Tuberous Sclerosis Complex Patient Research Articles

Radiosensitivity in individuals with tuberous sclerosis complex

Benign tumors, but rarely cancer, are common in patients with tuberous sclerosis complex (TSC). Blood samples from patients undergoing treatment for TSC at our institution were analyzed for their individual sensitivity to ionizing radiation. Blood samples were collected from 13 adult patients with TSC. The samples were irradiated ex vivo and analyzed by 3-color fluorescence in situ hybridization. In each patient, aberrations were analyzed in 200 metaphases of chromosomes 1, 2, and 4 and scored as breaks. Radiosensitivity was determined by mean breaks per metaphase (B/M) and compared to both healthy donors and oncologic patients. The radiosensitivity (B/M) of the TSC patient cohort (n = 13; female: 46.2%, B/M: 0.48 ± 0.11) was clearly increased compared to healthy individuals of similar age (n = 90; female: 54.4%; B/M: 0.40 ± 0.09; p = 0.001). There was no difference compared to age-matched oncological patients (n = 78; female: 67.9%; B/M 0.49 ± 0.14; p = 0.246). Similarly, the proportion of radiosensitive (B/M > 0.5) and distinctly radiosensitive individuals (B/M > 0.6) was increased in the TSC and oncological patient cohorts (TSC: 30.8% and 7.7%, oncological patients: 46.2% and 14.1%) compared to the healthy individuals (11.1% and 2.2%). Although patients with TSC develop mostly benign and rarely malignant tumors, they are similarly sensitive to radiation as patients with malignant tumors.

Neoadjuvant everolimus in renal angiomyolipoma with or without tuberous sclerosis complex: Results from a multicenter, retrospective study.

To assess the efficacy and safety of preoperative neoadjuvant everolimus in renal angiomyolipomas (AML) patients with or without Tuberous Sclerosis Complex (TSC). This multi-institutional retrospective study enrolled renal AML patients who underwent partial nephrectomy (PN) or total nephrectomy after receiving at least 1 month of pre-operative everolimus. Imaging evaluations were collected before and after treatment, along with demographic, surgical, and follow-up information. The primary outcome was tumor volume reduction of ≥25%, with additional outcomes including recurrence, perioperative outcomes, renal function, and safety. From January 2015 to July 2022, 68 renal AML patients were studied-41 with TSC and 27 without. During everolimus treatment, 61.0% (25/41) of TSC patients and 44.4% (12/27) of non-TSC patients achieved tumor reduction of ≥25%. Additionally, 41.5% (17/41) of TSC patients and 18.5% (5/27) of non-TSC patients achieved a ≥ 50% reduction. Three TSC patients and 1 non-TSC patient discontinued treatment due to side-effects. Most patients (92.7% TSC, 85.2% non-TSC) underwent PN. After everolimus treatment, the necessary total nephrectomy decreased to 41.2% (7/17) from baseline. Postoperatively, 1 grade 3 and 3 grade 2 complications occurred, with no grade 4 or 5 complications. After a median follow-up of 24 months, only 1 TSC patient recurred with a diameter >3 cm. Retrospective nature is the major limitation of this study. Everolimus was effective and well-tolerated in neoadjuvant treatment for renal AML, especially in TSC patients. This neoadjuvant combination strategy of everolimus and PN could effectively controls recurrence and preserves renal function.

Aberrant TSC-Rheb axis in Oxytocin receptor+ cells mediate stress-induced anxiety.

