Imataka George, Mori Satoshi, Yui Kunio, Igawa Ken, Shiraishi Hideaki, Yoshihara Shigemi
Department of Pediatrics, Dokkyo Medical University, Tochigi 321-0293, Japan.
Department of Dermatology, Dokkyo Medical University, Tochigi 321-0293, Japan.
Diseases. 2024 Dec 20;12(12):334. doi: 10.3390/diseases12120334.
Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder characterized by mutations in the TSC1 and TSC2 genes, leading to the dysregulation of the mammalian target of rapamycin (mTOR) pathway. This dysregulation results in the development of benign tumors across multiple organ systems and poses significant neurodevelopmental challenges. The clinical manifestations of TSC vary widely and include subependymal giant cell astrocytomas (SEGAs), renal angiomyolipomas (AMLs), facial angiofibromas (FAs), and neuropsychiatric conditions such as autism spectrum disorder (ASD). mTOR inhibitors, notably everolimus, have become central to TSC management, with documented efficacy in reducing the sizes of SEGAs and AMLs and showing promise in addressing additional TSC-related symptoms.
We report the case of an 11-year-old male diagnosed with TSC, presenting with hallmark features including hypopigmented macules, early-onset infantile spasms, SEGA, and AMLs. Initial interventions included adrenocorticotropic hormone (ACTH) therapy and sodium valproate for seizure management and a minimally invasive keyhole craniotomy for SEGA reduction. At age 12, oral everolimus therapy was introduced to address both SEGA recurrence risk and ASD-related social deficits. Over the course of 24 weeks, a reduction in the size and erythema of the patient's FAs was observed, alongside improvements in social engagement, suggesting potential added benefits of systemic mTOR inhibition beyond tumor control.
Treatment with everolimus over a 24-month period led to significant reductions in both FA and AML size, as well as measurable improvements in ASD-associated behaviors. Therapeutic drug monitoring maintained serum levels within the effective range, minimizing adverse effects and underscoring the tolerability and feasibility of long-term everolimus administration.
This case underscores the efficacy of oral everolimus in reducing FA size in a pediatric TSC patient, with broader therapeutic benefits that support the potential of mTOR inhibition as a multi-targeted strategy for TSC management. Further studies are needed to explore the full range of applications and long-term impact of mTOR inhibitors in TSC care.
结节性硬化症（TSC）是一种常染色体显性遗传病，其特征为TSC1和TSC2基因发生突变，导致雷帕霉素哺乳动物靶点（mTOR）信号通路失调。这种失调会导致多个器官系统出现良性肿瘤，并带来重大的神经发育挑战。TSC的临床表现差异很大，包括室管膜下巨细胞星形细胞瘤（SEGA）、肾血管平滑肌脂肪瘤（AML）、面部血管纤维瘤（FA）以及神经精神疾病，如自闭症谱系障碍（ASD）。mTOR抑制剂，尤其是依维莫司，已成为TSC治疗的核心药物，已证明其在缩小SEGA和AML大小方面有效，并在解决其他TSC相关症状方面显示出前景。
我们报告一例11岁男性TSC患者，其具有色素减退斑、早发性婴儿痉挛、SEGA和AML等典型特征。初始干预措施包括使用促肾上腺皮质激素（ACTH）疗法和丙戊酸钠控制癫痫发作，并进行微创锁孔开颅手术以缩小SEGA。12岁时，开始口服依维莫司治疗，以应对SEGA复发风险和与ASD相关的社交缺陷。在24周的疗程中，观察到患者FA的大小和红斑减少，同时社交参与度有所改善，这表明全身mTOR抑制除了控制肿瘤外可能还有其他益处。
依维莫司治疗24个月导致FA和AML大小显著减小，同时ASD相关行为有可测量的改善。治疗药物监测将血清水平维持在有效范围内，将不良反应降至最低，突出了长期服用依维莫司的耐受性和可行性。
该病例强调了口服依维莫司在减少儿科TSC患者FA大小方面的疗效，其具有更广泛的治疗益处，支持mTOR抑制作为TSC多靶点治疗策略的潜力。需要进一步研究以探索mTOR抑制剂在TSC治疗中的全面应用和长期影响。
