Refining the phenotype of SINO syndrome: A comprehensive cohort report of 14 novel cases.

PURPOSE: Spastic paraplegia, intellectual disability, nystagmus, and obesity syndrome (SINO) is a rare autosomal dominant condition caused by heterozygous variants in KIDINS220. A total of 12 individuals are reported, comprising 8 with SINO and 4 with an autosomal recessive condition attributed to biallelic KIDINS220 variants. METHODS: In our international cohort, we have included 14 individuals, carrying 13 novel pathogenic KIDINS220 variants in heterozygous form. We assessed the clinical and molecular data of our cohort and previously reported individuals and, based on functional experiments, reached a better understanding of the pathogenesis behind the KIDINS220-related disease. RESULTS: Using fetal tissue and in vitro assays, we demonstrate that the variants generate KIDINS220 truncated forms that mislocalize in punctate intracellular structures, with decreased levels of the full-length protein, suggesting a trans-dominant negative effect. A total of 92% had their diagnosis within 3 years, with symptoms of developmental delay, spasticity, hypotonia, lack of eye contact, and nystagmus. We identified a KIDINS220 variant associated with fetal hydrocephalus and show that 58% of examined individuals present brain ventricular dilatation. We extend the phenotypic spectrum of SINO syndrome to behavioral manifestations not previously highlighted. CONCLUSION: Our study provides further insights into the clinical spectrum, etiology, and predicted functional impact of KIDINS220 variants.

[Greater vigilance in medication for children and adolescent is warranted in Denmark].

Only 30% of medication used for children and adolescents and 10% of the medication used for neonates has been evaluated for use in these populations. Infants and children differ from adults regarding pharmacodynamic and -kinetics, but they also differ from each other due to e.g. age, weight, and body composition, as we argue in this review. There is only limited knowledge within this area leading to the use of off-label, extemporaneous and unlicensed medication. Greater national vigilance in medication for children and adolescent is warranted to secure better and safer medicine for newborns, infants, children and adolescents.