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

Abstract

Tuberous 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.

Keywords

tuberous sclerosis - focal megalencephaly - updated diagnostic criteria for TSC 2012 - TSC2 variant - epilepsy surgery

• References

• 1 Zeng L-H, Rensing NR, Zhang B, Gutmann DH, Gambello MJ, Wong M. Tsc2 gene inactivation causes a more severe epilepsy phenotype than Tsc1 inactivation in a mouse model of tuberous sclerosis complex. Hum Mol Genet 2011; 20 (03) 445-454
• 2 Northrup H, Krueger DA. ; International Tuberous Sclerosis Complex Consensus Group. Tuberous sclerosis complex diagnostic criteria update: recommendations of the 2012 Iinternational Tuberous Sclerosis Complex Consensus Conference. Pediatr Neurol 2013; 49 (04) 243-254
• 3 Cartwright MS, McCarthy SC, Roach ES. Hemimegalencephaly and tuberous sclerosis complex. Neurology 2005; 64 (09) 1634 . Doi: 10.1212/01.WNL.0000154465.87255.78
• 4 Galluzzi P, Cerase A, Strambi M, Buoni S, Fois A, Venturi C. Hemimegalencephaly in tuberous sclerosis complex. J Child Neurol 2002; 17 (09) 677-680
• 5 Maloof J, Sledz K, Hogg JF, Bodensteiner JB, Schwartz T, Schochet SS. Unilateral megalencephaly and tuberous sclerosis: related disorders?. J Child Neurol 1994; 9 (04) 443-446
• 6 Griffiths PD, Gardner SA, Smith M, Rittey C, Powell T. Hemimegalencephaly and focal megalencephaly in tuberous sclerosis complex. Am J Neuroradiol 1998; 19 (10) 1935-1938
• 7 Flores-Sarnat L. Hemimegalencephaly: part 1. Genetic, clinical, and imaging aspects. J Child Neurol 2002; 17 (05) 373-384 , discussion 384
• 8 Flores-Sarnat L. Hemimegalencephaly Syndrome. In: Curatolo P, Sarnat HB. , eds. Malformations of the Nervous System. Handbook of Clinical Neurology. Edinburgh: Elsevier; 2008
• 9 Sarnat HB, Flores-Sarnat L. Infantile tauopathies: Hemimegalencephaly; tuberous sclerosis complex; focal cortical dysplasia 2; ganglioglioma. Brain Dev 2015; 37 (06) 553-562