ESPE Abstracts

The phenotype in male individuals with a mosaic sex chromosomal abnormality is heterogenous, but ambiguous genitalia, delayed puberty, disturbed spermatogenesis, and short stature are frequently seen. Genetic investigation in boys with idiopathic/isolated short stature usually includes SHOX gene analysis (sequencing and copy number detection by MLPA), genome wide array analysis, and/or whole exome sequencing (WES). In the Netherlands, conventional karyotyping is not part of this standard diagnostic workup. Here, we present three cases in whom a mosaic sex chromosomal abnormality was identified by WES or SHOX MLPA. In two of them, short stature was the only clear clinical feature. In case 1 (11 years, height SDS: -2,4), WES was performed (SNV and CNV analysis) with a bioinformatic filter for our short stature/skeletal dysplasia gene panel (565 genes). CNV analysis showed a terminal deletion of Yq11.221qter in ~50% of the cells and a deletion of the whole Y-chromosome in the remaining 50% of the cells. These results were confirmed by genome wide array analysis and are indicative for a 45,X/46,X,del(Y)(q11.221) karyotype. In case 2 (30 years, height SDS: <-2,5, sitting index 0.56 (>P97), very mild Madelung deformity), SHOX MLPA showed a mosaic deletion of the entire SHOX gene. To further characterize the deletion, genome wide array analysis was executed, showing a deletion of the entire Y-chromosome in ~40% of the cells, indicative for a 45,X/46,XY karyotype. In case 3 (15 years, height SDS: -2.45), a gain of the entire SHOX gene was identified by MLPA. Array analysis showed a terminal gain of Ypterq11.221 in ~75% of the cells and a terminal deletion of Yq11.222qter in all cells, indicative for a isodicentric Y-chromosome (idic(Y)). Karyotyping and FISH analysis on leukocytes could confirm the presence of this idic(Y) in mosaic form: 46,X,idic(Y)(q11.221)[20].ish idic(Y)(SRY++,CEP(Y)++)[5]/45,X[10]. These cases show that (mosaic) sex chromosomal abnormalities should be in the differential diagnosis of short statue in males, as they can result in i.e. delayed puberty, fertility issues, or cardiac problems. Early detection can provide new treatment options to influence height. Non-conventional/non-cytogenetic techniques (WES, array analysis, SHOX MLPA) might have a more prominent role in the genetic diagnosis of these chromosomal abnormalities in the near future. Conventional cytogenetics (karyotyping or FISH) remain necessary to investigate the structure of the abnormal sex chromosome and/or the mosaic status in different tissues.