We found evidence that oral everolimus significantly increased the proportion of people who achieved a 50% reduction in the size of sub-ependymal giant cell astrocytoma and renal angiomyolipoma. Although we were unable to ascertain the relationship between the reported adverse events and the treatment, participants who received treatment had a similar risk of experiencing adverse events as compared to those who did not receive treatment. Nevertheless, the treatment itself significantly increased the risk of having dose reduction, interruption or withdrawal. This supports ongoing clinical applications of oral everolimus for renal angiomyolipoma and subependymal giant cell astrocytoma. Although oral everolimus showed beneficial effect on skin lesions, topical rapamycin only showed a non-significant tendency of improvement. Efficacy on skin lesions should be further established in future research. The beneficial effects of rapamycin or rapalogs on tuberous sclerosis complex should be further studied on other manifestations of the condition.

Tuberous sclerosis complex (TSC) is an autosomal dominant neurocutaneous disorder characterized by tumor growth in multiple organs and caused by mutations in either TSC1 or TSC2 genes. Because of their relatively large genomic sizes, absence of hotspots, and common type of mutations, mutation detection in TSC1 and TSC2 genes has been challenging. We devised a combination of multiple ligation-dependent probe amplification (MLPA) and amplicon sequencing (AS) to simplify the detection strategy, yet we come up with reasonably high detection rate. Thirty-four Malaysian patients diagnosed with TSC were referred to Human Genome Center, Universiti Sains Malaysia. We used a combination of MLPA to detect large copy number changes and AS to detect smaller mutations. TSC1 pathogenic or likely pathogenic mutations were found in 6 patients (18%) and TSC2 in 21 patients (62%), whereas 6 patients (18%) show no mutations and 1 patient (2%) showed only TSC2 missense variant with uncertain significance. Six of the mutations are novel. Our detection strategy costs 81% less and require 1 working week less than the conventional strategy. Confirmatory sequencing using Sanger method on a few representative mutations showed agreement with results of the AS. Combination of MLPA and Illumina MiSeq AS provides a simplified strategy and reasonably high detection rate for TSC1/TSC2 mutation, which suggested application of the strategies into clinical molecular diagnostics.

BackgroundRapamycin has gained significant attention for its potential activity in reducing the size of TSC-associated tumors, thus providing alternative to surgery. This study aimed at determining the efficacy of rapamycin and rapalogs for reducing the size of TSC-associated solid tumors in patients with Tuberous Sclerosis Complex (TSC).MethodsOur data sources included electronic searches of the PubMed. We included into our meta-analysis any type of non-randomized study that reported the use of rapamycin and rapalogs for reducing the size of TSC-associated solid tumors in patients with TSC. Data was entered into Cochrane Review Manager Version 5.3 and analyzed.ResultsFour case reports and 4 clinical trials were included. Five patients from the case reports (all with SEGA) and 91 patients from the clinical trials (41 with SEGA, 63 with kidney angiomyolipoma and 5 with liver angiomyolipoma) were included into the analysis. Volume and diameter of SEGAs were significantly reduced by mean difference of 1.23 cc (95 % CI −2.32 to −0.13; p = 0.03) and 7.91 mm (95 % CI −11.82 to −4.01; p < 0.0001), respectively. Volume and mean of sum of longest diameter of kidney angiomyolipomas were significantly reduced by mean difference of 39.5 cc (95 % CI −48.85 to −30.15; p <0.00001) and 69.03 mm (95 % CI −158.05 to 12.65; p = 0.008), respectively. In liver angiomyolipomas, however, reduction in tumor size was not evident. Sum of longest diameter of liver angiomyolipomas in 4 patients were enlarged by 2.7 mm (95 % CI 28.42 to −23.02) by the end of treatment, though not significant (p = 0.84).ConclusionsRapamycin and rapalogs showed efficacy towards reducing the size of SEGA and kidney angiomyolipoma but not liver angiomyolipomas. This finding is strengthening the conclusion of our Cochrane systematic review on the randomized trials.

Tuberous sclerosis complex is an autosomal dominant neurocutaneous disorder affecting multiple organs. Tuberous sclerosis complex is caused by mutation in either one of the two disease-causing genes, TSC1 or TSC2, encoding for hamartin and tuberin, respectively. TSC2/PKD1 contiguous gene deletion syndrome is a very rare condition due to deletion involving both TSC2 and PKD1 genes. Tuberous sclerosis complex cannot be easily diagnosed since there is no pathognomonic feature, although there are consensus diagnostic criteria for that. Mutation analysis is useful and plays important roles. We report here two novel gross deletions of TSC2 gene in Malay patients with tuberous sclerosis complex and TSC2/PKD1 contiguous gene deletion syndrome, respectively.

A 10-year-old girl with mixed Malaysian -Burmese parentage under follow-up for tuberous sclerosis complex (TSC), epilepsy and mental retardation was noted to have a slow enlargement of her right thumb and index finger over a 5-year duration (Fig. 1). A white patch on the head (poliosis) was also present (Fig. 2). The diagnosis of TSC was confirmed by the presence of hypomelanotic macules, cortical tubers, subependymal nodules, periungual fibroma and poliosis. Although our molecular genetic analyses of TSC1 and TSC2 in this patient failed to identify any disease-causing mutation, information on genetic mutation is not mandatory in establishing TSC diagnosis. Magnetic resonance imaging scan of the brain showed cortical tubers (Fig. 3-white arrows) as well as subependymal nodules (Fig. 3-black arrows). X-ray of the right hand showed irregular periosteal new bone formation (Fig. 4). Her epilepsy is currently controllable by medication but she remains mentally retarded.TSC has been associated with numerous tumor growths in various organs such as brain, retina, lung, heart, kidney, ovaries and testis. However, the involvement of new bone formation and soft tissue overgrowth has not been commonly described. We postulate that the macrodactyly is a form of tumorigenesis. Tumorigenesis has been associated with the pathogenesis of TSC. Our finding of macrodactyly has not been described in the current diagnostic criteria for TSC (2013) and thus could be an addition to the existing clinical features of TSC.

No abstract

No abstract