Tetraploid/Diploid Mosaicism in Cultured Genital Skin Fibroblasts: Is It Causally Related to Penoscrotal Hypospadias?

Tetraploid/diploid mosaicism is a rare chromosomal abnormality that is infrequently reported in patients with severe developmental delay, growth retardation, and short life span. Here, we present a 6-year-old patient with severe penoscrotal hypospadias and a coloboma of the left eye but with normal growth, normal psychomotor development, and without dysmorphisms. We considered a local, mosaic sex chromosomal aneuploidy as a possible cause of his genital anomaly and performed karyotyping in cultured fibroblasts from the genital skin, obtained during surgical correction. Tetraploid/diploid (92,XXYY/46,XY) mosaicism was found in 43/57 and 6/26 metaphases in 2 separate cultures, respectively. Buccal smear cells, blood lymphocytes, and cells from urine sediment all showed diploidy. We investigated whether this chromosomal abnormality could be found in other patients with severe hypospadias and karyotyped genital fibroblasts of 6 additional patients but found only low frequencies (<11%) of tetraploid cells, not statistically different from those found in control males with no hypospadias. This is the first time tetraploid mosaicism is found in such a high percentage in a patient without psychomotor retardation, dysmorphisms or growth delay. Although the relationship between this observed mosaicism in cultured cells and the underlying pathogenetic mechanism in penoscrotal hypospadias remains to be determined, our data clearly illustrate the power of cytogenetic techniques in detecting mosaicism compared to next-generation sequencing techniques, in which DNA pooled from multiple cells is used.