Chromosome 17p13.3 is a gene rich region that when deleted is associated with the well-known Miller-Dieker syndrome. A recently described duplication syndrome involving this region has been associated with intellectual impairment, autism and occasional brain MRI abnormalities. We report 34 additional patients from 21 families to further delineate the clinical, neurological, behavioral, and brain imaging findings. We found a highly diverse phenotype with inter- and intrafamilial variability, especially in cognitive development. The most specific phenotype occurred in individuals with large duplications that include both the YWHAE and LIS1 genes. These patients had a relatively distinct facial phenotype and frequent structural brain abnormalities involving the corpus callosum, cerebellar vermis and cranial base. Autism spectrum disorders were seen in a third of duplication probands, most commonly in those with duplications of YWHAE and flanking genes such as CRK. The typical neurobehavioral phenotype was usually seen in those with the larger duplications. We did not confirm the association of early overgrowth with involvement of YWHAE and CRK, or growth failure with duplications of LIS1. Older patients were often overweight. Three variant phenotypes included cleft lip/palate (CLP), split hand/foot with long bone deficiency (SHFLD), and a connective tissue phenotype resembling Marfan syndrome. The duplications in patients with clefts appear to disrupt ABR, while the SHFLD phenotype was associated with duplication of BHLHA9 as noted in two recent reports. The connective tissue phenotype did not have a convincing critical region. Our experience with this large cohort expands knowledge of this diverse duplication syndrome.

Objectives

Mosaic trisomy 18 occurs when two different cell lines exist in the same individual; one cell line has two copies of chromosome 18, while the other has three copies. Here we present two new patients with mosaic trisomy 18, summarize 31 reported cases from the literature, and discuss management and counseling themes. Our first patient is an 8(1/2)-year-old female with normal intelligence and no significant dysmorphic features other than short stature and cubitus valgus. The second patient is a 21-month-old male with developmental delay, several dysmorphic features, including a patent ductus arteriosus, and normal growth. In general, the phenotype of individuals with mosaic trisomy 18 varies greatly. Some individuals have the complete trisomy 18, Edwards syndrome phenotype with early death while others are phenotypically completely normal. The latter group is exemplified by four normal appearing adults with mosaic trisomy 18 who were identified only after giving birth to children with complete trisomy 18. Further, a wide range of anomalies have been reported, 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 mental retardation to above average intelligence. There appears to be no correlation with the percentage of trisomic cells in either fibroblasts or leukocytes and the individual's phenotype or intellectual function. We also discuss a variety of counseling issues including long-term survival, reproductive capacity of individuals with mosaic trisomy 18, and recurrence risks.