Complex X chromosome rearrangement associated with multiorgan autoimmunity

Abstract

BackgroundTurner syndrome, a congenital condition that affects 1/2,500 births, results from absence or structural alteration of the second sex chromosome. Turner syndrome is usually associated with short stature, gonadal dysgenesis and variable dysmorphic features.The classical 45,X karyotype accounts approximately for half of all patients, the remainder exhibit mosaicism or structural abnormalities of the X chromosome. However, complex intra-X chromosomal rearrangements involving more than three breakpoints are extremely rare.ResultsWe present a unique case of a novel complex X chromosome rearrangement in a young female patient presenting successively a wide range of autoimmune diseases including insulin dependent diabetes mellitus, Hashimoto’s thyroiditis, celiac disease, anaemia perniciosa, possible inner ear disease and severe hair loss. For the genetic evaluation, conventional cytogenetic analysis and FISH with different X specific probes were initially performed. The complexity of these results and the variety of autoimmune problems of the patient prompted us to identify the exact composition and breakpoints of the rearranged X as well as methylation status of the X chromosomes. The high resolution array-CGH (assembly GRCh37/hg19) detected single copy for the whole chromosome X short arm. Two different sized segments of Xq arm were present in three copies: one large size of 80,3 Mb from Xq11.1 to Xq27.3 region and another smaller (11,1 Mb) from Xq27.3 to Xq28 region. An 1,6 Mb Xq27.3 region of the long arm was present in two copies. Southern blot analysis identified a skewed X inactivation with ≈ 70:30 % ratios of methylated/unmethylated fragments. The G-band and FISH patterns of the rearranged X suggested the aspect of a restructured i(Xq) chromosome which was shattered and fortuitously repaired. The X-STR genotype analysis of the family detected that the patient inherited intact maternal X chromosome and a rearranged paternal X chromosome.The multiple Xq breakages and fusions as well as inverted duplication would have been expected to cause a severe Turner phenotype. However, the patient lacks many of the classic somatic features of Turner syndrome, instead she presented multiorgan autoimmune diseases.ConclusionsThe clinical data of the presented patient suggest that fragmentation of the i(Xq) chromosome elevates the risk of autoimmune diseases.

Novel Complex Unbalanced Dicentric X-Autosome Rearrangement in a Thoroughbred Mare with a Mild Effect on the Phenotype

“…Of the 2 previously described X-autosome translocations in the horse, one was balanced and reciprocal [64,X,t(1p;Xp)(1q;Xq); Bugno-Poniewierska et al, 2018] and the other unbalanced [64,X,der(X),t(Xq;l5q)] with Xp deletion and trisomy ECA15 [Power, 1987]. Some of the few complex X chromosome rearrangements described in humans share elements with the presented equine case, but at the same time, are also different [Haltrich et al, 2015;Villa et al, 2017;Peterson et al, 2018]. Unfortunately, as we did not have access to additional tissue samples, it was not possible to study this case for chromatin features, replication patterns, or methylation to determine the functional status of the der and its centromeres.…”

“…Compared to aneuploidies, reports about structural aberrations involving the X chromosome are less common. Of these, rearrangements resulting in the loss of the entire short arm either by Xp deletion or due to the formation of isochromosomes of the long arm i(Xq) typically have phenotypes similar to X monosomy as reported in humans [Haltrich et al, 2015;Skuse et al, 2018] and horses [Lear and Bailey, 2008;Lear and Villagomez, 2011]. Other types of X chromosome structural rearrangements, however, are rare in both species.…”

“…In animals, only a handful of cases of X-autosome translocations have been reported in pigs [Koykul et al, 2000;Szczerbal and Switonski, 2016] and cattle [Gustavsson et al, 1968;Basrur et al, 2001], and just 2 cases in the horse [Power, 1987;Bugno-Poniewierska et al, 2018]. However, more complex X chromosome rearrangements with multiple breakpoints are extremely rare, with just a few cases so far reported in humans [Haltrich et al, 2015].…”

A rare case of solitary brain Langerhans cell histiocytosis with intratumoral hemorrhage in a patient affected by Turner syndrome

“…It is usually associated with short stature, gonadal dysgenesis, and variable dysmorphic features. [ 7 ] Although many reports describe the association between TS and various immunological disorders,[ 10 ] to date, there is no evidence about the association of LCH and TS.…”

Seronegative Myasthenia Gravis, as a Rare Autoimmune Condition in Turner Syndrome

“…The isochromosome 46,X,i(X)(q10) is a duplication of the long arm of the X chromosome, fused at the head with a missing short arm [ 4 ]. Other less common structural abnormalities include ring chromosome (r) and deletion of Xp or Xq; both could present as mosaic with another cell line.…”