Stress is a major risk for the onset of several maladaptive processes including pathological anxiety, a diffuse state of heightened apprehension over anticipated threats1. Pathological anxiety is prevalent in up to 59% of patients with Tuberous Sclerosis complex (TSC)2, a neurodevelopmental disorder (NDD) caused by loss-of-function mutations in genes for Tuberin (Tsc2) and/or Hamartin (Tsc1) that together comprise the eponymous protein complex. Here, we generated cell type-specific heterozygous knockout of Tsc2 in cells expressing oxytocin receptor (OTRCs) to model pathological anxiety-like behaviors observed in TSC patient population. The stress of prolonged social isolation induces a sustained negative affective state that precipitates behavioral avoidance, often by aberrant oxytocin signaling in the limbic forebrain3,4. In response to social isolation, there were striking sex differences in stress susceptibility in conditional heterozygote mice when encountering situations of approach-avoidance conflict. Socially isolated male mutants exhibited behavioral avoidance in anxiogenic environments and sought more social interaction for buffering of stress. In contrast, female mutants developed resilience during social isolation and approached anxiogenic environments, while devaluing social interaction. Systemic and medial prefrontal cortex (mPFC)-specific inhibition of downstream effector of TSC, the integrated stress response (ISR), rescued behavioral approach toward anxiogenic environments and conspecifics in male and female mutant mice respectively. Further, we found that Tsc2 deletion in OTRCs leads to OTR-signaling elicited network suppression, i.e., hypofrontality, in male mPFC, which is relieved by inhibiting the ISR. Our findings present evidence in support of a sexually dimorphic role of prefrontal OTRCs in regulating emotional responses in anxiogenic environments, which goes awry in TSC. Our work has broader implications for developing effective treatments for subtypes of anxiety disorders that are characterized by cell-autonomous ISR and prefrontal network suppression.

Rescue of impaired blood-brain barrier in tuberous sclerosis complex patient derived neurovascular unit

BackgroundTuberous sclerosis complex (TSC) is a multi-system genetic disease that causes benign tumors in the brain and other vital organs. The most debilitating symptoms result from involvement of the central nervous system and lead to a multitude of severe symptoms including seizures, intellectual disability, autism, and behavioral problems. TSC is caused by heterozygous mutations of either the TSC1 or TSC2 gene and dysregulation of mTOR kinase with its multifaceted downstream signaling alterations is central to disease pathogenesis. Although the neurological sequelae of the disease are well established, little is known about how these mutations might affect cellular components and the function of the blood–brain barrier (BBB).MethodsWe generated TSC disease-specific cell models of the BBB by leveraging human induced pluripotent stem cell and microfluidic cell culture technologies.ResultsUsing microphysiological systems, we demonstrate that a BBB generated from TSC2 heterozygous mutant cells shows increased permeability. This can be rescued by wild type astrocytes or by treatment with rapamycin, an mTOR kinase inhibitor.ConclusionOur results demonstrate the utility of microphysiological systems to study human neurological disorders and advance our knowledge of cell lineages contributing to TSC pathogenesis and informs future therapeutics.

Myocardial fatty foci on cardiac MRI in an adult with tuberous sclerosis complex.

We report cardiac MRI findings in a 38-year-old female Tuberous sclerosis complex (TSC) patient with regressed rhabdomyomas. Presence of myocardial fatty foci are associated with multiorgan involvement, although they are not a part of the current TSC diagnostic criteria. Presence of abnormal first pass perfusion and late Gadolinium enhancement in TSC patients should be carefully interpreted to avoid misdiagnosis.

Impaired GABAergic regulation and developmental immaturity in interneurons derived from the medial ganglionic eminence in the tuberous sclerosis complex

GABAergic interneurons play a critical role in maintaining neural circuit balance, excitation–inhibition regulation, and cognitive function modulation. In tuberous sclerosis complex (TSC), GABAergic neuron dysfunction contributes to disrupted network activity and associated neurological symptoms, assumingly in a cell type-specific manner. This GABAergic centric study focuses on identifying specific interneuron subpopulations within TSC, emphasizing the unique characteristics of medial ganglionic eminence (MGE)- and caudal ganglionic eminence (CGE)-derived interneurons. Using single-nuclei RNA sequencing in TSC patient material, we identify somatostatin-expressing (SST+) interneurons as a unique and immature subpopulation in TSC. The disrupted maturation of SST+ interneurons may undergo an incomplete switch from excitatory to inhibitory GABAergic signaling during development, resulting in reduced inhibitory properties. Notably, this study reveals markers of immaturity specifically in SST+ interneurons, including an abnormal NKCC1/KCC2 ratio, indicating an imbalance in chloride homeostasis crucial for the postsynaptic consequences of GABAergic signaling as well as the downregulation of GABAA receptor subunits, GABRA1, and upregulation of GABRA2. Further exploration of SST+ interneurons revealed altered localization patterns of SST+ interneurons in TSC brain tissue, concentrated in deeper cortical layers, possibly linked to cortical dyslamination. In the epilepsy context, our research underscores the diverse cell type-specific roles of GABAergic interneurons in shaping seizures, advocating for precise therapeutic considerations. Moreover, this study illuminates the potential contribution of SST+ interneurons to TSC pathophysiology, offering insights for targeted therapeutic interventions.

