Background: Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disease affecting multiple body systems with wide variability in presentation. In 2013, Pediatric Neurology published articles outlining updated diagnostic criteria and recommendations for surveillance and management of disease manifestations. Advances in knowledge and approvals of new therapies necessitated a revision of those criteria and recommendations. Methods: Chairs and working group cochairs from the 2012 International TSC Consensus Group were invited to meet face-to-face over two days at the 2018 World TSC Conference on July 25 and 26 in Dallas, TX, USA. Before the meeting, working group cochairs worked with group members via e-mail and telephone to (1) review TSC literature since the 2013 publication, (2) confirm or amend prior recommendations, and (3) provide new recommendations as required. Results: Only two changes were made to clinical diagnostic criteria reported in 2013: "multiple cortical tubers and/or radial migration lines" replaced the more general term "cortical dysplasias," and sclerotic bone lesions were reinstated as a minor criterion. Genetic diagnostic criteria were reaffirmed, including highlighting recent findings that some individuals with TSC are genetically mosaic for variants in TSC1 or TSC2. Changes to surveillance and management criteria largely reflected increased emphasis on early screening for electroencephalographic abnormalities, enhanced surveillance and management of TSCassociated neuropsychiatric disorders, and new medication approvals. Conclusions: Updated TSC diagnostic criteria and surveillance and management recommendations presented here should provide an improved framework for optimal care of those living with TSC and their families.
Subscribe to PCMR and stay up-to-date with the only journal committed to publishing basic research in melanoma and pigment cell biology As a member of the IFPCS or the SMR you automatically get online access to PCMR. Sign up as a member today at www.ifpcs.org or at www.societymelanomaresarch.org dramatically induced IL-1b, IL-6, and TNF-a production in skin-resident cells such as keratinocytes and fibroblasts. Our results provide evidence of the influence of a complex Th17 cell-related cytokine environment in local depigmentation in addition to CD8 + cell-mediated melanocyte destruction in autoimmune vitiligo.
Inhibitors of mammalian target of rapamycin complex 1, such as sirolimus, effectively target skin lesions in tuberous sclerosis complex (TSC). However, systemic treatment causes adverse effects, and topical sirolimus has shown promise in the treatment of facial angiofibromas.OBJECTIVE To evaluate the efficacy, safety, and optimal concentration of a topical sirolimus gel vs placebo for treatment of facial angiofibromas in TSC. DESIGN, SETTING, AND PARTICIPANTSA double-blind, placebo-controlled, parallel-group, dose-escalation, phase 2 randomized clinical trial using 3 sirolimus gel concentrations was performed at
Skin and dental findings comprise 4 of 11 major features and 3 of 6 minor features in the diagnostic criteria. A definite diagnosis of TSC is defined as the presence of at least 2 major features or 1 major and 2 or more minor features; in addition, a pathological mutation in TSC1 or TSC2 is diagnostic. Skin and oral examinations should be performed annually and every 3 to 6 months, respectively. Intervention may be indicated for TSC skin or oral lesions that are bleeding, symptomatic, disfiguring, or negatively affecting function. Options presented include surgical excision, laser(s), or use of a mammalian target of rapamycin inhibitor.
Tuberous sclerosis complex (TSC) is an autosomal dominant disorder with multi-system involvement and variable manifestations. There has been significant progress in TSC research and the development of technologies used to diagnose this disorder. As a result, individuals with mild TSC are now being diagnosed, including many older adults who have not developed seizures or cognitive abnormalities. We conducted a statistical analysis of the frequency of TSC manifestations in a population of Japanese adults and children, comparing our findings with historical data. The chi-square test was used to examine the frequency of each manifestation by age. A total of 166 outpatients at the Department of Dermatology of Osaka University Hospital during the period from January 2001 to March 2011 were included in the study. Compared to previous reports, the frequency of neurologic manifestations (excepting autism) was lower in this cohort, and the frequency of skin manifestations (excepting hypomelanotic macules) was higher in this cohort. The frequencies of pulmonary lymphangioleiomyomatosis and renal manifestations were not significantly different from those previously reported. Regarding the association of each manifestation with age, the frequency of neurologic manifestations (excepting subependymal giant cell astrocytoma) was significantly higher in younger patients than in older patients. The frequency of skin manifestations and renal angiomyolipoma were significantly higher in older patients than in younger patients. Because of their high frequency and visibility, skin manifestations are useful in the diagnosis of TSC. Moreover, uterine perivascular epithelioid cell tumor was also characterized as a new findings associated with TSC.
