Abstract
BackgroundIsolated growth hormone deficiency (IGHD) and multiple pituitary hormone deficiency (MPHD) are heterogeneous disorders with several different etiologies and they are responsible for most cases of short stature. Mutations in different genes have been identified but still many patients did not present mutations in any of the known genes. Chromosomal rearrangements may also be involved in short stature and, among others, deletions of 18q23 defined a critical region for the disorder. No gene was yet identified.Methodology/Principal FindingsWe now report a balanced translocation X;18 in a patient presenting a breakpoint in 18q23 that was surprisingly mapped about 500 Kb distal from the short stature critical region. It separated from the flanking SALL3 gene a region enriched in highly conserved non-coding elements (HCNE) that appeared to be regulatory sequences, active as enhancers or silencers during embryonic development.ConclusionWe propose that, during pituitary development, the 18q rearrangement may alter expression of 18q genes or of X chromosome genes that are translocated next to the HCNEs. Alteration of expression of developmentally regulated genes by translocation of HCNEs may represent a common mechanism for disorders associated to isolated chromosomal rearrangements.
Highlights
Isolated growth hormone deficiency (IGHD) and multiple pituitary hormone deficiency (MPHD) are endocrine disorders responsible of most cases of short stature
As it was the case for many other heterogeneous disorders, chromosomal variations may be involved in determining the short stature phenotype
In the analysis of a X;18 balanced translocation in a patient affected with GHD and ectopic posterior pituitary, we were surprised to find that the 18q breakpoint did not interrupt the short stature critical region in 18q23 [6,7]
Summary
IGHD and MPHD are endocrine disorders responsible of most cases of short stature They may have different etiologies and are often associated with structural hypothalamic-pituitary (H-P) defects detectable by neuroimaging [1,2]. It is likely that other genes may be involved in the etiology of GH-dependent short stature, as the majority of patients did not present mutations in any of the known genes [3,4] As it was the case for many other heterogeneous disorders, chromosomal variations may be involved in determining the short stature phenotype. We report a balanced translocation X;18 in a patient presenting a breakpoint in 18q23 that was surprisingly mapped about 500 Kb distal from the short stature critical region It separated from the flanking SALL3 gene a region enriched in highly conserved non-coding elements (HCNE) that appeared to be regulatory sequences, active as enhancers or silencers during embryonic development. Alteration of expression of developmentally regulated genes by translocation of HCNEs may represent a common mechanism for disorders associated to isolated chromosomal rearrangements
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