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Treatment of tuberous sclerosis complex manifestations in children with mTOR inhibitors

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Abstract

Purpose

Tuberous sclerosis complex (TSC) is a rare autosomal dominant genetic disorder that affects multiple organ systems. Mutations in the TSC1 and TSC2 genes result in the constitutive hyperactivation of the mammalian target of rapamycin (mTOR) pathway, contributing to the growth of benign tumors or hamartomas in various organs. Due to the implication of mTOR pathway dysregulation in the disease pathology, increasing evidence supports the use of mTOR inhibitors for treating multiple manifestations of TSC.

Methods

In this study, we conducted a retrospective analysis of clinical findings and treatment data from 38 patients diagnosed with tuberous sclerosis who were followed up in the Pediatric Oncology Clinic between 2010 and 2020. We collected information on patients’ ages, genders, affected sites, familial history, imaging findings, presence of tumors, and treatments.

Results

Among the patients, nine individuals with TSC manifestations were treated with mTOR inhibitors. Specifically, everolimus was successfully administered to five patients with inborn cardiac rhabdomyoma causing hemodynamic impairment. In addition, two patients with refractory seizures received everolimus in combination with anti-epileptic drugs. A patient with renal angiomyolipomas larger than 3 cm was treated with everolimus, while a patient with extensive facial angiofibroma received topical sirolimus. All patients tolerated the mTOR inhibitors well, and the side effects were deemed acceptable.

Conclusion

The utilization of mTOR inhibition in TSC is expected to become more prevalent in clinical practice, as current research is anticipated to provide a better understanding of the therapeutic roles of these treatments in TSC.

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References

  1. -Curatolo P, Bombardieri R, Jozwiak S (2008) Tuberous sclerosis. Lancet 372:657–668

    Article  CAS  PubMed  Google Scholar 

  2. -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 

  3. -van Slegtenhorst M, de Hoogt R, Hermans C et al (1997) Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34. Science 277:805–808

    Article  CAS  PubMed  Google Scholar 

  4. -Schwartz RA, Fernández G, Kotulska K et al (2007) Tuberous sclerosis complex: advances in diagnosis, genetics, and management. J Am Acad Dermatol 57:189–202

    Article  PubMed  Google Scholar 

  5. Krueger DA, 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 

  6. Krueger DA, Northrup H (2013) Tuberous sclerosis complex diagnostic criteria update: recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference. Pediatr Neurol 49:243–254

    Article  PubMed  PubMed Central  Google Scholar 

  7. -Uysal SP, Şahin M (2020) Tuberous sclerosis: a review of the past, present, and future. Turk J Med Sci 50:1665–1676

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. -Hofbauer GF, Marcollo-Pini A, Corsenca A et al (2008) The mTOR inhibitor rapamycin significantly improves facial angiofibroma lesions in a patient with tuberous sclerosis. Br J Dermatol 159:473–475

    Article  CAS  PubMed  Google Scholar 

  9. -Merkel S, Mogilevskaja N, Mengel M et al (2006) Side effects of sirolimus. Transplant Proc. 38:714-5

  10. -Wataya-Kaneda M, Tanaka M, Nakamura A et al (2011) A topical combination of rapamycin and tacrolimus for the treatment of angiofibroma due to tuberous sclerosis complex (TSC): a pilot study of nine Japanese patients with TSC of different Disease severity. Br J Dermatol 165:912–916

    Article  PubMed  Google Scholar 

  11. -Cinar LS, Kartal D, Bayram AK et al (2017) Topical sirolimus for the treatment of angiofibromas in tuberous sclerosis. Indian J Dermatology Venereol Leprology 83(1):27–32

    Article  Google Scholar 

  12. -Kingswood JC, Jozwiak S, Belousova ED et al (2014) The effect of everolimus on renal angiomyolipoma in patients with tuberous sclerosis complex being treated for subependymal giant cell astrocytoma: subgroup results from the randomized, placebo-controlled, phase 3 trial EXIST-1. Nephrol Dial Transplant 29:1203–1210

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. -Bissler JJ, Kingswood JC, Radzikowska E et al (2013) Everolimus for Angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis (EXIST-2): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet 381:817–824

    Article  CAS  PubMed  Google Scholar 

  14. -Bissler JJ, Kingswood JC, Radzikowska E et al (2016) Everolimus for renal angiomyolipoma in patients with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis: extension of a randomized controlled trial. Nephrol Dial Transplant 31:111–119