IMPORTANCE Most patients with tuberous sclerosis complex (TSC), an autosomal-dominant disorder that is caused by the constitutive activation of mammalian target of rapamycin, experience disfigurement caused by skin lesions involving facial angiofibromas. Many have been left untreated because of a lack of therapeutic options that are less invasive than surgery or laser treatment. OBJECTIVE To confirm the efficacy and safety of sirolimus gel, 0.2%, for treatment of patients with angiofibromas and/or skin lesions. DESIGN, SETTING, AND PATIENTS Multicenter, randomized clinical trial at 9 centers in Japan from December 2015 to October 2016 including 62 children and adults with TSC. INTERVENTIONS Patients who developed angiofibromas were randomly assigned, in a 1:1 ratio, to receive sirolimus gel, 0.2%, or placebo, each applied topically twice daily for 12 weeks. MAIN OUTCOMES AND MEASURES The primary end point was composite improvement in the size and color of angiofibromas in photographs at week 12 of treatment. It was assessed by an independent review committee comprising 3 blinded dermatologists who categorized patient results into the following 6 categories: "markedly improved," "improved," "slightly improved," "unchanged," "slightly aggravated," and "aggravated." RESULTS Sixty-two patients (27 pediatric and 35 adult; 34 [55%] female; mean [SD] age, 22.5 [11.9] years) were enrolled and randomly assigned to receive sirolimus gel, 0.2% (30 patients), or placebo (32 patients). The response rates of angiofibromas at weeks 4, 8, and 12 of treatment were 0 each in the placebo group in contrast to 20% (95% CI, 8%-39%; P = .01), 43% (95% CI, 26%-63%; P < .001), and 60% (95% CI, 41%-77%; P < .001), respectively, in the sirolimus group. None of the 31 assessable patients in the placebo group were rated improved or better, and 26 of them (84%) were rated unchanged. In contrast, 5 (17%) and 13 (43%) patients in the sirolimus group were rated markedly improved and improved, respectively. Adverse events were mild to moderate and were observed in 27 (90%) and 22 (69%) patients in the sirolimus and placebo groups, respectively; however, none of the trial participants discontinued treatment. Acute pancreatitis developed as a serious adverse event in 1 patient in the sirolimus group, and the patient recovered soon after hospitalization without discontinuing treatment. CONCLUSIONS AND RELEVANCE Sirolimus gel, 0.2%, demonstrated a significant clinical benefit for patients with TSC involving angiofibromas, thus providing a promising therapeutic modality.
SummaryBackground Tuberous sclerosis complex (TSC) is an autosomal dominant disorder causing multiple hamartomas. Treatment of TSC lesions with mammalian target of rapamycin inhibitors is effective. Recently, several reports have shown the efficacy of topical rapamycin (sirolimus) for angiofibromas. However, almost all studies have been case studies and the 0Á1% solution caused skin irritation. A comparative study of topical rapamycin and a vehicle has not yet been reported. Objectives To compare the efficacy of topical rapamycin formulation with that of vehicle for angiofibromas. Methods A left-right comparative study between rapamycin 0Á2% topical formulation and vehicle was conducted in 11 patients with TSC. Two formulations, an ointment and a gel, were prepared and in vitro percutaneous absorption of rapamycin was determined. Results In vitro percutaneous absorption of rapamycin was significantly greater with the gel compared with the ointment. In the clinical study, the rapamycin-treated cheek showed significant improvements relative to the vehicle-treated cheek in all outcome measures after 12 weeks of treatment. The improvement was particularly remarkable in children aged ≤ 10 years. No side-effects were noted, and rapamycin was not detected in the blood of the patients. Conclusions Topical rapamycin was significantly effective against angiofibromas. Both formulations used were effective and safe. The 0Á2% gel is especially useful because of its better skin penetration and low irritancy. Initiation of topical rapamycin therapy in early childhood would be beneficial for patients with TSC.
Tuberous sclerosis complex is an autosomal dominant inherited disorder characterized by generalized involvement and variable manifestations with a birth incidence of 1:6000. In a quarter of a century, significant progress in tuberous sclerosis complex has been made. Two responsible genes, TSC1 and TSC2, which encode hamartin and tuberin, respectively, were discovered in the 1990s, and their functions were elucidated in the 2000s. Hamartin-Tuberin complex is involved in the phosphoinositide 3-kinase-protein kinase B-mammalian target of rapamycin signal transduction pathway, and suppresses mammalian target of rapamycin complex 1 activity, which is a center for various functions. Constitutive activation of mammalian target of rapamycin complex 1 causes variable manifestations in tuberous sclerosis complex. Recently, genetic tests were launched to diagnose tuberous sclerosis complex, and mammalian target of rapamycin complex 1 inhibitors are being used to treat tuberous sclerosis complex patients. As a result of these advances, new diagnostic criteria have been established and an indispensable new treatment method; that is, "a cross-sectional medical examination system," a system to involve many experts for tuberous sclerosis complex diagnosis and treatments, was also created. Simultaneously, the frequency of genetic tests and advances in diagnostic technology have resulted in new views on symptoms. The numbers of tuberous sclerosis complex patients without neural symptoms are increasing, and for these patients, renal manifestations and pulmonary lymphangioleiomyomatosis have become important manifestations. New concepts of tuberous sclerosis complex-associated neuropsychiatric disorders or perivascular epithelioid cell tumors are being created. The present review contains a summary of recent advances, significant manifestations and therapy in tuberous sclerosis complex.
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