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Analysis of genotypes and phenotypes in Chinese children with tuberous sclerosis complex

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Abstract

Tuberous sclerosis complex (TSC) is a neurocutaneous syndrome with serious clinical presentations, an autosomal dominant genetic disorder involving multiple organs and systems. We retrospectively investigated the clinical manifestations and genotypes of 20 Chinese children with TSC to enable informed diagnostic and surveillance recommendations in China. A retrospective analysis of clinical manifestations in 20 children (7.00±5.30 years old) with TSC was conducted. A genetic testing of the genes TSC1 and TSC2 was performed in 14 children.The earliest manifestations of TSC were skin lesions (80% of patients) and seizures (75%). Fourteen of the children presented with retinal hamartomas, and 2 of these underwent eye enucleation at other hospitals through misdiagnosis. On magnetic resonance imaging, 18 children exhibited subependymal nodules, and 16 ones showed cortical nodules. 5 cases of non-renal hamartomas, 5 cases of multiple renal cysts, and 5 cases of cardiac rhabdomyomas were observed. The genotyping of TSC1 and TSC2 in 14 children revealed 11 with mutations in TSC2, 2 with mutations in TSC1, and no mutations of either gene in one patient. Eight of these observed mutations are reported here in for the first time. The illness presentations of the TSC2-mutated patients were more severe than that of patients carrying TSC1 mutations.There were differences in the mutations of TSC genes in Chinese children from those reported in other countries. The described clinical characteristics and genotyping will help pediatric neurologists to understand, diagnosis, and treat TSC.

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References

  • Bai, D.Y., Wang, X., Zhao, J.Y., Li, L., Gao, J., and Wang, N.L. (2016). Comparison of color fundus photography, infrared fundus photography, and optical coherence tomography in detecting retinal hamartoma in patients with tuberous sclerosis complex. Chin Med J 129, 1229–1235.

    Article  PubMed  PubMed Central  Google Scholar 

  • Cheadle, J.P., Reeve, M.P., Sampson, J.R., and Kwiatkowski, D.J. (2000). Molecular genetic advances in tuberous sclerosis, Hum Genet 107, 97–114.

    Article  CAS  PubMed  Google Scholar 

  • European Chromosome 16 Tuberous Sclerosis Consortium. (1993). Identification and characterization of the tuberous sclerosis gene on chromosome 16, Cell 75, 1305–1315.

    Article  Google Scholar 

  • Curatolo, P., Bombardieri, R., and Jozwiak, S. (2008). Tuberous sclerosis. Lancet 372, 657–668.

    Article  CAS  PubMed  Google Scholar 

  • Dabora, S.L., Jozwiak, S., Franz, D.N., Roberts, P.S., Nieto, A., Chung, J., Choy, Y.S., Reeve, M.P., Thiele, E., Egelhoff, J.C., Kasprzyk-Obara, J., Domanska-Pakiela, D., and Kwiatkowski, D.J. (2001). Mutational analysis in a cohort of 224 tuberous sclerosis patients indicates increased severity of TSC2, compared with TSC1, disease in multiple organs. Am J Human Genets 68, 64–80.

    Article  CAS  Google Scholar 

  • de Ribaupierre, S., Dorfmüller, G., Bulteau, C., Fohlen, M., Pinard, J.M., Chiron, C., and Delalande, O. (2007). Subependymal giant-cell astrocytomasin pediatric tuberous sclerosis disease: when should we operate? Neurosurgery 60, 83–90.

    Article  PubMed  Google Scholar 

  • DiMario, F.J.Jr., Sahin, M., and Ebrahimi-Fakhari, D. (2015). Tuberous sclerosis complex. Pediatric Clinics North Am 62, 633–648.

    Article  Google Scholar 

  • Ewalt, D.H., Sheffield, E., Sparagana, S.P., Delgado, M.R., and Roach, E.S. (1998). Renal lesion growth in children with tuberous sclerosis complex. J Urol 160, 141–145.

    Article  CAS  PubMed  Google Scholar 

  • Franz, D.N., Belousova, E., Sparagana, S., Bebin, E.M., Frost, M., Kuperman, R., Witt, O., Kohrman, M.H., Flamini, J.R., Wu, J.Y., Curatolo, P., de Vries, P.J., Berkowitz, N., Anak, O., Niolat, J., and Jozwiak, S. (2014). Everolimus for subependymal giant cell astrocytoma in patients with tuberous sclerosis complex: 2-year open-label extension of the randomised EXIST-1 study. Lancet Oncol 15, 1513–1520.

