A Novel TSC2 Variant Associated with an Extremely Rare Magnetic Resonance Imaging Finding of Focal Megalencephaly

Abstract

AbstractTuberous sclerosis complex (TSC) is a neurocutaneous syndrome with an autosomal dominant pattern of inheritance. It is a multisystem genetic disease caused by mutations in the TSC1 and TSC2 genes. The neuroradiographic findings of TSC include cortical dysplasia (cortical tubers and cerebral white matter radial migration lines), subependymal nodules, and subependymal giant cell astrocytoma. In this article, we describe an interesting case of TSC with an extremely rare radiographic finding of focal right megalencephaly. Molecular genetic testing detected a heterozygous c.3814+2T>G (p.?) variant, not previously described in the literature. As per the 2012 International Tuberous Sclerosis Complex Consensus Group guidelines and the findings of the genetic testing, this mutation most probably should be considered as a pathogenic variant. There are few cases of hemimegalencephaly (HME) reported in the literature, associated with TSC. To our knowledge focal megalencephaly is an extremely rare neuroradiographic finding in patients with TSC and has been previously reported only once by Griffiths et al based on clinical diagnostic criteria. Despite the uncommon association, TSC is the only neurocutaneous syndrome with similar histological appearance to HME. It is recognized that the pathological features in TSC and HME are due to abnormal cell proliferation, migration, and organization which could also be a possible mechanism for the development of focal megalencephaly. The uncommon association of HME and TSC with cytological similarities makes us wonder if there could be similarities in the pathogenesis of these two conditions. The advances in molecular genetic testing, increasing use of next-generation sequencing, and discovery of new pathogenic variants could answer some of these questions.