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Tuberous sclerosis is a rare genetic disease which leads to formation of benign tumours in the brain and other organs of the body. It is a multisystem disease with various clinical manifestations. Renal angiomyolipomas are the most common renal manifestations whereas renal cell carcinoma is the least. Renal cysts are found in around 20% of the patients but polycystic kidney disease is present in less than 2% cases and is relatively rare manifestation of the disease. We present a case of tuberous sclerosis in a 60-year-old man who presented to the medicine outpatient department for routine evaluation of his hypertension. He was diagnosed as tuberous sclerosis. His ultrasound and CT scan of abdomen revealed polycystic kidney disease. His kidney function test and urine analysis were suggestive of chronic kidney disease.

Background: Tuberous sclerosis complex is a genetic disorder affecting every organ system, but disease manifestations vary significantly among affected individuals. The diverse and varied presentations and progression can be life-threatening with significant impact on cost and quality of life. Current surveillance and management practices are highly variable among region and country, reflective of the fact that last consensus recommendations occurred in 1998 and an updated, comprehensive standard is lacking that incorporates the latest scientific evidence and current best clinical practices., Methods: The 2012 International Tuberous Sclerosis Complex Consensus Group, comprising 79 specialists from 14 countries, was organized into 12 separate subcommittees, each led by a clinician with advanced expertise in tuberous sclerosis complex and the relevant medical subspecialty. Each subcommittee focused on a specific disease area with important clinical management implications and was charged with formulating key clinical questions to address within its focus area, reviewing relevant literature, evaluating the strength of data, and providing a recommendation accordingly., Results: The updated consensus recommendations for clinical surveillance and management in tuberous sclerosis complex are summarized here. The recommendations are relevant to the entire lifespan of the patient, from infancy to adulthood, including both individuals where the diagnosis is newly made as well as individuals where the diagnosis already is established., Conclusions: The 2012 International Tuberous Sclerosis Complex Consensus Recommendations provide an evidence-based, standardized approach for optimal clinical care provided for individuals with tuberous sclerosis complex., (Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.)

Intellectual disability is common and is associated with significant morbidity. Until the latter half of the 20th century, there were no efficacious treatments. Following initial breakthroughs associated with newborn screening and metabolic corrections, little progress was made until recently. With improved understanding of genetic and cellular mechanisms, novel treatment options are beginning to appear for a number of specific conditions. Fragile X and tuberous sclerosis offer paradigms for the development of targeted therapeutics, but advances in understanding of other disorders such as Down syndrome and Rett syndrome, for example, are also resulting in promising treatment directions. In addition, better understanding of the underlying neurobiology is leading to novel developments in enzyme replacement for storage disorders and adjunctive therapies for metabolic disorders, as well as potentially more generalizable approaches that target dysfunctional cell regulation via RNA and chromatin. Physiologic therapies, including deep brain stimulation and transcranial magnetic stimulation, offer yet another direction to enhance cognitive functioning. Current options and evolving opportunities for the intellectually disabled are reviewed and exemplified., (Copyright © 2013 American Neurological Association.)

Objective: To explore the diagnosis and treatment of tuberous sclerosis complex complicated with renal angiomyolipoma., Methods: The clinical data of 22 patients with tuberous sclerosis complex complicated with renal angiomyolipoma were analyzed retrospectively., Results: There were 12 males and 10 females with a mean age of 23 (1-46) years. All of them had bilateral multiple renal angiomyolipomas. The mean tumor size was 8.5 (0.7-18.0) cm in diameter. The presence or absence of clinical symptoms showed a significant correlation with tumor size.Eight patients with angiomyolipoma under 4 cm in diameter were continuously monitored at an outpatient clinic. There were 8 patients with lesions of 4-10 cm.Five of them underwent nephron-sparing surgeries and another 3 monitored at an outpatient clinic. There were 6 patients with tumor over 10 cm. Three of them underwent transcatheter arterial embolization and one case took rapamycin after embolization.One patient with concurrent renal cell carcinoma underwent partial nephrectomy. Chronic renal failure occurred in one case dying of pulmonary lymphangiomyomatosis with serious hemoptysis. During a mean follow-up of 25 months, neither severe renal hemorrhage nor symptomatic aggravation was found.In the case of rapamycin, there was 10% reduction in the size of angiomyolipoma., Conclusions: Most cases of tuberous sclerosis complex are complicated with bilateral multiple renal angiomyolipoma. The small lesions under 4 cm in diameter may be monitored at an outpatient clinic.For those larger (>4 cm) or symptomatic ones, medication, embolization or surgery is necessary.