    Article  CAS  PubMed  Google Scholar 

  • Hung, C.C., Su, Y.N., Chien, S.C., Liou, H.H., Chen, C.C., Chen, P.C., Hsieh, C.J., Chen, C.P., Lee, W.T., Lin, W.L., and Lee, C.N. (2006). Molecular and clinical analyses of 84 patients with tuberous sclerosis complex. BMC Med Genet 7, 72.

    Article  PubMed  PubMed Central  Google Scholar 

  • Jang, M.A., Hong, S.B., Lee, J.H., Lee, M.H., Chung, M.P., Shin, H.J., Kim, J.W., and Ki, C.S. (2012). Identification of TSC1 and TSC2 mutations in Korean patients with tuberous sclerosis complex. Pediatr Neurol 46, 222–224.

    Article  PubMed  Google Scholar 

  • Jones, A.C., Shyamsundar, M.M., Thomas, M.W., Maynard, J., Idziaszczyk, S., Tomkins, S., Sampson, J.R., and Cheadle, J.P. (1999). Comprehensive Mutation Analysis of TSC1 and TSC2—and Phenotypic Correlations in 150 Families with Tuberous Sclerosis. Am J Human Genets 64, 1305–1315.

    Article  CAS  Google Scholar 

  • Józwiak, S., Kotulska, K., Domanska-Pakiela, D., Lojszczyk, B., Syczewska, M., Chmielewski, D., Dunin-Wasowicz, D., Kmiec, T., Szymkiewicz-Dangel, J., Kornacka, M., Kawalec, W., Kuczynski, D., Borkowska, J., Tomaszek, K., Jurkiewicz, E., and Respondek-Liberska, M. (2011). Antiepileptic treatment before the onset of seizures reduces epilepsy severity and risk of mental retardation in infants with tuberous sclerosis complex. Eur J Paediatric Neurol 15, 424–431.

    Article  Google Scholar 

  • Kövesdi, E., Hadzsiev, K., Komlósi, K., Kassay, M., Barsi, P., and Melegh, B. (2013). NovelTSC1 mutation associated with variable phenotypes in tuberous sclerosis. Orvosi Hetilap 154, 914–918.

    Article  PubMed  Google Scholar 

  • Krueger, D.A., and Northrup, H. (2013). Tuberous sclerosis complex surveillance and management: recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference. Pediatr Neurol 49, 255–265.

    Article  PubMed  PubMed Central  Google Scholar 

  • Lawson, J.A., Chan, C.F., Chi, C.S., Fan, P.C., Kim, H.D., Kim, K.J., Likasitwatanakul, S., Ortiz, M., Riney, K., Tay, S.K.H., and Tham, C.K. (2014). Managing tuberous sclerosis in the Asia-Pacific region: Refining practice and the role of targeted therapy. J Clin Neurosci 21, 1180–1187.

    Article  PubMed  Google Scholar 

  • Lopez, E., Escovich, L., and Vigna, A. (2003). Tuberous sclerosis: presentation of a clinical case with oral manifestations. Med Oral 8, 122–128.

    PubMed  Google Scholar 

  • Mettin, R.R., Merkenschlager, A., Bernhard, M.K., Elix, H., Hirsch, W., Kiess, W., and Syrbe, S. (2014). Wide spectrum of clinical manifestations in children with tuberous sclerosis complex–Follow-up of 20 children. Brain Dev 36, 306–314.

    Article  PubMed  Google Scholar 

  • Monteiro, T., Garrido, C., Pina, S., Chorão, R., Carrilho, I., Figueiroa, S., Santos, M., and Temudo, T. (2014). Esclerosis tuberosa: caracterización clínica e intento de correlación fenotipo/genotipo. Anales de Pediatría 81, 289–296.

    Article  CAS  PubMed  Google Scholar 

  • Nellist, M., Brouwer, R.W.W., Kockx, C.E.M., van Veghel-Plandsoen, M., Withagen-Hermans, C., Prins-Bakker, L., Hoogeveen-Westerveld, M., Mrsic, A., van den Berg, M.M.P., Koopmans, A.E., de Wit, M.C., Jansen, F.E., Maat-Kievit, A.J.A., van den Ouweland, A., Halley, D., de Klein, A., and van IJcken, W.F.J. (2015). Targeted Next Generation Sequencing reveals previously unidentified TSC1 and TSC2 mutations. BMC Med Genet 16, 10.

    Article  PubMed  PubMed Central  Google Scholar 

  • Osborne, J.P., Fryer, A., and Webb, D. (1991). Epidemiology of tuberous sclerosis. Ann NY Acad Sci 615, 125–127.

    Article  CAS  PubMed  Google Scholar 

  • Orlova, K.A., and Crino, P.B. (2010). The tuberous sclerosis complex. Ann New York Acad Sci 1184, 87–105.