A rare association of insulinoma in tuberous sclerosis complex patient

A rare association of insulinoma in tuberous sclerosis complex patient

The effect of pregnancy on renal angiomyolipoma; a world of knowledge to gain, specifically in women with TSC

BackgroundWomen are counseled preconceptionally about the potential risks of rAML progression and chance of complications during and due to pregnancy. However, a systematic search investigating the evidence on which this advice is based does not exist. The aim of this systematic review is to determine the effect of pregnancy on renal angiomyolipoma (rAML) size and risk of haemorrhage in patients with tuberous sclerosis complex (TSC).MethodsWe searched PubMed, EMBASE, Medline and ClinicalTrials.gov using terms for “renal angiomyolipoma” and “pregnancy”. English-language articles published between January 1st 2000, and December 31st 2020 of which full-text was available were included. The initial search resulted in 176 articles. After the screening process we included 45 case reports and 1 retrospective study. For the retrospective study we assessed the risk of bias using the Newcastle–Ottawa Scale. We included articles about renal AML and pregnancy with and without an established diagnosis of TSC. From these articles we recorded the rAML sizes and rAML complications.ResultsSeven case reports, from a total of 45 case reports, provided follow-up data on renal AML size (these were all cases of renal AML without a known diagnosis of TSC). Of these cases, renal AML size decreased in one patient, was stable in one patient, increased in three patients and fluctuated in two others. Renal AML size of women who suffered a haemorrhage were significantly larger (12.1 ± 4.6 cm) than rAMLs of women who did not suffer a haemorrhage (8.3 ± 3.2 cm). Data from the retrospective study showed no difference in renal complications between the women with and without a history of pregnancy. Haemorrhage occurred in 30% of the women with a history of pregnancy (n = 20) and in 11% in the patients without a history of pregnancy (n = 2), however this retrospective study had methodological limitations.ConclusionThe effect of pregnancy on renal AML size and complications in patients with TSC is unclear. More research is needed to determine the risk of pregnancy on TSC-associated kidney disease in TSC patient.

Hyperactivation of mTORC1 in a double hit mutant zebrafish model of tuberous sclerosis complex causes increased seizure susceptibility and neurodevelopmental abnormalities.

Tuberous sclerosis complex (TSC) is a multisystem genetic disorder caused by pathogenic variants in TSC1 and TSC2 genes. TSC patients present with seizures and brain abnormalities such as tubers and subependymal giant cells astrocytoma (SEGA). Despite common molecular and clinical features, the severity of the disease varies greatly, even intrafamilially. The second hit hypothesis suggests that an additional, inactivating mutation in the remaining functional allele causes a more severe phenotype and therefore explains the phenotypic variability. Recently, second hit mutations have been detected frequently in mTORopathies. To investigate the pathophysiological effects of second hit mutations, several mouse models have been developed. Here, we opted for a double mutant zebrafish model that carries a LOF mutation both in the tsc2 and the depdc5 gene. To the best of our knowledge, this is the first time a second-hit model has been studied in zebrafish. Significantly, the DEP domain-containing protein 5 (DEPDC5) gene has an important role in the regulation of mTORC1, and the combination of a germline TSC2 and somatic DEPDC5 mutation has been described in a TSC patient with intractable epilepsy. Our depdc5 −/− x tsc2 −/− double mutant zebrafish line displayed greatly increased levels of mammalian target of rapamycin (mTORC1) activity, augmented seizure susceptibility, and early lethality which could be rescued by rapamycin. Histological analysis of the brain revealed ventricular dilatation in the tsc2 and double homozygotes. RNA-sequencing showed a linear relation between the number of differentially expressed genes (DEGs) and the degree of mTORC1 hyperactivity. Enrichment analysis of their transcriptomes revealed that many genes associated with neurological developmental processes were downregulated and mitochondrial genes were upregulated. In particular, the transcriptome of human SEGA lesions overlapped strongly with the double homozygous zebrafish larvae. The data highlight the clinical relevance of the depdc5 −/− x tsc2 −/− double mutant zebrafish larvae that showed a more severe phenotype compared to the single mutants. Finally, analysis of gene-drug interactions identified interesting pharmacological targets for SEGA, underscoring the value of our small zebrafish vertebrate model for future drug discovery efforts.