Subependymal giant cell astrocytoma (SEGA) is a type of brain tumour that develops in 10-15% of individuals with tuberous sclerosis complex (TSC). SEGAs can be unilateral or bilateral, developing from benign subependymal nodules (hamartomas) located near the foramen of Monro. These are usually slow-growing, glialneuronal tumours that develop within the first 2 decades of life. Traditionally, the management of SEGA involved monitoring using periodic neuroimaging, and surgical resection of tumours that exhibited growth and/or caused clinical signs of intracranial hypertension. Recent clinical research has demonstrated that mammalian target of rapamycin (mTOR) inhibitors can induce partial regression of SEGA associated with TSC and so might provide an acceptable alternative to neurosurgery for these tumours. This report summarizes the clinical recommendations for the management of SEGA made by a panel of European experts in March 2012. Current treatment options and outstanding questions are outlined., (Copyright © 2013 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.)

A middle-aged female patient, previously diagnosed with asthma, presented with a large spontaneous left pneumothorax. She had a history of nephrectomy for a ruptured renal angiomyolipoma (AML) with a postoperative spontaneous pneumothorax when she was an adolescent. High-resolution CT chest revealed multiple scattered thin-walled lung parenchyma cysts consistent with lymphangioleiomyomatosis (LAM). Hepatic AMLs and adenoma sebaceum skin lesions were also noted, consistent with an overall diagnosis of tuberous sclerosis. Her acute management included lung re-expansion via chest tube insertion, antibiotics for concurrent chest infection, nebulisation and chest physiotherapy. Since discharge, the patient had only occasional shortness of breath, relieved by bronchodilators. She is considering expanded immunisation as well as enrolment in a clinical trial. Her hepatic AMLs will be monitored via ultrasound for growth. LAM treatment is generally aimed at its complications with lung transplantation reserved for severe disease; however, hormonal therapy and the mTOR inhibitor aim at targeting systemic disease.

Seizures are a hallmark manifestation of tuberous sclerosis complex, yet data characterizing resource utilization are lacking. This retrospective chart review was performed to assess the economic burden of tuberous sclerosis complex with neurologic manifestations. Demographic and resource utilization data were collected for 95 patients for up to 5 years after tuberous sclerosis complex diagnosis. Mean age at diagnosis was 3.1 years, with complex partial and infantile spasms as the most common seizure types. In the first 5 years post-diagnosis, 83.2% required hospitalization, 30.5% underwent surgery, and the majority of patients (90.5%) underwent ≥3 testing procedures. In 79 patients with a full 5 years of data, hospitalizations, intensive care unit stays, diagnostic testing, and rehabilitation services decreased over the 5-year period. Resource utilization is cost-intensive in children with tuberous sclerosis complex and associated seizures during the first few years following diagnosis. Improving seizure control and reducing health care costs in this population remain unmet needs.

Tuberous sclerosis is an autosomal dominant disorder characterized by involvement of skin, nervous system, kidneys, and lungs. It results from mutations in 1 of 2 genes: TSC1 (encoding hamartin) or TSC2 (encoding tuberin), leading to dysregulation and activation of the mammalian target of rapamycin (mTOR) pathway. Constitutive activation of mTOR signaling has recently been reported in systemic lupus erythematosus (SLE), and inhibition of this pathway may benefit patients with SLE nephritis. We report a case of a young woman with tuberous sclerosis who developed fulminant SLE, with lower extremity edema, massive proteinuria, and class IV lupus glomerulonephritis. She died despite treatment with high-dose steroids, plasmapheresis, and cyclophosphamide. Although there are no prior reports of coexistence of these 2 rare diseases, this case is of considerable interest because of the possibility that activation of mTOR by the TSC mutations may have led to activation of the immune system and the development of unusually severe SLE.

