Trisomy 18 

Updated: Sep 25, 2018
Author: Mithilesh K Lal, MD, MBBS, MRCP, FRCPCH, MRCPCH(UK); Chief Editor: Luis O Rohena, MD, FAAP, FACMG 

Overview

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.[3] See the images below.

Note the microphthalmia, micrognathia/retrognathia Note the microphthalmia, micrognathia/retrognathia, microstomia, low-set/malformed ears, short sternum, and abnormally clenched fingers in an infant with trisomy 18 (Edwards syndrome).
Note the characteristic clenched hand of trisomy 1 Note the characteristic clenched hand of trisomy 18 (Edwards syndrome) with the index finger overriding the middle finger and the fifth finger overriding the fourth finger.
Note the rocker-bottom foot with a prominent calca Note the rocker-bottom foot with a prominent calcaneus in an infant with trisomy 18 (Edwards syndrome).
This photo shows the hands of a fetus with trisomy This photo shows the hands of a fetus with trisomy 18 (Edwards syndrome). Note that hands typically present with overlapping digits, in which the second and fifth fingers override the third and fourth fingers, respectively. The overall posturing of the wrists and fingers in this fetus is suggestive of contractures.

Pathophysiology

See the list below:

  • 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.

Epidemiology

Frequency

United States

Prevalence is approximately 1 in 6000-8000 live births.

At the time of first trimester screening, the incidence of trisomy 18 is 1 in 400, but due to high spontaneous loss, the birth prevalence is 1 in 6500.

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.

For liveborn infants with trisomy 18, the estimated probability of survival to age 1 month was 38.6% and to age 1 year was 8.4%. Median survival time was 14.5 days (population based study).[4]  Nonetheless, in a multistate study of 1113 children with trisomy 18, Meyer et al found a 5-year survival rate of 12.3%. In the study, gestational age had the greatest impact on mortality, while the lowest mortality rates were found among females and the children of non-Hispanic black mothers.[5]  Long-term survival up to age 27 years has been reported.[6, 7, 8]

The high mortality rate in trisomy 18 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 trisomy 18 cases occur in females. The preponderance of females with trisomy 18 among liveborn infants[4, 9] (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.[10, 11, 12]

 

Age

Trisomy 18 is detectable during the prenatal and newborn periods.

 

Presentation

History

Prenatal history in trisomy 18

See the list below:

  • 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 in trisomy 18

See the list below:

  • Apneic episodes

  • Poor feeding

  • Marked failure to thrive

Physical

See the list below:

  • 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

  • GI -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

  • Phenotypic spectrum of mosaic trisomy 18[13]

    • Phenotype of individuals with mosaic trisomy 18 varies widely. Some individuals who have the complete trisomy 18 (typical Edwards syndrome) phenotype experience early death whereas others are phenotypically completely normal. The latter group is exemplified by several normal-appearing adults with mosaic trisomy 18 who were identified only after giving birth to children with complete trisomy 18.

    • Anomalies vary widely, most at low frequencies, including microcephaly, delayed bone age, brachydactyly, congenital heart defects, developmental delay, short stature, and premature ovarian failure.

    • Intellectual capabilities range from profound intellectual disability to above-average intelligence. No correlation between the percentage of trisomic cells in either fibroblasts or leukocytes and the individual’s phenotype or intellectual function is noted.

Causes

See the list below:

  • 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.[14] 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.[15]

  • 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.

Physical Examination

.

 

DDx

Diagnostic Considerations

These include the following:

  • Fetal akinesia sequence

  • Trisomy 13

  • Pena-Shokeir syndrome type I

  • Genomic dosage anomalies

  • Other autosomal trisomies and monosomies

Differential Diagnoses

 

Workup

Approach Considerations

First trimester noninvasive screening based on maternal age, serum markers, and sonographic “soft markers” have demonstrated a high sensitivity for the diagnosis of trisomy 18,[16, 17, 18] and it is now being applied routinely.[3]

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 is possible, because a retrospective study revealed reduced levels of pregnancy-associated plasma protein A (PAPP-A) and free beta–human chorionic gonadotropin (β-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.

Laboratory Studies

Prenatal diagnosis

Amniocentesis is routinely recommended at 14-16 weeks' gestation when trisomy 18 is suspected. 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 mid trimester 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.

False positive prenatal diagnosis of trisomy 18 using fluorescence in situ hybridization (FISH) has been reported due to rare familial variants involving the failure of hybridization of α-satellite DNA or hybridization to false target chromosomes.[19] This underscores the necessity to adhere to the American College of Medical Genetics guidelines for interpretation of FISH results.