Tuberous sclerosis complex-associated nonfunctional pancreatic neuroendocrine tumors: Management and surgical outcomes.

We aimed to further characterize pancreatic involvement in tuberous sclerosis complex (TSC), with a focus on management of TSC-associated nonfunctional pancreatic neuroendocrine tumors (PNETs). This was a retrospective chart review of a large cohort of TSC patients. A total of 637 patients with a confirmed diagnosis of TSC were seen at the Herscot Center for Tuberous Sclerosis Complex at Massachusetts General Hospital. Of the 637 total patients with a confirmed diagnosis of TSC, 28 patients were found to have varying pancreatic findings ranging from simple-appearing cysts to well-differentiated PNETs. Thirteen of the 28 patients had PNET confirmed on pathology; 10 of these tumors were resected at Massachusetts General Hospital. None of the patients had serious perioperative or postoperative complications; only one of the patients had a recurrence following resection. As roughly 4.4% of our TSC patient population had pancreatic involvement, surveillance abdominal imaging should include evaluation of the pancreas instead of limiting to a renal protocol. Additionally, given the low risk of complications and recurrence combined with documented risk of metastasis in TSC-associated PNET, TSC patients with pancreatic lesions suspicious for PNETs should be considered as surgical candidates.

The association of neurodevelopmental abnormalities, congenital heart and renal defects in a tuberous sclerosis complex patient cohort

BackgroundTuberous sclerosis complex (TSC) is a rare multi-system genetic disorder characterised by the presence of benign tumours throughout multiple organs including the brain, kidneys, heart, liver, eyes, lungs and skin, in addition to neurological and neuropsychiatric complications. Intracardiac tumour (rhabdomyoma), neurodevelopmental disorders (NDDs) and kidney disorders (KD) are common manifestations of TSC and have been linked with TSC1 and TSC2 loss-of-function mutations independently, but the dynamic relationship between these organ manifestations remains unexplored. Therefore, this study aims to characterise the nature of the relationship specifically between these three organs’ manifestations in TSC1 and TSC2 mutation patients.MethodsClinical data gathered from TSC patients across South Wales registered with Cardiff and Vale University Health Board (CAV UHB) between 1990 and 2020 were analysed retrospectively to evaluate abnormalities in the heart, brain and kidney development. TSC-related abnormalities such as tumour prevalence, location and size were analysed for each organ in addition to neuropsychiatric involvement and were compared between TSC1 and TSC2 mutant genotypes. Lastly, statistical co-occurrence between organ manifestations co-morbidity was quantified, and trajectories of disease progression throughout organs were modelled.ResultsThis study found a significantly greater mutational frequency at the TSC2 locus in the cohort in comparison to TSC1. An equal proportion of male and female patients were observed in this group and by meta-analysis of previous studies. No significant difference in characterisation of heart involvement was observed between TSC1 and TSC2 patients. Brain involvement was seen with increased severity in TSC2 patients, characterised by a greater prevalence of cortical tubers and communication disorders. Renal pathology was further enhanced in TSC2 patients, marked by increased bilateral angiomyolipoma prevalence. Furthermore, co-occurrence of NDDs and KDs was the most positively correlated out of investigated manifestations, regardless of genotype. Analysis of disease trajectories revealed a more diverse clinical outcome for TSC2 patients: however, a chronological association of rhabdomyoma, NDD and KD was most frequently observed for TSC1 patients.ConclusionsThis study marks the first empirical investigation of the co-morbidity between congenital heart defects (CHD), NDDs, and KDs in TSC1 and TSC2 patients. This remains a unique first step towards the characterisation of the dynamic role between genetics, heart function, brain function and kidney function during the early development in the context of TSC.

