رد: حدوث اضطراب طيف التوحد واضطراب التصلب الدرين يف وقت واحد يف ثالثة أطفال تقارير حالة ومراجعة األدبيات Re: Coexistence of Autism Spectrum Disorders Among Three Children with Tuberous Sclerosis Complex Case reports and review of literature Sir, I read with interest the case report by Al-Futaisi et al. published in the November 2016 issue of SQUMJ which described three children with both autism spectrum disorders (ASDs) and tuberous sclerosis complex (TSC).1 In case one, computed tomography (CT) of the brain appeared normal. In case two, a magnetic resonance imaging (MRI) scan of the brain revealed nodular heterotopias and tubers in the brain, adjacent to the right lateral ventricle; these MRI findings, along with clinical features, confirmed a diagnosis of TSC.1 In the third case, an MRI scan demonstrated multiple cortical and subcortical tubers and subependymal nodules in the brain, which subsequently led to the TSC diagnosis. Although the TSC diagnoses were confirmed by MRI or CT scans in all three cases, the authors stated that it was difficult to correlate MRI findings with the severity of autistic features in each patient.1 However, I believe for the following two reasons that an in-depth evaluation of the MRI findings could help to establish that correlation. First, the appearance of cortical tubers on an MRI represents an important feature in the diagnosis of TSC. Gallagher et al. identified three different types of cortical tubers: (1) type A tubers which were isointense on volumetric T1-weighted images and subtly hyperintense on T2-weighted and fluid-attenuated inversion recovery (FLAIR) images; (2) type B tubers which were hypointense on volumetric T1-weighted images and homogeneously hyperintense on T2-weighted and FLAIR images; and (3) type C tubers which were hypointense on volumetric T1-weighted images, hyperintense on T2-weighted images and heterogeneous on FLAIR images with a hypointense central region surrounded by a hyperintense rim.2 Accordingly, the clinical significance of the dominant tuber type was identified, with patients with type A tubers demonstrating a milder TSC phenotype.2 Moreover, those with tubers predominantly of type C had an increased number of MRI abnormalities—such as subependymal giant cell tumours—and were more likely to have an ASD compared to patients with type A or B tubers.2 Second, cortical tubers vary widely in size, location and appearance.2 Cortical tubers in the temporal lobe and insular area have been found to be associated with ASDs.3 Moreover, the presence of cystic-like tubers on MRI scans might also offer a structural marker for ASDs in TSC.3 On the other hand, large tubers are reportedly more likely to be associated with ASDs, even in comparison to cases with numerous smaller tubers.4 Mahmood D. Al-Mendalawi Department of Paediatrics, Al-Kindy College of Medicine, Baghdad University, Baghdad, Iraq E-mail: mdalmendalawi@yahoo.com References 1. Al-Futaisi A, Idris A, Al-Sayegh A, Al-Mamari WS. Coexistence of autism spectrum disorders among three children with tuberous sclerosis complex: Case reports and review of literature. Sultan Qaboos Univ Med J 2016; 16:e520−4. doi: 10.18295/squmj.2016.16.04.022. 2. Gallagher A, Grant EP, Madan N, Jarrett DY, Lyczkowski DA, Thiele EA. MRI findings reveal three different types of tubers in patients with tuberous sclerosis complex. J Neurol 2010; 257:1373−81. doi: 10.1007/s00415-010-5535-2. 3. Huang CH, Peng SS, Weng WC, Su YN, Lee WT; National Taiwan University Hospital Tuberous Sclerosis Complex (NTUH TSC) Study Group. The relationship of neuroimaging findings and neuropsychiatric comorbidities in children with tuberous sclerosis complex. J Formos Med Assoc 2015; 114:849−54. doi: 10.1016/j.jfma.2014.02.008. 