PC1104: Tenorio Syndrome: Review of the Clinical and Molecular Features

Background: Tenorio syndrome (TNORS) is a relatively recent disorder with very few cases described so far. Clinical features include macrocephaly, intellectual disability, hypotonia, enlarged ventricles and autoimmune diseases. Molecular underlying mechanism included missense variants and large deletions encompassing RNF125, a gene that encodes for an U3 ubiquitin ligase protein, involved in the regulation of several proteins by its binding and degradation through the proteasome. Since the initial description of the disorder and families, several new patients were diagnosed, adding more evidence of the clinical manifestations.

Methods: Thus, the aim of this project is to perform a deep phenotyping of the current cases and review all cases in which a pathogenic variant has been found in RNF125 in patients with Tenorio Syndrome. This included clinical phenotypic description and molecular analysis of the variants detected. All cases have been collected worldwide from different hospitals/research centres. All patients signed inform consent to participate in the study and the project was approved by the ethical committe of the University Hospital La Paz (Madrid)

Results: Interestingly, not all patients with pathogenic variants in RNF125 manifest overgrowth, but instead, there is a common pattern of neurodevelopmental disease, with mild to moderate degrees. Segregation analysis showed that in some cases, though the variant was inherited by an apparently normal parent, deep phenotyping suggested a mild form of the disease in their progenitors. The mechanism underlying the development of this disease is not well understood yet and the description of more cases will help to a better understanding and clinical characterization.

Conclusion: In summary, we report nine new cases of Tenorio syndrome (MIM, 616260), in patients with a variable degree of the disease, and a common concurrent neurodevelopmental disorder. Not all cases have overgrowth, and this must be considering for a correct diagnosis. In total, 21 cases have been described having Tenorio syndrome since our intiial publication in 2014, as far as we know. There is still a lot of work to do regarding the clinical manifestations, follow up, molecular underlying mechanism but this results will help physicians and all practitioners involved in the management of patients wih this disease.