The American College of Obstetricians and Gynecologists (ACOG) recommends that patients categorized by screening as high risk for fetal aneuploidy be offered invasive testing such as amniocentesis or chorionic villus sampling. Although these invasive procedures are highly accurate, they are expensive and entail a risk of miscarriage.[20, 21]

ACOG also recommends that pregnant women be offered noninvasive screening for fetal chromosomal abnormalities.[22] The realization that fetal nucleic acids are present in maternal blood[23] spawned efforts to analyze cell-free DNA (cfDNA) for fetal conditions. Chromosome-selective sequencing of cfDNA can distinguish 98% of trisomy 18 in the first trimester (and all cases of trisomy 21) from euploid pregnancies.[24]

Postnatal diagnosis

See the list below:

  • Hematological studies in patients with trisomy 18 during the first week of life

    • Thrombocytopenia: This is the most common hematological abnormality detected, occurring in 83% of those with trisomy 18; some patients need platelet transfusions.[25]

    • Neutropenia: This is the second most commonly detected abnormality. Neutrophil concentrations exceeding the reference range for age were reported in 42% of patients with trisomy 18.[25]

    • Abnormal erythrocyte values: This is the third most common hematological abnormality detected. Only 43% of patients with trisomy 18 had normal erythrocyte values;[25] anemia was detected in 40%, and polycythemia was detected in 17%.

  • Conventional cytogenetic and fluorescence in situ hybridization (FISH) studies

    • FISH for rapid diagnosis (most laboratories, ≤24 hours) is more sensitive for mosaicism in the neonatal period (if unknown prenatally), followed by karyotyping, which is necessary even if FISH confirms the diagnosis for the rare translocation; karyotyping is also necessary if the diagnosis is made prenatally to confirm the type of trisomy 18.

    • The genetic studies are what is important for diagnosis and to help the family with difficult decisions in these fragile infants; rapid confirmation of diagnosis is crucial.

    • Full trisomy 18 (about 95% of cases)

    • Trisomy 18 mosaicism (about 5% of cases)

    • Translocation type trisomy 18 syndrome (very rare)

Imaging Studies

Prenatal ultrasonography

Most fetuses with trisomy 18 have detectable structural abnormalities.[26]

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 GI 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%

First trimester ultrasonographic findings in fetuses with trisomy 18 are as follows[27] :

  • Nuchal translucency (> 95th percentile) - 91%

  • Nuchal translucency (> 99th percentile) - 77%

  • Absent/hypoplastic nasal bone - 53%

  • Generalized subcutaneous edema - 49%

  • Omphalocele - 21%

  • Abnormal posturing of hands - 6%

  • Megacystis - 4%

  • Cardiac defect - 4%

  • Pleural effusions - 4%

  • Echogenic yolk sac - 4%

  • None - 2%

Three-dimensional and four-dimensional ultrasonography

These offer diagnostic advantages for many anomalies associated with trisomy 18, especially for anomalies of the extremities and face. These studies can be a powerful adjunct to two-dimensional ultrasonography in the prenatal anatomic evaluation of fetuses with trisomy 18.[28]

Fetal echocardiography

Abnormal cardiac findings are detectable using echocardiography in most patients with trisomy 18. A wide spectrum of heart defects is observed. In a study from Lin et al, the anomalies identified included ventricular septal defect (94%), patent ductus arteriosus (77%), atrial septal defect (68%), and complex congenital heart defects (32%).[29]

Heart malformations can be reliably diagnosed, even in the first trimester at the time of nuchal translucency measurement. These require follow-up beyond the first trimester. Most cardiologists would want to obtain fetal echocardiography after 18 weeks' gestation to confirm a cardiac malformation, especially to determine the specific type.

Other Tests

See the list below:

  • A barium swallow is indicated for gastrointestinal (GI) anomalies.

  • In Lin et al's study, using brain ultrasonography, the most common brain lesion revealed was cerebellar hypoplasia (32%), followed by brain edema (29%), enlarged cisterna magna (26%), and choroid plexus cysts (19%).[29] Ultrasonography is also indicated for genitourinary anomalies.

  • Skeletal radiography is used 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.

 

Treatment

Medical Care

See the list below:

  • A goal-directed management plan based on careful risk-benefit assessment for the individual patient and developed collaboratively between health professionals and parents is recommended.[30]

  • There are confirmed 20+-year-old patients with this disorder; at least 5-10% of these patients survive, and parents are not typically prepared to care for them long term. Cardiac management is perhaps the most important decision parents have to make.

