Long term follow‐up of developmental delay in a child with prenatally‐diagnosed trisomy 20 mosaicism

Prenatal diagnosis of trisomy 20 mosaicism presents a genetic counseling challenge, as its clinical significance remains unclear. It is a relatively common finding in amniotic cell cultures with a reported incidence of roughly 1 in 7,000 pregnancies tested [Bui et al., 1984; Hsu and Perlis, 1984; Worton and Stern, 1984]. A few groups [Hsu et al., 1987, 1991; Wallerstein et al., 2000; James et al., 2002] have collected data on pregnancy outcome in an effort to determine the associated risks of prenatally diagnosed trisomy20mosaicism.Todate, no specific phenotype or syndrome has been associated with this cytogenetic finding, and the overwhelming majority of cases (approximately 90%–93%) appear to result in a normal phenotype [Hsu et al., 1987, 1991; Wallerstein et al., 2000; Warren et al., 2001; James et al., 2002]. There has been a suggestion of increased risk for congenital heart defects and renal anomalies [Hsu et al., 1991]. Thus, while some long-term follow-up is available on prenatally-diagnosed trisomy 20 mosaicism, the risk for significant neurocognitive dysfunction in these children remains elusive. We report on a case of a 10-year-old girl diagnosed prenatally with low-level trisomy 20mosaicism in amniocytes, which was later confirmed by urine sediment analysis. Our patient demonstrates significant developmental delay that is likely attributable to this chromosomal aberration. In addition to the series of James et al. [2002], this is the longest follow-up of a patient reported with prenatal diagnosis and postnatal confirmation of trisomy 20 mosaicism. The patient’s mother was a gravida 1 para 0 woman originally referred for genetic counseling during pregnancy for advanced maternal age (36 years). Result of amniocentesis showed 4 out of 63 colonies with trisomy 20. Amniotic fluid alpha fetoprotein concentration was normal. A targeted sonogram performed late in the second trimester showed no obvious fetal cardiac or renal malformations. Prenatal exposures to alcohol, tobacco, prescription or non-prescription drugs were denied. The pregnancy was uneventful and was delivered at 38weeks by normal spontaneous vaginal delivery. Birth weight was 2,860 g and Apgar scores were 9 at 1min and 10 at 5 min. The baby appeared phenotypically normal, and cord blood karyotype showed 50 cells with a 46,XX complement. Early infancy was notable for poor weight gain and feeding difficulties. At 11 months, her weight was below the 5th centile, and generalized hypotonia was noted. By 14 months of age speech delay was evident. Urine and plasma amino acids, urine organic acids, ammonia, lactate and pyruvate, fragile X DNA, and celiac panel were normal. MRI of the head revealed no abnormalities. At 4 years of age, the diagnosis of pervasive developmental disorder (PDD) was made based upon clinical observation of inconsistent eye contact, decreased social interest, decreased attention span, and perseverations. Shewas also noted to have impaired expressive and receptive language skills and oromotor dyspraxia. Verbal IQ of 66 and performance IQ of 60 were recorded. On examination, the child was non dysmorphic. Severe apraxia, impaired social-relatedness, hypotonia, and fine motor delays were noted as were hyperextensible joints. There were no skin pigmentary findings. Weight was 16 kg (50th centile), height 99 cm (25th centile), and head circumference was 40.5 cm (near the 50th centile). Over the course of her life, the patient has been in good physical health.At 10years of age, she continues tohave severe behavioral problems, particularly impulsive behavior, and has static neurological impairment. She is treated with methylphenidate and risperdone. Weight continues at the 75th–90th centile and her height also continues at the 50th–75th centile. Subtelomeric probe analysis was performed with normal results. The patient has a younger sisterwithmild speech delay,who is otherwise noted to be in good health with no hypotonia or social relatedness issues. There is a maternal cousin with thalassemia minor and paternal cousin with a cleft lip and palate. There is no other family history of developmental disability. The parents are non-consanguineous. At age 4, urine sediment was analyzed by FISH with an alpha satellite probe for chromosome 20 (D20Z1). Interphase cells showed 13% (7/53) of cells with three signals for chromosome 20, compared to only 4% (6/155) in the urine of a 4-yearold control child. Dewald et al. [1998], devised a statistical approach based on the binomial distribution to relate analytical sensitivity of a probe to the numbers of observations required to assay formosaicisms and chimerisms. Based on the normal ranges for the centromeric region of chromosome 20 established in our laboratory, the analytical sensitivity of this assay is 98%. With 55 cells counted, and an analytical sensitivity of 98%, the probability of observing more than five cells from a second cell line (greater than 10% mosaicism) is 0.003 (probability cutoff 0.05). In the actual assay, 7 abnormal cells of 53 were observed, indicating a mosaicism of approximately 13.2%. Uniparental disomy (UPD) was ruled out by molecular analysis utilizing eight polymorphic markers from chromosome 20. Of these, five markers, (DS0S95, D20S178, D20S486, D20S120, and D20S171) were informative for normal biparental inheritance. FISH studies of a buccal smear *Correspondence to: Robert Wallerstein, Genetics Service, Joseph M. Sanzari Children’s Hospital, Hackensack University Medical Center, 30 Prospect Avenue, Imus Pediatric Center Room 258, Hackensack, NJ 07601. E-mail: rwallerstein@humed.com