Cardiac rhabdomyomas (CRs) are the most common heart tumors in children and closely associated with tuberous sclerosis complex (TSC). This study was performed to assess the presentation type, clinical course, treatment modalities, and outcome of the patients with rhabdomyoma, associated with TSC. We reviewed our patients with cardiac rhabdomyomas (CRs), who had received a diagnosis of TSC previously or during the follow-up period between June 1996 and January 2012, retrospectively. Thirty-two patients with TSC were evaluated and among them 11 patients (34%) were associated with CRs. Five patients (45%) had multiple tumors and consequently a total of 29 CRs were analyzed in our study. The median follow-up period was 2 years (range: 1 week-15 years). Clinical presentation was cardiac murmur in three patients, cyanosis in two patients and arrhythmia in one patient. Five patients were asymptomatic at the diagnosis and CRs were detected during routine cardiac evaluation for TSC. Cardiac tumors were diagnosed prenatally in two patients. Spontaneous regression rate was 31% and we experienced a complete regression of a tumor with an echogenic bordered tissue defect and septal thinning in a patient. Three patients had hemodynamically significant tumor obstruction; two of them underwent surgery. The other patient, who had multiple CRs, was treated medically with everolimus because of high-risk potential of surgery. Although surgical resection is the preferred treatment in most of the patients with hemodynamic instability, we need novel alternative medical therapies in some critically ill patients who cannot be operated due to various reasons.

Different minimally invasive methods have been proposed to treat renal manifestation of tuberous sclerosis complex (TSC), in order to preserve kidney parenchyma and avoid nephrectomy. The case of a boy with bleeding giant angiomyolipoma treated by selective arterial embolization is discussed. The extensive renal lesions resulted significantly decreased, with resolution of arterial hypertension and abdominal symptoms. Differential renal function increased from 26.6% to 32.6%. Renal involvement in TSC requires careful parenchymal-sparing procedures. Selective embolization of the main renal lesions should be considered as first line therapy.

Genetic disorders that present with a high incidence of autism spectrum disorders (ASD) offer tremendous potential both for elucidating the underlying neurobiology of ASD and identifying therapeutic drugs and/or drug targets. As a result, clinical trials for genetic disorders associated with ASD are no longer a hope for the future but rather an exciting reality whose time has come. Tuberous sclerosis complex (TSC) is one such genetic disorder that presents with ASD, epilepsy, and intellectual disability. Cell culture and mouse model experiments have identified the mTOR pathway as a therapeutic target in this disease. This review summarizes the advantages of using TSC as model of ASD and the recent advances in the translational and clinical treatment trials in TSC., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Neurofibromatosis type 1 (NF1) and tuberous sclerosis complex (TSC) are autosomal-dominant genetic disorders that result from dysregulation of the PI3K/AKT/mammalian target of rapamycin (mTOR) pathway. NF1 is caused by mutations in the NF1 gene on chromosome 17q11.2. Its protein product, neurofibromin, functions as a tumor suppressor and ultimately produces constitutive upregulation of mTOR. TSC is caused by mutations in either the TSC1 (chromosome 9q34) or TSC2 (chromosome 16p.13.3) genes. Their protein products, hamartin and tuberin, respectively, form a dimer that acts via the GAP protein Rheb (Ras homolog enhanced in brain) to directly inhibit mTOR, again resulting in upregulation. Specific inhibitors of mTOR are in clinical use, including sirolimus, everolimus, temsirolimus, and deforolimus. Everolimus has been shown to reduce the volume and appearance of subependymal giant cell astrocytomas (SEGA), facial angiofibromas, and renal angiomyolipomas associated with TSC, with a recent FDA approval for SEGA not suitable for surgical resection. This article reviews the use of mTOR inhibitors in these diseases, which have the potential to be a disease-modifying therapy in these and other conditions.

