Hypomelanosis of Ito with local overgrowth due to a somatic complex MTOR gene variant consistent with Smith–Kingsmore syndrome in one of monozygotic twins detectable only by RNA sequencing – A case report

Introduction: Smith–Kingsmore syndrome is a rare neurodevelopmental disorder that is caused by somatic variants in the MTOR gene. The present study reports on a monozygotic twin exhibiting hypomelanosis of Ito and localised brain overgrowth, attributable to a complex somatic MTOR variant, which is only detectable by RNA sequencing. Case Presentation: A 9-year-old girl with a healthy monozygotic twin developed seizures at the age of three months. Due to refractory epilepsy and focal cortical dysplasia identified on brain MRI, she underwent resective epilepsy surgery at the age of five years. Despite initial seizure control, seizures later persisted, and by the age of nine, she exhibited progressive autism spectrum features and intellectual impairment. Whole exome sequencing performed on a blood sample was unremarkable. On re-evaluation, faint Blaschko lines were observed under mobile phone light, raising suspicion of somatic mosaicism. Due to technical limitations of DNA-based testing in paraffin-embedded brain tissue, RNA sequencing of affected tissue was performed, revealing a complex somatic MTOR variant. Treatment with the mTOR inhibitor sirolimus resulted in approximately 50% reduction in seizure frequency and improvement in autistic features and verbal communication. Conclusions: This case highlights several important clinical insights. The presence of discordant clinical features in monozygotic twins may be indicative of mosaicism. Cutaneous findings, such as Blaschko lines, may be subtle and easily overlooked. The concept of mosaicism should be considered in the context of localized brain dysplasias. RNA sequencing has been identified as a valuable diagnostic tool, particularly in challenging samples such as paraffin-embedded tissues, where conventional genomic methods may be limited