  • Treat infections as appropriate. These are usually secondary to otitis media, upper respiratory tract infections (eg, bronchitis, pneumonia), and urinary tract infection. Sepsis is an ongoing 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. Optional treatment for cardiac lesions includes the following:

    • Intensive cardiac management with pharmacological intervention for ductal patency (indomethacin and/or mefenamic acid for closure, and prostaglandin E1 for maintenance) and palliative and corrective cardiac surgery was demonstrated to improve survival in patients with trisomy 18.[31]

    • In a study of patients with trisomy 18 who had cardiac lesions, 82% of patients undergoing heart surgery were discharged home with alleviated cardiac symptoms; congenital heart defect–related death occurred in only one patient, suggesting that cardiac surgery is effective in preventing congenital heart defect–related death; and initial palliative surgery was associated with longer survival than intracardiac repair.[32]

  • Neonatal intensive care (NICU) management

    • Management of neonates with trisomy 18 is controversial because of poor prognosis and the lack of information about the efficacy of treatment.[33, 34]

    • Improved survival (in one study,[33] survival rates at age 1 wk, 1 mo, and 1 y, respectively, were 88%, 83%, and 25%; median survival time, 152.5 d) through NICU treatment (eg, cesarean delivery, resuscitation, respiratory support, and surgical procedures) may help clinicians to offer informed treatment options to families of patients with trisomy 18.

    • A survey of US neonatologists regarding newborn care of trisomy 18 infants reported that 44% would provide medical intervention (including resuscitation), primarily because of parental wishes to support the baby.[35]

    • For an excellent recent review of survival rates and the evolving natural history of trisomy 18, please see Cereda A, Carey JC. The trisomy 18 syndrome. Orphanet J Rare Dis. 2012;7:81.[3]

  • 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.

    • The risk should be assessed based on the type of structural rearrangement and its segregation pattern.

    • The wide phenotypic variation and lack of correlation with the percentage of trisomic cells in mosaic trisomy 18 makes informative prediction of natural history and genetic counseling challenging.[13]

    • Patients with large 18q duplications (which may arise from parental translocations/inversions) or "partial trisomy 18" could benefit from the same routine ultrasonographic screening for Wilms tumor as those with full trisomy 18, because early detection is essential to optimizing survival.[36]

  • 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 may not be considered and should be discussed with parents.

A retrospective study by Nakai et al indicated that cardiac surgery can prolong survival in trisomy-18 patients who have high pulmonary blood flow. The study involved 20 patients, including 10 who underwent cardiac surgery with pulmonary artery banding and 10 who were treated conservatively; the surgical patients survived for a significantly longer period (495 days) than did the conservative management group (93.1 days).[37]

Using the Pediatric Health Information System database, a study by Furlong-Dillard et al found evidence that pediatric patients with trisomy 13 or 18 who undergo cardiac surgery are at greater perioperative risk of pulmonary hypertension, acute renal failure, cardiac arrest, and nosocomial infections.[38]

Consultations

See the list below:

  • Clinical geneticist

  • Developmental pediatrician

  • Cardiologist

  • Ophthalmologist

  • Orthopedist

  • Psychologist

  • Speech language pathologist

  • Audiologist

  • Early childhood educational programs

  • Community/outreach nursing support

  • Consider involving the institution's ethics committee if surgical intervention is recommended.

Diet

See the list below:

  • No special diet is required.

Activity

See the list below:

  • Activities are limited because of profound mental retardation and physical handicaps.

 

Medication

Medication Summary

See the list below:

  • Drug therapy currently is not a component of the standard of care for trisomy 18. See Treatment section.

 

Follow-up

Further Outpatient Care

See the list below:

  • Nasogastric or gastrostomy feeding

  • Orthopedic care of clubfoot in addition to scoliosis

  • Abdominal ultrasonographic surveillance recommendations is important in survivors to detect nephroblastoma/Wilms and hepatoblastoma not only in full trisomy 18 patients, but also in those with select 18q duplication.[36]

  • Audiologic evaluation for hearing loss

  • Apnea monitoring

Further Inpatient Care

See the list below:

  • If the parents decide to proceed with cardiac management for patients with trisomy 18 and depending on the lesion, treatment is typically be surgical rather than medical.

  • Provide gastrostomy for feeding problems.

Inpatient & Outpatient Medications

See the list below:

  • Diuretics and digoxin may be used for management of congestive heart failure secondary to congenital heart defect.

Complications

See the list below:

  • 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 and hepatoblastoma may develop in survivors with trisomy 18 and some patients with 18q duplication.

Prognosis

See the list below:

  • 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.[39]

    • 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, GI 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.

Support Organization for Trisomy 18, 13 and Related Disorders (SOFT)

2982 South Union Street

Rochester, NY 14624

Phone: (800) 716-SOFT (7638)

National Organization for Rare Disorders, Inc (NORD)

55 Kenosia Avenue

Danbury, CT 06810

Phone: (203) 744-0100

Fax: (203) 798-2291

Trisomy 18 Foundation

173 Keith Street

Number 3

Warrenton, VA 20186

Phone: (810) 867-4211