Purpose: To review existing literature and deduce guidelines for the management of renal disease in patients with tuberous sclerosis complex (TSC)., Patients: After review of literature, a core panel of five physicians wrote a draft that was evaluated by 14 reviewers who used a 9-level scale (1: total disagreement; 9: total agreement). The guidelines were then reformulated until each item received a median score superior or equal to 8., Results: Forty-eight to 80 % of TSC patients have significant renal involvement including angiomyolipomas (AMLs), cysts, malignant tumors and renal insufficiency. It is recommended to perform an abdominal ultrasound (and serum creatinine if abnormal ultrasound) when TSC is diagnosed. This work-up will be repeated every 3-5years if normal. Associated autosomal dominant polycystic kidney disease must be suspected in case of numerous and large cysts. After the age of 20, follow-up should use computed tomography (CT) or MRI that are more precise than ultrasound for the measurement of AMLs. Biopsy of a renal mass should be discussed in case of calcifications, necrosis or rapid growth. Females with TSC should undergo screening for pulmonary lymphangioleiomyomatosis by CT at the age of 18, and, if negative at the age of 30-40. Acute bleeding should be treated with percutaneous embolization. Asymptomatic angiomyolipomas with several risk factors (size>80mm, predominant vascular component, micro-aneurysms) should undergo prophylactic treatment, if possible using embolization. The role of mTOR inhibitors in the management of angiomyolipomas needs to be defined., Conclusion: Standardization of follow-up and treatment is necessary to improve the management of TSC renal involvement., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)

Tuberous sclerosis complex is a genetic disorder characterized by the formation of nonmalignant hamartomas in the brain, heart, skin, kidney, lung, and other organs. It is associated with autism, epilepsy, and other neurocognitive and behavioral disabilities. Wide phenotypic variation occurs in disease severity and natural course: some patients demonstrate minimal effects, e.g., skin changes; others manifest profound seizures and mental retardation. Tuberous sclerosis complex is caused by mutations in either the tuberous sclerosis complex 1 or 2 gene (coding for hamartin and tuberin, respectively). The tuberous sclerosis complex 1/tuberous sclerosis complex 2 protein dimer complex is a crucial inhibitory element in the mammalian target of rapamycin pathway, regulating cell growth and proliferation. Until recently, few options existed, other than surgery, for treating symptoms of tuberous sclerosis complex related to the growth of hamartomas. Increased understanding of the genetic cause of the disease and underlying dysregulation of the mammalian target of rapamycin pathway has led to clinical trials of mammalian target of rapamycin inhibitors, including sirolimus and everolimus. This review gives an overview of tuberous sclerosis complex and its molecular causes, and summarizes results from recent clinical trials of mammalian target of rapamycin inhibitors in patients with the disease., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Tuberous Sclerosis Complex, also known as Epiloia or Bourneville-Pringle disease is an autosomal dominant neurocutaneous syndrome with variable clinical expression. It is a multisystem disorder that may be associated with hamartomas in multiple organs in an unpredictable manner. The dermatologist plays an essential role in the history of the disease, since skin manifestations represent the most prevalent clinical features, enabling early diagnosis and intervention in its natural course. This article aims to inform the scientific community about advances made in the study of genetics and molecular biology. Recent findings regarding stimulation of tumor growth have been changing the history of this condition, making therapeutic trials with topical and systemic drugs possible. Knowledge of these topics enables better management of the patients affected, since tissue replacement by tumors can result in significant morbidity and mortality.

Objectives: Tuberous sclerosis complex (TSC) is a progressive genetic disorder characterized by pervasive benign tumor growth. We sought to assess the current understanding of burden of TSC-related neurological manifestations., Methods: We systematically searched MEDLINE- and EMBASE-indexed, English-language literature (5/2000-5/2010) and non-indexed materials., Results: In total, 119 articles were included, 115 on epidemiology and treatment. Recent prevalence estimates from Ireland and Taiwan report TSC in 1:14,000-25,000 individuals, below older estimates of 1:10,000. While neurological manifestations are common, treatment is largely unaddressed by guidelines and focuses on symptoms, with resection standard for subependymal giant cell astrocytomas (SEGAs) and common practice for refractory epilepsy. Antiepileptic drugs and mammalian target of rapamycin inhibitors safely, effectively minimize the need for surgery for severe epilepsy and SEGAs., Conclusion: Morbidity and treatment burden of prevalent neurological manifestations is significant, suggesting substantial economic and humanistic burden; however, these areas are poorly studied, indicating total disease burden is unknown. Future research should assess quality of life, caregiver burden, and costs.

