ATR-X syndrome: genetics, clinical spectrum, and management

Phenotypic Spectrum and Molecular Findings in 17 ATR-X Syndrome Italian Patients: Some New Insights

“…Our results indicate that certain anomalies with an impact on long-term prognoses, such as gastrointestinal issues and long-lasting hypotonia, are more prevalent in this series than in other series [ 6 ]. Among the less frequently reported features, osteosarcoma occurrence should be carefully evaluated.…”

“…Rarely reported skeletal features are present in only two cases: occipital dysraphism in one and a hemivertebra in another. In order to have a comparison with the literature data, clinical categories have been designed in accordance with those of the largest ATR-X patient series [ 6 , 14 ].…”

“…Nowadays, clinical characterization is much more detailed, and the phenotypic spectrum has expanded to include characteristic dysmorphisms, hypotonia, gastrointestinal, skeletal, and urogenital anomalies, variably combined in affected individuals. Moreover, atypical phenotypes have been recently reported, mainly due to the increasing recourse to multigenic analysis [ 6 , 7 ].…”

“…Different ATRX mutations are also found in many types of pediatric and adult cancers. Unlike the germline variants underlying the syndrome, somatic mutations are distributed along the gene without preferential localization [ 6 , 9 , 15 ] and are considered to be loss-of-function. They are presumptuously more severe and, therefore, incompatible with embryo development.…”

“…For instance, it has been suggested that a more severe psychomotor impairment is caused by variants affecting the PHD-like region of the ADD domain and that severe urogenital abnormalities are more frequent in cases where mutations are close to the C-terminus [ 13 , 14 ]. However, specific phenotypic differences related to specific ATRX protein domains are not well established and should not be used at this moment for prognostic purposes [ 6 ]. On the other hand, a significant correlation has been established between milder phenotypes and premature stop codons, such as the p.R37*, where translation is initiated from a different methionine residue and a smaller and less abundant protein is produced [ 16 , 17 ].…”