Abstract
We report a patient with a unique and complex cytogenetic abnormality involving mosaicism for a small ring X and deleted Xp derivative chromosome with tandem duplication at the break point. The patient presented with failure to thrive, muscular hypotonia, and minor facial anatomic anomalies, all concerning for Turner syndrome. Brain MRI revealed mild thinning of the corpus callosum, an apparent decrease in ventricular white matter volume, and an asymmetric myelination pattern. Array comparative genome hybridization analysis revealed mosaicism for the X chromosome, deletion of the short arm of an X chromosome, and a duplication of chromosome region Xp11.21-p11.22. G-banded chromosome and FISH analyses revealed three abnormal cell lines: 46,X,der(X)del(X)(p11.23)dup(X)(p11.21p11.22)/46,X,r(X)(q11.1q13.1)/45,X. The small ring X chromosome was estimated to be 5.2 Mb in size and encompassed the centromere and Xq pericentromeric region. X chromosome inactivation (XCI) studies demonstrated a skewed pattern suggesting that the ring X remained active, likely contributing to the observed clinical features of brain dysmyelination. We hypothesize that a prezygotic asymmetric crossing over within a loop formed during meiosis in an X chromosome with a paracentric inversion resulted in an intermediate dicentric chromosome. An uneven breakage of the dicentric chromosome in the early postzygotic period might have resulted in the formation of one cell line with the X chromosome carrying a terminal deletion and pericentromeric duplication of the short arm and the second cell line with the X chromosome carrying a complete deletion of Xp. The cell line carrying the deletion of Xp could have then stabilized through self-circularization and formation of the ring X chromosome.
Highlights
Turner syndrome is diagnosed in 1 of 5,000 live female births
We present a patient with clinical features of Turner syndrome and a complex X chromosome rearrangement, which was detected by chromosomal microarray analysis, and further characterized by G-banding chromosome analysis and X chromosome inactivation studies
Array CGH using bacterial artificial chromosome (BAC)/PAC suggested mosaicism for the X chromosome, which was confirmed by G-banding chromosome analysis showing the presence of three abnormal cell lines: 46,X,del(X)(p11.23)/46,X,r(X)/45,X (Figure 1A–C)
Summary
Turner syndrome is diagnosed in 1 of 5,000 live female births. Six to fifteen percent of patients with Turner syndrome are mosaic carriers of a ring X chromosome. [1,2].Several studies in the last decade have made significant contributions to our understanding of the clinical phenotype in patients with r(X) [2,3,4,5,6,7]. Patients with r(X) can be at a higher risk for other findings, including mental retardation, learning difficulties, autistic spectrum disorders, and structural brain abnormalities [4,8,9]. These additional features can be partially explained by the status of X inactivation, size, origin, and replication timing of the ring, genes affected by copy number variations, and the percent of mosaicism [3,6,8,10]. McGinniss et al (1997) have hypothesized that overexpression of dosage sensitive genes from an X chromosome lacking XIST is responsible for some cases with Kabuki syndromelike features
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