Cutaneous and neurological profile of tuberous sclerosis complex in children: A case series and literature review

Tuberous sclerosis complex (TSC) is a rare genetic disease, belongs to the group of neurocutaneous syndrome. The consequence of genetic mutation is inadequate inhibition of the mammalian target of rapamycin (mTOR) signal pathway that results in inactivation of regulated cells growth and formation of dysgenic tissues/ hamartomas in multiple systems. The updated version of diagnostic criteria for TSC and management has been laid down after second International Tuberous Sclerosis Complex Consensus Conference (2012). To describe the clinico-neuroradiological profile and aspects of antiepileptic treatment of “ definite” TSC casesWe report a case series of four TSC cases attended in a teaching hospital. The “ definite” TSC cases are diagnosed by updated diagnostic criteria (2012) and data obtained retrospectively from records. We discuss the present series in the light of the current literature.We report three female and one male TSC patients. The “definite” TSC diagnosed by two major criteria - one or more cutaneous lesions and neuropathological lesion by neuroimaging. No family history of TSCs have been reported in the series.Hypomelanotic macules were observed in all (n=4) patients. Two TSC patients (n=2) had facial angiofibroma and one TSC had (n=1) shagreen patch. In neuroimaging studies, subependymal nodules were reported in three TSC patients (n=3) and one TSC had cortical dysplasias.The most common neurological manifestation in the TCS series is epilepsy; three TSC patients (n=3) had epilepsy. One TSC patient (n=1) did not present with epilepsy. Infantile spasms, tonic-clonic seizure and focal seizure were the phenotype of seizures. Vigabatrin, valporate and phenobarbitone have been prescribed in TSC patients. Scholastic performance was normal in one TSC patient (n=1) and subnormal in another patient(n=1).TSC -associated cutaneous lesions, the major features for diagnosis, develop in age-dependant manner. The prospective evaluation with a neuroimaging is an integral part of TSC management. Infantile spasm, focal seizure are the first manifested seizures with subtle presentation. First-contact physician must be well knowledgeable about updated 2012 diagnostic criteria, so timely management could be advocated. Vigabatrin is the first choice for infantile spsams in TSC patients as well as for focal seizures. Cognitive outcome/ scholastic performance may varies in TSC patients.

Prosthodontic management of tuberous sclerosis complex patient with deranged occlusal plane– A case report

Tuberous sclerosis complex (TSC) is a syndrome that is not uncommon affecting many organs of the body. Dental manifastations are fibrous growth, enamel pits, enamel hypoplasia. Long term partial edentulous condition of such TSC patient resulted in tooth positional changes altering the occlusal curve and the esthetics. Broadrick occlusal plane analyzer was used to coorect the deranged occlusal plane and to improve the esthetics and functional occlusion.

Chemical Biology Screening Identifies a Vulnerability to Checkpoint Kinase Inhibitors in TSC2-Deficient Renal Angiomyolipomas.

The tuberous sclerosis complex (TSC) is a rare genetic syndrome and multisystem disease resulting in tumor formation in major organs. A molecular hallmark of TSC is a dysregulation of the mammalian target of rapamycin (mTOR) through loss-of-function mutations in either tumor suppressor TSC1 or TSC2. Here, we sought to identify drug vulnerabilities conferred by TSC2 tumor-suppressor loss through cell-based chemical biology screening. Our small-molecule chemical screens reveal a sensitivity to inhibitors of checkpoint kinase 1/2 (CHK1/2), regulators of cell cycle, and DNA damage response, in both in vitro and in vivo models of TSC2-deficient renal angiomyolipoma (RA) tumors. Further, we performed transcriptional profiling on TSC2-deficient RA cell models and discovered that these recapitulate some of the features from TSC patient kidney tumors compared to normal kidneys. Taken together, our study provides a connection between mTOR-dependent tumor growth and CHK1/2, highlighting the importance of CHK1/2 inhibition as a potential antitumor strategy in TSC2-deficient tumors.

Aberrant mTOR/autophagy/Nurr1 signaling is critical for TSC-associated tumor development.

