RARE DOSAGE ABNORMALITIES - COPY NUMBER VARIATIONS FLANKING THE SHOX GENE.

Background: Molecular defects in the SHOX gene including deletions, duplications or pathogenic point mutations are responsible for well-known pathologies involving short stature as a clinical manifestation: Léri-Weill dyschondrosteosis, Langer mesomelic dysplasia, Turner syndrome or idiopathic short stature. Duplications flanking the SHOX gene (upstream or downstream of the intact SHOX gene involving conserved non-coding cis-regulatory DNA elements - CNEs) have been described but their clinical involvement is still difficult to understand. Results: We describe two cases with short stature and normal GH-IGF1 status. Multiplex ligation-dependent probe amplification (MLPA) and array comparative genomic hybridization (arrayCGH) identified in both cases heterozygous duplications involving downstream regions of SHOX gene, within CNEs (CNE8, CNE9 and CNE4, CNE5, CNE6, ECR1, CNE8, CNE9 and surrounding areas, respectively). One of the cases showed a maternally inherited duplication. Although every case has several particularities, we consider that duplications in these non-coding regions of SHOX gene may explain the short stature phenotype. Conclusion: To our knowledge, these are the first Romanian-reported cases of ISS with a large duplication of downstream SHOX enhancers CNEs region. The spectrum of phenotypic consequences and the exact mechanism of the presumed clinical expression of these genetic alterations still needs to be evaluated and described.

Ring autosomes: some unexpected findings.

Ring chromosomes are rare entities, usually associated with phenotypic abnormalities in correlation with the loss of genetic material. There are various breakpoints and sometimes there is a dynamic mosaicism that is reflected in clinical features. Most of the ring chromosomes are de novo occurrences. Our study reflects the experience of three Romanian cytogenetic laboratories in the field of ring chromosomes. We present six cases with ring chromosomes involving chromosomes 5, 13, 18, and 21. All ring chromosomes were identified after birth in children with plurimalformative syndromes. The ring chromosome was present in mosaic form in three cases, and this feature reflects the ring's instability. In case of ring chromosome 5, we report a possible association with oculo-auriculo-vertebral spectrum.