Background: Tuberous sclerosis (TSC) is a genetic multisystem disorder associated with hamartomas in several organs including subependymal giant cell tumors (SGCT). SGCT have the potential to grow and therefore to become symptomatic and are one of the main causes of death in TSC individuals. Surgical resection is the procedure of choice for SGCT. However, the discovery of mTOR pathway upregulation in TSC-associated tumors and recent evidence that mTOR inhibitors may induce regression of SGCT open up new treatment strategies. Based on a review of the currently available literature and on personal experience, current options for the management of TSC patients and appropriate indications, taking into account benefits and risks of surgery and pharmacotherapy, are discussed., Discussion: An earlier diagnosis of SGCT in neurologically asymptomatic children may allow a precocious surgical removal of the tumor, thus minimizing surgery-related morbidity and mortality. Biologically targeted pharmacotherapy with mTOR inhibitors such as sirolimus and everolimus provides a safe and efficacious treatment option for patients with SGCT and has the potential to change the clinical management of these tumors. However, whether pharmacotherapy is sufficient to control growth or if it only delays the need for surgical removal of symptomatic SGCT remains unclear. Further studies are needed to determine the optimal levels of mTOR inhibitors that preserve maximal anti-tumor efficacy while minimizing side effects.

Purpose of Review: Mendelian disorders that affect cognition provide a unique opportunity to study the mechanisms of neurodevelopmental disorders through the examination of genetic defects in animals and development of hypotheses that can be tested in human beings. Tuberous sclerosis complex (TSC) is a genetic disease that presents with epilepsy, autism, and intellectual disability. Here we review recent advances in our understanding of TSC pathogenesis and signaling pathways that may be modulated to treat the neurological symptoms., Recent Findings: Accumulating evidence suggests that TSC patients have nontuber abnormalities that contribute to the development of the neurological phenotype- in particular, disorganization of axon tracts and deficient myelination. TSC mouse models have failed to replicate the human neuropathology entirely, but have shed light on the cellular abnormalities and the neurobehavioral phenotypes. Most importantly, cell culture and animal models have identified the mTORC1 pathway as a therapeutic target in this disease., Summary: Preclinical data strongly suggest that TSC is a disease of abnormal neuronal connectivity. The high incidence of neurodevelopmental deficits, early detection of the disease in very young ages, and availability of mTORC1 inhibitors make TSC a model for other Mendelian disorders of neurocognition and an avenue for the mechanism-based treatment trials of neurodevelopmental disorders.

Tuberous sclerosis (TS) is an autosomal dominant disorder characterized by benign hamartomas in multiple organ systems, including rhabdomyomas in the heart and subependymal giant cell astrocytomas in the brain. Mutations in the hamartin (TSC1) and tuberin (TSC2) genes have been identified as causative. We report an infant who presented with seizures and cardiac rhabdomyomas and whose diagnosis of TS was confirmed by a TSC2 C1605T nonsense mutation. In addition, we review the literature of cardiac tumors. Despite the typical natural history of tumor regression, lifelong follow-up is necessary for the appropriate management of these patients. Elucidation of the genetics and pathogenesis of cardiac tumors, as illustrated by the TS rhabdomyoma described in this case, may lead to novel therapies., (© 2011 Copyright the Authors. Congenital Heart Disease © 2011 Wiley Periodicals, Inc.)

Objective: Renal angiomyolipomas (R-AMLs) are major complications of lymphangioleiomyomatosis (LAM). The objective of this study was to better understand the influence of R-AMLs in patients with LAM on the prognosis and other clinical factors related to respiration, and to investigate the management of R-AMLs in patients with LAM., Patients and Methods: We retrospectively investigated the clinical features of 7 patients with LAM [4 were TSC (Tuberous sclerosis complex)-LAM and 3 were S (sporadic)-LAM] complicated by R-AMLs admitted to our hospital from 1997 to 2008., Results: All patients were females and the mean age at diagnosis of LAM was 40.7 years (31.7 years for TSC-LAM and 52.7 years for S-LAM). Although 5 patients had symptoms related to R-AMLs, only 1 patient experienced symptoms related to R-AMLs at the time of diagnosis. Five patients had bilateral and 2 patients had unilateral R-AMLs. R-AMLs ruptured in 4 cases (3 patients were TSC-LAM) including 2 patients in whom they ruptured bilaterally, and who underwent bilateral nephrectomy. In 1 case, unilateral R-AMLs grew larger and appeared on the other side during the follow-up period., Conclusion: Although only rare cases of LAM show symptoms related to R-AMLs initially, R-AMLs are a notable complication. To avoid nephrectomy, R-AMLs should be diagnosed when they are small and should be followed up carefully by periodic echograms or CT scans., (© 2011 The Japanese Society of Internal Medicine)