Tuberous sclerosis complex (TSC), an inherited neurocutaneous disease, is caused by mutations in either the TSC1 or TSC2 gene. This genetic disorder is characterized by the growth of benign tumors in the brain, kidneys, and other organs. As a member of the orphan nuclear receptor family, nuclear receptor related 1 (Nurr1) plays a vital role in some neuropathological diseases and several types of benign or malignant tumors. Here, we explored the potential regulatory role of TSC1/2 signaling in Nurr1 and the effect of Nurr1 in TSC-related tumors. We found that Nurr1 expression was drastically decreased by the disruption of the TSC1/2 complex in Tsc2-null cells, genetically modified mouse models of TSC, cortical tubers of TSC patients, and kidney tumor tissue obtained from a TSC patient. Deficient TSC1/2 complex downregulated Nurr1 expression in an mTOR-dependent manner. Moreover, hyperactivation of mTOR reduced Nurr1 expression via suppression of autophagy. In addition, Nurr1 overexpression inhibited cell proliferation and suppressed cell cycle progression. Therefore, TSC/mTOR/autophagy/Nurr1 signaling is partially responsible for the tumorigenesis of TSC. Taken together, Nurr1 may be a novel therapeutic target for TSC-associated tumors, and Nurr1 agonists or reagents that induce Nurr1 expression may be used for the treatment of TSC.

A bistable, multiport valve enables microformulators creating microclinical analyzers that reveal aberrant glutamate metabolism in astrocytes derived from a tuberous sclerosis patient.

There is a need for valves and pumps that operate at the microscale with precision and accuracy, are versatile in their application, and are easily fabricated. To that end, we developed a new rotary planar multiport valve to faithfully select solutions (contamination = 5.22 ± 0.06 ppb) and a rotary planar peristaltic pump to precisely control fluid delivery (flow rate = 2.4 ± 1.7 to 890 ± 77 μL/min). Both the valve and pump were implemented in a planar format amenable to single-layer soft lithographic fabrication. These planar microfluidics were actuated by a rotary motor controlled remotely by custom software. Together, these two devices constitute an innovative microformulator that was used to prepare precise, high-fidelity mixtures of up to five solutions (deviation from prescribed mixture = ±|0.02 ± 0.02| %). This system weighed less than a kilogram, occupied around 500 cm3, and generated pressures of 255 ± 47 kPa. This microformulator was then combined with an electrochemical sensor creating a microclinical analyzer (μCA) for detecting glutamate in real time. Using the chamber of the μCA as an in-line bioreactor, we compared glutamate homeostasis in human astrocytes differentiated from human-induced pluripotent stem cells (hiPSCs) from a control subject (CC-3) and a Tuberous Sclerosis Complex (TSC) patient carrying a pathogenic TSC2 mutation. When challenged with glutamate, TSC astrocytes took up less glutamate than control cells. These data validate the analytical power of the μCA and the utility of the microformulator by leveraging it to assess disease-related alterations in cellular homeostasis.

Clonally Focused Public and Private T Cells in Resected Brain Tissue From Surgeries to Treat Children With Intractable Seizures.

Using a targeted transcriptomics approach, we have analyzed resected brain tissue from a cohort of 53 pediatric epilepsy surgery cases, and have found that there is a spectrum of involvement of both the innate and adaptive immune systems as evidenced by the differential expression of immune-specific genes in the affected brain tissue. The specimens with the highest expression of immune-specific genes were from two Rasmussen encephalitis cases, which is known to be a neuro-immunological disease, but also from tuberous sclerosis complex (TSC), focal cortical dysplasia, and hemimegalencephaly surgery cases. We obtained T cell receptor (TCR) Vβ chain sequence data from brain tissue and blood from patients with the highest levels of T cell transcripts. The clonality indices and the frequency of the top 50 Vβ clonotypes indicated that T cells in the brain were clonally restricted. The top 50 Vβ clonotypes comprised both public and private (patient specific) clonotypes, and the TCR Vβ chain third complementarity region (CDR3) of the most abundant public Vβ clonotype in each brain sample was strikingly similar to a CDR3 that recognizes an immunodominant epitope in either human cytomegalovirus or Epstein Barr virus, or influenza virus A. We found that the frequency of 14 of the top 50 brain Vβ clonotypes from a TSC surgery case had significantly increased in brain tissue removed to control recurrent seizures 11 months after the first surgery. Conversely, we found that the frequency in the blood of 18 of the top 50 brain clonotypes from a second TSC patient, who was seizure free, had significantly decreased 5 months after surgery indicating that T cell clones found in the brain had contracted in the periphery after removal of the brain area associated with seizure activity and inflammation. However, the frequency of a public and a private clonotype significantly increased in the brain after seizures recurred and the patient underwent a second surgery. Combined single cell gene expression and TCR sequencing of brain-infiltrating leukocytes from the second surgery showed that the two clones were CD8 effector T cells, indicating that they are likely to be pathologically relevant.