4. Pascual-Castroviejo I, Hernández-Moneo JL, Pascual-Pascual SI, Viaño J, Gutiérrez-Molina M, Velazquez-Fragua R, et al. Significance of tuber size for complications of tuberous sclerosis complex. Neurologia 2013; 28:550−7. doi: 10.1016/j.nrl.2012.11.002. LETTER TO THE EDITOR Sultan Qaboos University Med J, February 2017, Vol. 17, Iss. 1, pp. e127–128, Epub. 30 Mar 17 Submitted 24 Dec 16 Accepted 19 Jan 17 doi: 10.18295/squmj.2016.17.01.027 Re: Coexistence of Autism Spectrum Disorders Among Three Children with Tuberous Sclerosis Complex Case reports and review of literature e128 | SQU Medical Journal, February 2017, Volume 17, Issue 1 Response from the Authors Sir, Thank you for your interest in our article. Recently, several studies have suggested an association between tuberous sclerosis complex (TSC) severity and parameters such as the genotype of the mutation, morphological and radiological features of tubers on magnetic resonance imaging (MRI) and the pathological characteristics of brain biopsies.1–4 However, the clinical phenotype of TSC is highly variable, thus making prediction of the phenotype based on just one parameter challenging.2 In addition, to the best of our knowledge, there are currently no published studies focusing on the accumulative effects of all known TSC parameters on its clinical phenotype. Furthermore, the exclusive correlation of neuromorphological features to clinical phenotype may under- estimate the fact that TSC is a global disorder of brain development. Conventional MRI features of brain hamartomas may represent only a small portion of brain TSC lesions, as extensive disease has been found in white matter which appears structurally normal but has abnormal microstructures as demonstrated by histopathological analysis.5 In addition, increased axial diffusivity has been noted in major white matter tracts on diffusion tensor imaging.6 Therefore, MRI findings alone are not a good tool for predicting the phenotype severity of TSC cases. In conclusion, according to the current available literature, predicting the clinical phenotype of TSC is not possible. More clinical and genetic data are needed from large numbers of patients to help define more valid and clinically- oriented genotype or phenotype correlations. Amna Al-Futaisi,1 Ahmed Idris,1 Abeer Al-Sayegh,2 *Watfa S. Al-Mamari1 Departments of 1Child Health and 2Genetics, Sultan Qaboos University Hospital, Muscat, Oman *Corresponding Author e-mail: watfa.almamari@gmail.com References 1. Overwater IE, Swenker R, van der Ende EL, Hanemaayer KB, Hoogeveen-Westerveld M, van Eeghen AM, et al. Genotype and brain pathology phenotype in children with tuberous sclerosis complex. Eur J Hum Genet 2016; 24:1688−95. doi: 10.1038/ejhg.2016.85. 2. Curatolo P, Moavero R, Roberto D, Graziola F. Genotype/phenotype correlations in tuberous sclerosis complex. Semin Pediatr Neurol 2015; 22:259−73. doi: 10.1016/j.spen.2015.10.002. 3. Hu S, Hu D, Zhu WZ, Wang L, Wang Z. Tuberous sclerosis complex: Imaging characteristics in 11 cases and review of the literature. J Huazhong Univ Sci Technolog Med Sci 2016; 36:601−6. doi: 10.1007/s11596-016-1632-5. 4. Ridler K, Suckling J, Higgins N, Bolton P, Bullmore E. Standardized whole brain mapping of tubers and subependymal nodules in tuberous sclerosis complex. J Child Neurol 2004; 19:658−65. doi: 10.1177/08830738040190090501. 5. Meikle L, Talos DM, Onda H, Pollizzi K, Rotenberg A, Sahin M, et al. A mouse model of tuberous sclerosis: Neuronal loss of Tsc1 causes dysplastic and ectopic neurons, reduced myelination, seizure activity, and limited survival. J Neurosci 2007, 27:5546−58. doi: 10.1523/ JNEUROSCI.5540-06.2007. 6. Zikou AK, Xydis VG, Astrakas LG, Nakou I, Tzarouchi LC, Tzoufi M, et al. Diffusion tensor imaging in children with tuberous sclerosis complex: Tract-based spatial statistics assessment of brain microstructural changes. Pediatr Radiol 2016; 46:1158−64. doi: 10.1007/s00247- 016-3582-2. https://doi.org/10.1038/ejhg.2016.85 https://doi.org/10.1016/j.spen.2015.10.002 https://doi.org/10.1007/s11596-016-1632-5 https://doi.org/10.1177/08830738040190090501 https://doi.org/10.1523/JNEUROSCI.5540-06.2007 https://doi.org/10.1523/JNEUROSCI.5540-06.2007 https://doi.org/10.1007/s00247-016-3582-2 https://doi.org/10.1007/s00247-016-3582-2