    Article  CAS  Google Scholar 

  • Roach, E.S., DiMario, F.J., Kandt, R.S., and Northrup, H. (1999). Tuberous Sclerosis Consensus Conference: recommendations for diagnostic evaluation. J Child Neurology 14, 401–407.

    Article  CAS  Google Scholar 

  • Rodrigues, D.A., Gomes, C.M., and Costa, I.M.C. (2012). Tuberous sclerosis complex. An Bras Dermatol 87, 184–196.

    Article  PubMed  Google Scholar 

  • Schwartz, R.A., Fernández,.G, Kotulska, K., and Józwiak, S. (2007). Tuberous sclerosis complex: Advances in diagnosis, genetics, and management. J Am Acad Dermatol 57, 189–202.

    Article  PubMed  Google Scholar 

  • Shields, C.L., Benevides, R., Materin, M.A., and Shields, J.A. (2006). Optical coherence tomography of retinal astrocytic hamartoma in 15 cases. Ophthalmology 113, 1553–1557.

    Article  PubMed  Google Scholar 

  • van Slegtenhorst, M., deHoogt, R., Hermans, C., Nellist, M., Janssen, B., Verhoef, S., Lindhout, D., van den Ouweland, A., Halley, D., Young, J., Burley, M., Jeremiah, S., Woodward, K., Nahmias, J., Fox, M., Ekong, R., Osborne, J., Wolfe, J., Povey, S., Snell, R.G., Cheadle, J.P., Jones, A.C., Tachataki, M., Ravine, D., Sampson, J.R., Reeve, M.P., Richardson, P., Wilmer, F., Munro, C., Hawkins, T.L., Sepp, T., Ali, J.B., Ward, S., Green, A.J., Yates, J.R., Kwiatkowska, J., Henske, E.P., Short, M.P., Haines, J.H., Jozwiak, S., and Kwiatkowski, D.J. (1997). Identification of the tuberous sclerosis gene TSC1 on Chromosome 9q34. Science 277, 805–808.

    Article  PubMed  Google Scholar 

  • Staley, B.A., Vail, E.A., and Thiele, E.A. (2011). Tuberous sclerosis complex: diagnostic challenges, presenting symptoms, and commonly missed signs. Pediatrics 127, e117–e125.

    Article  PubMed  Google Scholar 

  • Toyoshima, M., Ohno, K., Katsumoto, T., Maki, H., and Takeshita, K. (1999). Cellular senescence of angiofibroma stroma cells from patients with tuberous sclerosis. Brain Dev 21, 184–191.

    Article  CAS  PubMed  Google Scholar 

  • Wilson, P.J., Ramesh, V., Kristiansen, A., Bove, C., Jozwiak, S., Kwiatkowski, D.J., Short, M.P., and Haines, J.L. (1996). Novel mutations detected in the TSC2 gene from both sporadic and familial TSC patients. Hum Mol Genet 5, 249–256.

    Article  CAS  PubMed  Google Scholar 

  • Xu, L., Burke, T.R., Greenberg, J.P., Mahajan, V.B., and Tsang, S.H. (2012). Infrared imaging and optical coherence tomography reveal early-stage astrocytic hamartomas not detectable by fundoscopy. Am J Ophthalmol 153, 883–889.e2.

    Article  PubMed  PubMed Central  Google Scholar 

  • Yamamoto, T., Pipo, J.R., Feng, J.H., Takeda, H., Nanba, E., Ninomiya, H., and Ohno, K. (2002). Novel TSC1 and TSC2 mutations in Japanese patients with tuberous sclerosis complex. Brain Dev 24, 227–230.

    Article  PubMed  Google Scholar 

  • Yates, J.R.W. (2006). Tuberous sclerosis. Eur J Hum Genet 14, 1065–1073.

    Article  CAS  PubMed  Google Scholar 

  • Zimmer-Galler, I.E., and Robertson, D.M. (1995). Long-term observation of retinal lesions in tuberous sclerosis. Am J Ophthalmol 119, 318–324.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by the Capital Health Research and Development of Special (2014-1-4091).

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  1. Contributed equally to this work

Authors and Affiliations

  1. Department of Ophthalmology, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, 100045, China

    Dayong Bai, Junyang Zhao & Li Li

  2. Department of Radiology, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, 100045, China

    Jun Gao

  3. Department of Neurology, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, 100045, China

    Xu Wang

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  1. Dayong Bai
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  5. Xu Wang
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Correspondence to Xu Wang.

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Bai, D., Zhao, J., Li, L. et al. Analysis of genotypes and phenotypes in Chinese children with tuberous sclerosis complex. Sci. China Life Sci. 60, 763–771 (2017). https://doi.org/10.1007/s11427-017-9091-x

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