Tuberous sclerosis complex is a genetic multisystem disease characterized by hamartic development of many organs, most notably the brain, heart, kidneys, lungs, and skin. This autosomic dominant disorder results from mutations in one of two genes, TSC1 and TSC2, coding for hamartin and tuberin, respectively. The hamartin-tuberin complex inhibits the mammalian target of rapamycin pathway, which controls cell growth and proliferation. The clinical presentation is highly variable and most features of tuberous sclerosis become evident only in childhood after the child is several years of age, limiting their usefulness for early diagnosis. The aim of this article is to define the pediatric clinical manifestations of tuberous sclerosis in correlation with patient age. Sometimes, a prenatal diagnosis can be made based on fetal ultrasound and MRI, which show cardiac and brain lesions. However, newborns are most often asymptomatic. In the 1st year, seizures are the most common symptoms, with a high incidence of infantile spasms. In children between 2 and 10 years of age, neurological symptoms are the most frequent with epilepsy, mental retardation, and autism, but extraneurological manifestations can be diagnosed. In adolescents, most features of tuberous sclerosis become evident and renal and pulmonary manifestations must be sought. The knowledge of age-dependent clinical features of tuberous sclerosis can provide an earlier diagnosis and improve the management of these patients with a special role for multidisciplinary consultation., (Copyright © 2010 Elsevier Masson SAS. All rights reserved.)

Autism spectrum disorders have been reported as being much more frequent in individuals with tuberous sclerosis than in the general population. Previous studies have implicated early seizure onset and the localization of cortical tubers in the temporal lobes as risk factors for autism. However, the underlying reasons for this association remain largely unclear. The dysregulation of intracellular signaling through the activation of mTOR pathway could play a direct role in determining susceptibility to autism. Early control of seizures and an early intensive behavioral intervention of autism during the period of brain plasticity can mitigate, but not reverse the final outcome. A greater understanding of the pathogenetic mechanisms underlying autism in tuberous sclerosis could help in devising targeted and potentially more effective treatment strategies.

The goal of the study was to assess the long-term seizure and neuropsychologic outcomes of patients with tuberous sclerosis and refractory epilepsy who received vagus nerve stimulator implantation. Eleven patients with a follow-up period of at least 12 months were studied retrospectively. The mean age at the time of implantation was 14 years (range, 2-35). Seizure outcome was rated as class I (>80% seizure frequency reduction) in 1 (9%), class II (50-79% reduction) in 7 (63%), and class III (<50% reduction) in 3 (27%). No patient experienced permanent adverse effects after the procedure. A significant increase of adaptive behaviors and quality of life was observed. Patients who had implantation during childhood exhibited a greater improvement in cognitive and neuropsychologic functioning. Vagus nerve stimulation can be considered an effective and safe therapeutic option in patients with tuberous sclerosis and refractory epilepsy who are not candidates for epilepsy surgery.

Until recently, the neuropsychiatric phenotype of tuberous sclerosis complex (TSC) was presumed to be caused by the structural brain abnormalities and/or seizures seen in the disorder. However, advances in the molecular biology of the disorder have shown that TSC is a mammalian target of rapamycin (mTOR) overactivation syndrome, and that direct molecular pathways exist between gene mutation and cognitive/neurodevelopmental phenotype. Molecularly-targeted treatments using mTOR inhibitors (such as rapamycin) are showing great promise for the physical and neurological phenotype of TSC. Pre-clinical and early-phase clinical studies of the cognitive and neurodevelopmental features of TSC suggest that some of the neuropsychiatric phenotypes might also be reversible, even in adults with the disorder. TSC, fragile X, neurofibromatosis type 1, and disorders associated with phosphatase and tensin homo (PTEN) mutations, all signal through the mTOR signaling pathway, with the TSC1-TSC2 protein complex as a molecular switchboard at its center. Together, these disorders represent as much as 14% of autism spectrum disorders (ASD). Therefore, we suggest that this signaling pathway is a key to the underlying pathophysiology of a significant subset of individuals with ASD. The study of molecularly targeted treatments in TSC and related disorders, therefore, may be of scientific and clinical value not only to those with TSC, but to a larger population that may have a neuropsychiatric phenotype attributable to mTOR overactivation or dysregulation., ((c) 2010 The American Society for Experimental NeuroTherapeutics, Inc. Published by Elsevier Inc. All rights reserved.)

