OVERVIEW: What every practitioner needs to know

Trisomy 18, caused by having 3 copies of chromosome 18 rather than the typical 2 copies, is the second most common chromosome abnormality in live births following trisomy 21, or Down syndrome. Trisomy 18 is a severe condition leading to severe to profound intellectual disability, pre- and postnatal growth retardation, microcephaly, and multiple organ system involvement.

Characteristic features of trisomy 18 are clenched fists with the second and fifth fingers overriding the second and fourth, respectively, and rocker bottom feet. Survival to live birth is only 5%, and only 5%-10% of live births survive to 1 year because of cardiac, renal, and brain abnormalities.

Are you sure your patient has trisomy 18? What are the typical findings for this disease?

Multiple organ systems are involved in patients with trisomy 18. Anomalies are detected on prenatal level II ultrasonography in up to 90% of pregnancies; polyhydramnios is a common finding. Other anomalies detected at birth and in infancy include the following:

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Severe pre- and postnatal growth retardation

Central nervous system (CNS): severe to profound developmental delay/intellectual impairment (100%); hypotonia and/or hypertonia; microcephaly and a variety of brain malformations

Facial dysmorphic features: microphthalmia, epicanthal folds, short palpebral fissures, coloboma of the iris, congenital cataracts, short nose with upturned nares, choanal atresia, small mouth, micrognathia, low-set and malformed ears

Short sternum

Cardiac abnormalities (90%): most commonly ventricular septal defect (VSD) but also atrial septal defect (ASD), patent ductus arteriosus (PDA), coarctation of the aorta, hypoplastic left heart syndrome, tetralogy of Fallot, and transposition of the great vessels

Skeletal: symmetric growth retardation, radial hypoplasia or aplasia, characteristic clenched hands with second finger overriding third finger and fifth finger overriding fourth finger, single palmar creases, rocker bottom feet or club feet, arthrogryposis or joint contractures, hypoplastic nails

Gastrointestinal: omphalocele, esophageal atresia, tracheoesophageal fistula, pyloric stenosis, imperforate anus

Pulmonary: pulmonary hypoplasia

What other disease/condition shares some of these symptoms?

There are many chromosome abnormalities that can mimic the dysmorphic features and multiple congenital anomalies present in trisomy 18. Additionally, a partial trisomy 18 caused by an unbalanced translocation or duplication of part of chromosome 18 can have some features of trisomy 18, depending on where the extra genetic material is located on the chromosome. Typically, the presentation of partial trisomy 18 would be milder than that of full trisomy 18. A karyotype can distinguish full trisomy 18 from mosaic or partial trisomy 18.

Fetal akinesia deformation sequence (FADS), or Pena-Shokeir syndrome type 1, has characteristics similar to trisomy 18, including intrauterine growth retardation and postnatal growth restriction, hypertelorism, short palpebral fissures, and abnormal ears.

Multiple joint contractures are characteristic, and common findings include rocker bottom feet, club feet, brain abnormalities, and pulmonary hypoplasia. Cardiac, renal, and gastrointestinal involvement are less common. Stillbirth is common in this condition. Around 50% of cases are autosomal recessive and are caused by mutations in the DOK7 or RAPSN genes. Genetic testing is available clinically.

What caused this disease to develop at this time?

Trisomy 18 is caused by the presence of an extra chromosome 18 in every cell of the body (full trisomy 18) in 94% of cases. Mosaic trisomy 18 is rare. Unbalanced translocations leading to partial trisomy 18 can also occur in around 2% of cases.

Approximately 90% of cases of trisomy 18 are due to maternal nondisjunction, most commonly occurring in meiosis II (rather than meiosis I as in most other trisomy conditions).The risk of nondisjunction rises with maternal age; thus a women who is 45 years old has a risk of of 1 in 21 of having a child with a trisomy of some type (e.g., Down syndrome, trisomy 13, trisomy 18) versus a 20-year-old woman’s risk of 1 in 526.

Mosaic trisomy 18 typically occurs from postzygotic trisomy rescue, causing a cell line with trisomy 18 and a normal cell line. The phenotype of mosaic trisomy 18 is typically milder, but severity is dependent on where the trisomic cell line is present in organ system development.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

A karyotype, or chromosome analysis, should be ordered if trisomy 18 is suspected. If mosaicism is considered, a karyotype counting at least 20 cells should be requested.

Fluorescence in situ hybridization (FISH) can determine trisomy 18 with a rapid turnaround time. A chromosomal microarray can also diagnose trisomy 18, partial trisomy 18, or other more subtle chromosomal abnormalities but is typically more expensive with a longer turnaround time.

Prenatal screening is performed to determine pregnancies at risk for trisomy 18, including first- and second-trimester maternal serum screening. Definitive prenatal diagnosis is available to those with abnormal serum screening results or abnormal ultrasonographic findings, or in women who are of advanced maternal age (considered to be 35 years of age or older in most institutions) by chorionic villus sampling or amniocentesis.

Would imaging studies be helpful? If so, which ones?