    Article  CAS  PubMed  Google Scholar 

  15. -Bissler JJ, Radzikowska E, Zonnenberg BA et al (2016) Everolimus for renal angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis: final long-term results from EXIST-2. Munich: Presented at the 31st European Association of Urology (EAU) Annual Congress

  16. -Kapoor A, Girard L, Lattouf JB et al (2016) Evolving strategies in the treatment of Tuberous Sclerosis Complexassociated Angiomyolipomas (TSC-AML). Urology 89:19–26

    Article  PubMed  Google Scholar 

  17. -Cai Y, Guo H, Wang W et al (2018) Assessing the outcomes of everolimus on renal angiomyolipoma associated with tuberous sclerosis complex in China: a two years trial. Orphanet J Rare Dis 13:43

    Article  PubMed  PubMed Central  Google Scholar 

  18. -Bissler JJ, McCormack FX, Young LR et al (2008) Sirolimus for Angiomyolipoma in tuberous sclerosis complex or lymphangioleiomyomatosis. N Engl J Med 358:140–151

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. -Luo C, Ye WR, Zu XB et al (2021) Low-dose Everolimus maintenance therapy for renal Angiomyolipoma Associated with Tuberous Sclerosis Complex. Front Med 8:744050

    Article  Google Scholar 

  20. -Hinton RB, Prakash A, Romp RL et al (2014) International Tuberous Sclerosis Consensus Group. Cardiovascular manifestations of tuberous sclerosis complex and summary of the revised diagnostic criteria and surveillance and management recommendations from the International Tuberous Sclerosis Consensus Group. J Am Heart Assoc 3(6):e001493

    Article  PubMed  PubMed Central  Google Scholar 

  21. -Staley BA, Vail EA, Thiele EA (2011) Tuberous sclerosis complex: diagnostic challenges, presenting symptoms, and commonly missed signs. Pediatrics 127:e117–e125

    Article  PubMed  Google Scholar 

  22. -DiMario FJ Jr (2004) Brain abnormalities in tuberous sclerosis complex. J Child Neurol 19:650–657

    Article  PubMed  Google Scholar 

  23. -Thiele EA (2004) Managing Epilepsy in tuberous sclerosis complex. J Child Neurol 19:680–686

    Article  PubMed  Google Scholar 

  24. -Chu-Shore CJ, Major P, Camposano S et al (2010) The natural history of Epilepsy in tuberous sclerosis complex. Epilepsia 51:1236–1241

    Article  PubMed  Google Scholar 

  25. -Franz DN, Capal JK (2017) mTOR inhibitors in the pharmacologic management of tuberous sclerosis complex and their potential role in other rare neurodevelopmental disorders. Orphanet J Rare Dis 51:1–9

    Google Scholar 

  26. -French JA, Lawson JA, Yapici Z et al (2016) Adjunctive everolimus therapy for treatment-resistant focal-onset seizures associated with tuberous sclerosis (EXIST-3): a phase 3, randomised, doubleblind, placebo-controlled study. Lancet 388:2153–2163

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Pediatric Hematology and Oncology, Ankara Etlik Integrated Health Campus, Ankara, Turkey

    Şule Yeşil, Burçak Kurucu & Melda Berber Hamamcı

  2. Department of Pediatric Radiology, Ankara Etlik Integrated Health Campus, Ankara, Turkey

    Şükriye Yılmaz

  3. Dr. Sami Ulus Maternity and Children’s Health and Diseases Training and Research Hospital, Department of Pediatric Hematology and Oncology, Ankara, Turkey

    Gürses Şahin

Authors
  1. Şule Yeşil
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  2. Burçak Kurucu
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  3. Melda Berber Hamamcı
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  4. Şükriye Yılmaz
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  5. Gürses Şahin
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Contributions

A wrote the main manuscript. D prepared Fig. 2a-d All authors.

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Correspondence to Şule Yeşil.

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Yeşil, Ş., Kurucu, B., Hamamcı, M.B. et al. Treatment of tuberous sclerosis complex manifestations in children with mTOR inhibitors. Childs Nerv Syst 40, 831–837 (2024). https://doi.org/10.1007/s00381-023-06218-2

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  • DOI: https://doi.org/10.1007/s00381-023-06218-2

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