An active ring X and haploinsufficiency of SHOX contribute to short stature, congenital anomalies, and developmental delay in a female.

We report on a female infant with short stature and mesomelic limb shortening, multiple congenital abnormalities, developmental delay, and Rieger anomaly. Cytogenetic analysis revealed a complex rearrangement of the sex chromosomes in this patient. In addition to a normal X chromosome, a derivative Y [der(Y)] chromosome composed of X and Y material and a ring X [r(X)] were present. Consistent with the fact that this infant had normal female genitalia, the SRY gene was not detected in the Y chromosome portion of the der(Y). By fluorescence in situ hybridization (FISH), XIST was present on the normal X and the r(X), but not on the der(Y). The normal X was late replicating (inactive) and the r(X) early replicating (active) in all lymphocyte metaphases examined. As the X chromosome material on the der(Y) cannot be inactivated, the unusual skew of activation toward the r(X) presumably resulted in the least amount of functional disomy of X-linked genes in the cells of this patient. Deletion of one copy of the SHOX gene was detected in this patient. Haploinsufficiency of this gene is known to be correlated with short stature and mesomelic limb shortening.