Echocardiography should be performed for possible cardiac anomalies associated with trisomy 18. Level II ultrasonography during the second trimester of pregnancy detects abnormalities associated with trisomy 18 in around 80%-90% of cases. Abdominal ultrasonography can detect the presence of renal anomalies and other defects such as an absent gallbladder and spleen abnormalities.

Ultrasonography of the head or magnetic resonance imaging (MRI) of the brain may be indicated to examine for the presence of central nervous system (CNS) anomalies such as cerebellar hypoplasia, holoprosencephaly, or corpus callosum abnormalities, among others.

If you are able to confirm that the patient has trisomy 18, what treatment should be initiated?

Trisomy 18 is a severe syndrome of multiple congenital anomalies and has a poor prognosis. Up to 95% of fetuses with trisomy 18 do not survive to live birth, and of those that do only 5%-10% survive to the first year of life.

Treatment of trisomy 18 is supportive, and surgical correction of associated abnormalities should be discussed with families based on the poor prognostic outcome. Some affected individuals have survived to childhood; thus management discussions with the family regarding prognosis should include the possibility that a severe to profoundly intellectually impaired and physically disabled child can survive several years.

Supportive care can involve nasogastric or gastrostomy tube placement for feeding difficulties, support for pulmonary hypoplasia, treatment of frequent infections, and pharmaceutical and/or cardiac management for heart defects.

What are the possible outcomes of trisomy 18?

Trisomy 18 has a poor prognosis in that 95% of conceptuses with trisomy 18 do not survive to term, and 90%-95% of live births do not survive to 1 year of age. Morbidity and mortality occur because of multiple congenital anomalies such as heart defects, genitourinary abnormalities, and CNS defects.

Severe to profound intellectual disability is universal in full trisomy 18. It is important for families to understand the poor prognosis when making decisions about surgical and medical intervention in the neonatal period. However, it is also important to discuss the possibility that an infant with trisomy 18 may live for an extended time, which will require a great deal of medical management and physical, emotional, and financial strain on the family.

Mosaic or partial trisomy 18 is typically milder but is variable depending on the percentage of cells with an extra chromosome 18 in the former and the size of the duplicated area on chromosome 18 in the latter. Treatment will depend on the severity of the condition and organs that are affected.

What causes this disease and how frequent is it?

Trisomy 18 is caused by the presence of an extra chromosome 18 (47,XX+18 or 47,XY+18) in every cell of the body in 94% of cases. The majority of cases are due to maternal nondisjunction in meiosis II. Rarely, paternal meiosis II errors are causative. The risk for trisomy 18 increases with maternal age.

Around 3% of cases are due to mosaic trisomy 18, usually caused by a trisomic fetus losing the extra chromosome in a cell (called trisomy rescue), resulting in 2 cell lines. Trisomy 18 is caused by an unbalanced translocation or partial chromosome 18 duplication in around 2%-3% of cases.

Recurrence risk for full trisomy 18 is around 1% or lower for subsequent pregnancies. If a parent is a carrier of a balanced translocation leading to an unbalanced translocation in the child, recurrence risk is typically 15-20% for each pregnancy. Incidence at first-trimester screening is 1 in 400, but only 1 in 6500 survive to live birth in the United States.

There are no known environmental or infectious causes for trisomy 18.

How do these pathogens/genes/exposures cause the disease?

Trisomy 18 is caused by having 3 copies of genes located on chromosome 18 due to a dosage effect.

How can trisomy 18 be prevented?

There is no way to prevent the occurrence of trisomy 18. Prenatal screening and diagnosis are available in the general population. First-trimester serum screening, performed at 11 to 14 weeks’ gestation to determine beta human chorionic gonadotropin (HCG) and pregnancy-associated plasma protein A (PAPP-A) levels, detects around 90% of cases of trisomy 18, as does level II ultrasonography.

Second-trimester quadruple maternal serum screening is performed at or after 14-18 weeks’ gestation and determines the values for alpha fetoprotein, beta HCG, unconjugated estriol, and inhibin A levels, creating a calculated risk comparing the values to normal and trisomic 18 fetuses at this point in gestation. The typical pattern for trisomy 18 is relatively lower levels of all these markers than would be expected. Sensitivity is around 60%-65% for trisomy 18.

Level II fetal ultrasonography is approximately 80%-90% sensitive for detecting some abnormality associated with trisomy 18. Prenatal diagnosis by chorionic villus sampling (10-13 weeks’ gestation ) or amniocentesis (15-18 weeks’ gestation) is offered to women with abnormal screening test results, abnormal ultrasonograms, advanced maternal age (considered to be 35 years of age or greater at delivery in most institutions), or a family history of chromosome abnormalities.

These tests look directly at the chromosomal makeup of the fetus and are thus considered 100% sensitive for trisomy 18, but they carry a risk of miscarriage of around 1 in 200-400.

What is the evidence?

(Patient-friendly information discussing the clinical features, natural history, and etiology of the condition. Provides other resources and support group information.)

(Summary of the clinical features, etiology, and management of the condition.)

Gardner, RJM, Sutherland, GR. Chromosome abnormalities and genetic counseling. 2004. (Textbook discussing the etiology and recurrence risk of chromosome abnormalities.)