Tuberous sclerosis complex patient fulfilling the criteria set by the 2012 international tuberous sclerosis complex consensus conference

Tuberous sclerosis complex (TSC) is a rare multisystem neurocutaneous disorder associated with the growth of benign tumors in different organs such as the brain, lungs, kidneys, heart, and eyes. The dermatological findings of this disorder are very common, present at early age and not easy to miss. The neurological manifestations of TSC include seizures, autism, and intellectual disabilities. Furthermore, intracranial abnormalities and hamartoma formation in the heart and other organs are found among sufferers. The clinical diagnostic criteria have been critically evaluated and updated in the 2012 International Tuberous Sclerosis Conference. The diagnosis is based on genetic criteria, clinical criteria, and various manifestations of skin, kidneys, lungs, and brain. The management involves multispecialty and multidisciplinary approaches. Here, we present a case of a 13-year-old female with characteristic clinical, radiological, and pathological features of TSC.

13684 Hair graying may occur early in life in tuberous sclerosis complex and is distinct from poliosis

Introduction: Tuberous sclerosis complex (TSC) presents during infancy with hypomelanotic macules and sometimes poliosis. Hypomelanotic macules arise from a two-hit mechanism involving TSC1 or TSC2, resulting in activation of mechanistic target of rapamycin (mTOR). There is only one report of a TSC patient with premature canities. We sought to investigate the occurrence of early-onset canities in TSC.

Living Donor Preemptive Kidney Transplantation in Tuberous Sclerosis Complex Patient and the Role of Mammalian Target of Rapamycin Inhibitor: A Case Report

BackgroundKidney transplantation (KT) is the preferred treatment for end-stage kidney disease (ESKD), while preemptive (PE) living donor (LD) KT is associated with better survival, quality of life, and lower costs. Tuberous sclerosis complex (TSC) is a genetic multisystem disorder. Renal involvement (multiple bilateral angiomyolipoma [AMLs], cysts, renal cell carcinoma [RCC]) is related to significant morbidity, including ESKD and KT. Nephrectomy in TSC patients before KT is controversial. Affected kidneys carry a risk of hemorrhage or malignancy, while AMLs may be fat-poor and are often hardly distinguishable from RCC in magnetic resonance (MR)/computed tomography. On the other hand nephrectomy impedes PE KT. Mammalian target of rapamycin inhibitors (mTORi) have proved efficacy in many TSC complications, including AMLs, fat-poor AMLs, TSC-related RCC, and immunosuppressive (IS) treatment. Case reportA 29-year-old female TSC patient was referred for evaluation to the TSC reference center. Her family history was negative for TSC. A clinical evaluation revealed multisystem TSC manifestation (skin, brain, lungs, kidneys). MR disclosed indeterminate fat-poor renal lesions, possibly AMLs, but RCC could not be excluded. A comparison with previous MR did not show any significant progression. Due to ESKD, the patient was qualified for PE LD (mother) KT. mTORi, sirolimus, was used in IS. Creatinine at discharge was 2.1 mg/dL. Sixteen months later, MR showed significant reduction in tumor size. Two years after KT, graft function remained stable (creatinine 1.98 mg/dL). No complications related to renal lesions occurred. ConclusionsmTORi are the therapy of choice in TSC patients after KT, achieving IS effect and improvement in TSC manifestations while avoiding nephrectomy and management of patients with indeterminate renal lesions, especially in the case of PE KT.