8p23 duplication reconsidered: is it a true euchromatic variant with no clinical manifestation?

Multiple patients with rearrangements of the short arm of 8p23.1 have been reported, including inverted and tandem duplications of 8p, deletions of 8p23, pericentric inversions (p23q22), and isolated duplications of 8p23. The clinical significance of duplication of 8p23.1 remains controversial. Krasikov et al, Williams et al, Barber et al, and O’Malley and Storto together have reported 29 patients in 13 kindreds with duplication of 8p23.1, the vast majority (27/29) of whom were phenotypically normal. One case was reported to be a developmentally delayed 18 month old male and one patient underwent cytogenetic analysis because of short stature. In most of these families (9/13), duplication of 8p23.1 was an incidental finding identified during prenatal diagnosis either for advanced maternal age or indicated by a previous child with an unrelated chromosomal abnormality. Two of the remaining cases had a history of spontaneous miscarriages. In many cases there has been no long term follow up to examine the possibility of developmental delay or other problems that may arise after the neonatal period. Recently, Engelen et al reported a 34 year old healthy and developmentally normal man with duplication of 8p23.1-p23.3 who underwent a cytogenetic examination because of oligoasthenozoospermia. Based on his otherwise normal phenotype, they consider this duplication to be a clinically innocuous rearrangement, but could not exclude a relationship between the oligoasthenozoospermia and the duplication. Gibbons et al reported on a mother and her two daughters with dup 8p23.1. All three had minimal pathology (the mother had bilateral clinodactyly but no other dysmorphic features, and the daughters had smallish heads and mild facial dysmorphism) and normal development. FISH analysis with 8p23.1 YAC HTY3020 showed an apparent duplication. Others, however, have found that duplication of 8p23.1 can be associated with significant pathology. Kennedy et al studied a 16 year old female patient with congenital heart defects accompanied by otherwise normal development. Karyotypic analysis showed dup 8p23.1. The patient’s father has an isolated right aortic arch and is mosaic for the 8p23.1 duplication. Kondoh et al reported a patient with dup 8p23.1 and features of Coffin-Lowry syndrome (CLS), including moderate mental retardation along with multiple physical abnormalities. Analysis of the CLS gene, RSK2, showed no mutations. The clinical findings in this patient, including mental retardation, hypotonia, and short stature, are similar to features described in our patients.