pediatrician has the challenge and the opportunity of helping the family face uncertainty regarding death and prepare for the possibility of caring for a significantly disabled child.
- The following resources are available to help parents:
Medical/Legal Pitfalls
- Failure to identify characteristic symptoms and signs of Edwards syndrome and to refer the patient to a geneticist for evaluation and genetic counseling
- Failure to request chromosome analysis upon the clinical diagnosis of Edwards syndrome
- Failure to offer prenatal screening for pregnant women
- Failure to offer prenatal diagnosis after birth of an affected child
Special Concerns
- Prenatal screening in families without history of trisomy 18 using maternal serum markers
- Low levels of human chorionic gonadotrophin (hCG) and low unconjugated estriol (uE3) in maternal serum during mid trimester are useful predictors for an increased risk for trisomy 18.
- A first-trimester biochemical screening for trisomy 18 might be possible in the future because a recent retrospective study revealed reduced levels of pregnancy-associated plasma protein A (PAPP-A) and free beta–human chorionic gonadotropin (beta-hCG) at 8-13 weeks' gestation
- The multiples of the mean (MoM) in affected pregnancies was 0.25 for PAPP-A and 0.34 for free beta-hCG.
- Screening for trisomy 18 using a combination of maternal age, PAPP-A, and beta-hCG has a detection rate of 76.6% with a false-positive rate of 0.5%.
- Additional studies are required to confirm these findings.
- Prenatal ultrasonography
- Most fetuses with trisomy 18 have detectable structural abnormalities.
- Ultrasonographic abnormalities include microcephaly and Dandy-Walker malformation (posterior fossa enlargement associated with cerebellar hypoplasia).
- Choroid plexus cysts may be present.
- Visceral anomalies are common and include gastrointestinal anomalies (eg, omphalocele, esophageal atresia), congenital heart defects (eg, septal defect with polyvalvular disease), and renal anomalies (eg, polycystic enlarged horseshoe kidneys, ectopic kidneys).
- Fetuses typically have overlapping digits, with the second and fifth fingers overlapping the third and fourth fingers, respectively. Overall posturing of the wrists suggests contractures, clubfeet, and rocker-bottom feet.
- The frequencies of congenital anomalies detectable with prenatal ultrasonography are as follows:
- Persistent abnormal position of fetal fingers - 89
- Choroid plexus cysts - 43%
- Abnormally shaped fetal head (strawberry or lemon) - 43%
- Two-vessel umbilical cord - 40%
- Cardiac defects - 37%
- Intrauterine growth retardation - 29%
- Omphalocele - 20%
- Neural tube defects - 9%
- Cystic hygroma or lymphangiectasia - 14%
- Oligohydramnios/polyhydramnios - 12%
- Renal defects - 9%
- Fetal echocardiography
- Abnormal cardiac findings are detectable using echocardiography in most patients with trisomy 18.
- A wide spectrum of heart defects is observed.
- Heart malformations can be reliably diagnosed, even in the first trimester at the time of nuchal translucency measurement.
- Prenatal diagnosis
- Amniocentesis is routinely performed at 14-16 weeks' gestation. It remains the criterion standard with which all other invasive diagnostic tests are compared. Amniocentesis testing for chromosome disorders is 99.5% accurate and is associated with a small risk of pregnancy loss (about 1 in 200-300).
- Chorionic villus sampling (CVS) is performed at 10-13 weeks' gestation. An earlier CVS test is thought to be associated with a small risk (1 in 300-1000) of fetal transverse limb deficiency, a small chance of maternal cell contamination, and a 0.5-1% risk of fetal loss after the procedure. The accuracy (96-98%) is less than that of midtrimester amniocentesis because of confined placental mosaicism and maternal cell contamination.
- Percutaneous umbilical blood sampling (PUBS) is of limited use, except in cases detected late in pregnancy. The preimplantation diagnosis is not of any realistic relevance for current care.
| Media file 1:
Infant with Edwards syndrome. Note microphthalmia, micrognathia/retrognathia, microstomia, low set/malformed ears, short sternum, and abnormal clenched fingers. |
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| Media file 2:
Note the characteristic clenched hand with the index finger overriding the middle finger and the fifth finger overriding the fourth fingers. |
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| Media file 4:
Note a rocker-bottom foot with prominent calcaneus. |
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Media type: Photo
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| Media file 5:
Hands of a fetus with Edwards syndrome. Note that fetus typically presents with overlapping digits with the second and fifth fingers overriding the third and fourth fingers respectively. Overall posturing of the wrists and fingers suggests contractures. |
 | View Full Size Image | |
Media type: Photo
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Trisomy 18 excerpt Article Last Updated: Aug 8, 2007
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