De novo FBXO11 mutations are associated with intellectual disability and behavioural anomalies.

Intellectual disability (ID) has an estimated prevalence of 1.5-2%. In most affected individuals, its genetic basis remains unclear. Whole exome sequencing (WES) studies have identified a multitude of novel causative gene defects and have shown that a large proportion of sporadic ID cases results from de novo mutations. Here, we present two unrelated individuals with similar clinical features and deleterious de novo variants in FBXO11 detected by WES. Individual 1, a 14-year-old boy, has mild ID as well as mild microcephaly, corrected cleft lip and alveolus, hyperkinetic disorder, mild brain atrophy and minor facial dysmorphism. WES detected a heterozygous de novo 1 bp insertion in the splice donor site of exon 3. Individual 2, a 3-year-old boy, showed ID and pre- and postnatal growth retardation, postnatal mild microcephaly, hyperkinetic and restless behaviour, as well as mild dysmorphism. WES detected a heterozygous de novo frameshift mutation. While ten individuals with ID and de novo variants in FBXO11 have been reported as part of larger studies, only one of the reports has some additional clinical data. Interestingly, the latter individual carries the identical mutation as our individual 2 and also displays ID, intrauterine growth retardation, microcephaly, behavioural anomalies, and dysmorphisms. Thus, we confirm deleterious de novo mutations in FBXO11 as a cause of ID and start the delineation of the associated clinical picture which may also comprise postnatal microcephaly or borderline small head size and behavioural anomalies.

Manufacture of custom-made cranial implants from DICOM® images using 3D printing, CAD/CAM technology and incremental sheet forming

INTRODUCTION: This work aims to pre-operatively manufacture custom-made low-cost implants and physical models (‘biomodels’) of fractured skulls. The pre-DOI: operative manufacturing of biomodels and implants allows physicians to study and plan surgery with a greater possibility of achieving the expected result. Customization contributes to both the esthetic and functional outcome of the implant because it considers the anatomy of each patient, while the low cost allows a greater number of people to potentially benefit. METHODS: From CT images of a fractured skull, a CAD model of the skull (biomodel) and a restorative implant were constructed digitally. The biomodel was then physically constructed with 3D Printing, and Incremental Sheet Forming (ISF) was used to manufacture the implant from a sheet of pure grade 2 titanium. Before cutting the implant’s final shape from a pre-formed sheet, heat treatment was performed to avoid deformations caused by residual stresses generated during the ISF process. RESULTS: A comparison of the dimensions of the implant and its respective CAD biomodel revealed geometric discrepancies that can affect both functional and aesthetic efficiency. Nevertheless, the final shape preserved symmetry between the right and left sides of the skull. Electron microscopy analysis did not indicate the presence of elements other than pure titanium. CONCLUSION: Dimensional variability can be decreased with changes in the manufacturing process (i.e., forming and cutting) and the heating ramp. Despite biomedical characteristics, there was no contamination of the implant by harmful chemical elements. 3D Printing was effective in making the biomodel, enabling pre-operative planning and improving physician-patient communication. Current results indicate that ISF is a process that can be used to obtain custom-made implants.