Trisomy 13 (ORPHA:3378)
A rare chromosomal anomaly characterized by the presence of extra chromosome 13 material and manifesting with severe intellectual disability and multiple congenital anomalies including holoprosencephaly, microcephaly, microphthalmia, scalp defect, cleft lip/palate, congenital heart defects, and postaxial polydactyly. Neurological involvement may lead to seizures and hypotonia.
Epidemiology
The incidence at birth is between 1/3500 and 1/5000. In 1st trimester diagnosis, the rate is 1/1,500 in the Danish register. Risk increases with maternal age.
Clinical description
In utero death occurs in over 95% of affected fetuses. Median survival is 7-10 days, and less than 30% survives beyond 1 year. Intrauterine growth retardation (IUGR) is common. Neurological manifestations are severe and present as hypotonia and hyporeactivity with an apparent lack of awareness of surroundings. Holoprosencephaly (resulting from a defect in the division of the brain into two hemispheres) is present in 70% of cases and can be observed as variable degrees of hemisphere fusion on MRI. Facial anomalies are variable and may range in severity from hypotelorism and premaxillary agenesis (80% of cases) to cyclopia. Cleft lip/palate (50-80%), micro- or anophthalmia (40%) eye coloboma, areas of cutaneous aplasia of the vertex (30%), postaxial polydactyly (50%), congenital heart defect (CHD) (80% of cases) and renal malformations (40%) may also be present.
Etiology
Free trisomy 13 (T13) is found in around 75% of cases. In 20% of cases, T13 is associated with a Robertsonian translocation in which the supernumerary chromosome 13 becomes attached to another acrocentric chromosome (chromosomes 13, 14, 15, 21 or 22). In rare cases, the syndrome is caused by reciprocal translocation between chromosome 13 and a non-acrocentric chromosome. Mosaic T13 (in which there is both trisomic and normal cell types) has been reported in a few patients with a clinical picture that varies between a normal phenotype and that of classical T13 according to the number of trisomic cells present in the tissues.
Diagnostic methods
T13 must be confirmed by conventional karyotyping. Chromosomal microarray will show T13 but may not discriminate free from translocation T13.
Differential diagnosis
The differential diagnosis includes trisomy 18, Smith-Lemli-Opitz syndrome, CHARGE Syndrome, Meckel syndrome and, in a minority of cases, other ciliopathies like Joubert syndrome and Bardet-Biedl syndrome (which may present with renal anomalies, polydactyly, brain anomalies).
Antenatal diagnosis
Analysis of fetal DNA in maternal blood (non-invasive prenatal testing; NIPT) has high sensitivity (> 97%). Maternal serum screening based on blood markers and nuchal translucency ultrasound scan may detect a proportion of T13 fetuses. Most T13 fetuses can be detected by routine fetal ultrasound scan (holoprosencephaly, polydactyly). Invasive prenatal testing like amniocentesis or chorionic villi sampling (CVS) will confirm any suspicion raised by prenatal screening.
Genetic counseling
The risk of recurrence of trisomy (21, 13 or 18) in families of an index case with T13 is around 1%. However, in families in which T13 is associated with translocation (Robertsonian or balanced) the risk of recurrence is higher if one of the parents is a carrier of a balanced translocation.
Management and treatment
Management is supportive/palliative only. Follow-up is needed for cardiac, respiratory, neurological, genitourinary, abdominal, otolaryngologic, and orthopedic complications.
Prognosis
Surgical treatment of the malformations does little to improve the poor prognosis associated with this syndrome: half of the infants born alive die within the first month of life, 70% die before 1 year of age from cardiac, renal or neurologic complications, and 10% more die before 5 years of age. Prolonged survival (in some cases into adulthood) has been reported and is more common in cases of mosaic or partial trisomy and in the absence of severe brain malformations. In general, non-mosaic patients develop only limited autonomy (absence of speech and ambulation).

                            Last update: 
                            September 2023


                            - Expert reviewer(s): 
                            Pr Alain VERLOES | ITHACA*


                                * European Reference Network