OVERVIEW: What every practitioner needs to know

Trisomy 13, caused by the presence of an extra chromosome 13 in every cell of the body, is the most rare and severe of the viable trisomic conditions. Mean survival is less than 1 week of age owing to cardiac or pulmonary complications, congenital heart defects, or severe neurologic compromise.

Are you sure your patient has trisomy 13? What are the typical findings for this disease?

Typical features of trisomy 13 include holoprosencephaly, cleft lip and/or palate, neural tube defects, heart defects, cutis aplasia of the scalp, and postaxial polydactyly. Severe to profound mental retardation is universal in this condition.

Typical abnormalities seen in trisomy 13 include physical features such as microcephaly, cutis aplasia, microphthalmia, postaxial polydactyly, and rocker bottom feet. Holoprosencephaly is a common feature and can lead to facial abnormalities such as hypotelorism, microphthalmia, absent or misshapen nose, cleft lip and/or palate, and/or single central incisor.

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Congenital heart defects are found in up to 80% of infants with trisomy 13, with the most common being patent ductus arteriosus, ventricular septal defects, and atrial septal defects. Neural tube defects, omphalocele, and renal abnormalities may also be present.

What other disease/condition shares some of these symptoms?

Individuals with various chromosome abnormalities could present with features similar to trisomy 13. Partial trisomy 13q or mosaic trisomy 13 may have a milder phenotype but one similar to that of full trisomy 13. Trisomy 18 may present with microcephaly, congenital heart defect, and rocker bottom feet but typically does not have postaxial polydactyly or holoprosencephalic sequelae. A karyotype or chromosomal microarray should be able to distinguish between related chromosome abnormalities.

Pseudotrisomy 13 syndrome, or holoprosencephaly-polydactyly syndrome, is an autosomal recessive condition with characteristics similar to trisomy 13, including holoprosencephaly (60%), microcephaly, microphthalmia, cleft lip/palate, postaxial polydactyly (60%), omphalocele, heart defects, and renal anomalies. The two conditions can be differentiated by karyotype.

What caused this disease to develop at this time?

Trisomy 13 is caused by the presence of an extra chromosome 13 in every cell of the body (full trisomy 13) in the majority of cases. Mosaic trisomy 13 is rare. Robertsonian translocations due to the inheritance of a chromosome 13 attached to another acrocentric chromosome (14, 15, 21, or 22) is also rare. Most cases of trisomy 13 are due to maternal nondisjunction, most commonly occurring in meiosis I.

The risk of nondisjunction rises with maternal age; thus a woman who is 45 years old has a risk of having a child with a trisomy of some type (e.g., Down syndrome, trisomy 13, trisomy 18 ) of 1 in 21 versus a 20-year-old woman’s risk of 1 in 526. Mosaic trisomy 13 cases typically arise from postzygotic trisomy rescue, resulting in a cell line with trisomy 13 and a normal cell line. The phenotype of mosaic trisomy 13 is typically milder but 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 13 is suspected. If mosaicism is considered, a karyotype counting at least 20 cells should be requested. Fluorescence in situ hybridization (FISH) can determine trisomy 13 with a rapid turnaround time. A chromosomal microarray can also diagnose trisomy 13, partial trisomy 13, 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 13. Of note, trisomy 13 is not screened for on first- or second-trimester maternal serum screening. Level II ultrasonography during the second trimester of pregnancy detects abnormalities associated with trisomy 13 in around 80%-90% of cases. Definitive prenatal diagnosis is available to those with 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 to examine for congenital heart defects. Abdominal ultrasonography can screen for the presence of renal abnormalities. A brain MRI would help to delineate structural brain abnormalities such as holoprosencephaly or more subtle abnormalities.

If you are able to confirm that the patient has trisomy 13, what treatment should be initiated?

Trisomy 13 is a severe syndrome with multiple congenital anomalies and a poor prognosis. Of the rare fetuses that survive to term, most die in the first week of life and 5% survive to 6 months of age.

Treatment of trisomy 13 is supportive, and surgical correction of associated anomalies should be discussed with the family based on the poor prognostic outcome. Despite the vast majority of patients succumbing in the first year of life, some affected individuals have survived to childhood or adolescence; 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 this disease?

Trisomy 13 has a poor prognosis. Of the few fetuses that survive to term, only 5% live to 6 months of age. Morbidity and mortality occur because of multiple congenital anomalies such as heart defects, neural tube defects, and CNS abnormalities. Severe to profound intellectual disability is universal in trisomy 13.

It is important for families to understand the poor prognosis in 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 13 may live for an extended time, particularly with medical intervention, which requires a great deal of medical management and physical, emotional, and financial strain on the family.

Mosaic or partial trisomy 13 is rare but typically milder than full trisomy 13. Severity depends on the percentage of cells with an extra chromosome 13 in the former and the size of the duplicated area on chromosome 13 in the latter. Treatment should depend on the severity of the condition and the organs that are affected.

What causes this disease and how frequent is it?

Trisomy 13 is caused by the presence of an extra chromosome 13 (47,XX+13 or 47,XY+13) in every cell of the body in the majority of cases. Most cases are due to maternal nondisjunction in meiosis I. The risk for trisomy 13 increases with maternal age. A rare number of cases are due to mosaic trisomy 13, usually caused by losing the extra chromosome in a cell line in an originally full trisomic fetus (called trisomy rescue), which results in 2 cell lines.

Trisomy 13 can also be caused by a robertsonian translocation in which an extra chromosome 13 is attached to another acrocentric chromosome (14, 15, 21, or 22). Recurrence risk for full trisomy 13 is around 1% or less of conceptuses (lower for live births) in subsequent pregnancies. If a parent is a carrier of a balanced robertsonian translocation leading to trisomy 13 in the child, the recurrence risk can be substantially higher (typically around 15%-20%). The incidence of trisomy 13 is around 1 in 8000-12,000 live births. There are no known environmental or infectious causes for trisomy 13.

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

Trisomy 13 is caused by an extra copy of the genes on chromosome 13 resulting from a dosage effect.

How can Trisomy 13 be prevented?

There is no way to prevent the occurrence of trisomy 13. Prenatal screening and diagnosis is available in the general population. First- and second-trimester serum screening does not screen for trisomy 13.

Level II fetal ultrasonography is around 80%-90% sensitive for detecting some abnormality associated with trisomy 13. Prenatal diagnosis by chorionic villus sampling (10-13 weeks’ gestation) or amniocentesis (15-18 weeks’ gestation) is offered to women with an abnormal ultrasonogram or 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 13, but they carry a risk of miscarriage of around 1 in 200-400 pregnancies.

What is the evidence?

(Patient-friendly resource for information about trisomy 13.)

(Overview of cytogenetics and clinical features of trisomy 13, written by cytogeneticist and expert in the field.)

Gardner, RJM, Sutherland, GR. Chromosome abnormalities and genetic counseling. 2004. (Textbook for professionals explaining chromosome abnormalities and their causes.)