Introduction: Angiomyolipomas (AML) are rare benign renal tumours which are associated with aneurysms that can cause haemorrhage. Embolisation of AML greater than 4 cm with a variety of embolic agents is now the first-line treatment in these cases., Methods: This was a retrospective analysis of all patients who underwent AML embolisation at Beaumont Hospital from 2000 to 2006 to review the efficacy of embolisation in the treatment of AMLs., Results: There were six patients in total (n = 6). One patient (16%) had a background of tuberous sclerosis. Half of the patients presented acutely with bleeding and abdominal pain (50%) while the other half were found incidentally. There were no mortalities overall and three patients (50%) developed post embolisation syndrome. Five patients (83%) had a good response to embolisation with no further growth or regression of the AML., Conclusion: Embolisation is a safe and effective method for treating patients with AML.

Of 105 children with epilepsy who had presurgical evaluation because of solitary extratemporal focal cortical dysplasia, the 5 cases reported here had a final diagnosis of tuberous sclerosis complex without classic findings on magnetic resonance imaging (MRI). Four were infants with spasms (n = 2) or partial seizures (n = 2); the fifth was a 12-year-old boy with right motor seizures. Cranial MRI indicated solitary left frontal dysplasia in two cases (one with calcification) and right frontal, left parietal, and right parietal dysplasia in one case each. Tuberous sclerosis complex was considered based on hypopigmented macules in three cases, on cardiac rhabdomyomas on echocardiography for hypotension in one case, and on calcification in the dysplastic region and a family history of seizures in one case. Four of the patients had mutations in the TSC1 (n = 2) and TSC2 (n = 2) genes. No mutation was found in the fifth patient, who had only TSC1 sequencing. Four had epilepsy surgery, and were seizure-free on one (three cases) or two antiepileptic drugs (one case) at 1-2 year follow-up. Pathologic examination revealed cortical dysplasia without any characteristic features of tuberous sclerosis complex. These findings suggest that, in tuberous sclerosis complex, solitary focal cortical dysplasia may be the only cranial MRI finding. Tuberous sclerosis complex should be considered when focal cortical dysplasia is associated with seizure onset in infancy, family history of seizures, and peridysplastic calcification., (Copyright 2010 Elsevier Inc. All rights reserved.)

Renal angiomyolipomas (AML) are benign tumors, which can acquire huge size and when bilateral, they are diagnostic of tuberous sclerosis (TS). Pulmonary lymphangiomyomatosis (LAM) is more common in female patients with TS and mostly diagnosed in patients with renal AMLs. We report a case of giant bilateral AMLs and pulmonary LAM in a 48-year-old female patient, who required nephrectomy for life-threatening hemorrhage.

Tuberous sclerosis complex (TSC) is an autosomal dominant multisystem neurocutaneous syndrome characterized by the development of multiple hamartomas distributed throughout the body, skin, brain, eyes, heart, kidney and lung. The affected genes are TSC1 and TSC2, encoding hamartin and tuberin respectively. The hamartin-tuberin complex inhibits the mammalian target of rapamycin pathway, which controls cell growth and proliferation. The most common neurological manifestations of TSC are epilepsy, mental retardation, and autistic behavior. Epilespsy usually occurs during childhood and they need anticonvulsant medications through their life. In adulthood, multiple hamartomas is distributed in the kidney and lung. Individuals with lesions more than 4 cm in diameter or with extensive renal involvement should be referred to a nephrologist or urologist. Understanding variable phenotype expression improve management of TSC.

Objective: To examine the presentation, management and outcomes of patients with renal angiomyolipoma (AML) over a period of 10 years, at St George's Hospital, London, UK., Patients and Methods: We assessed retrospectively 102 patients (median follow-up 4 years) at our centre; 70 had tuberous sclerosis complex (TSC; median tumour size 3.5 cm) and the other 32 were sporadic (median tumour size 1.2 cm). Data were gathered from several sources, including radiology and clinical genetics databases. The 77 patients with stable disease were followed up with surveillance imaging, and 25 received interventions, some more than one. Indications for intervention included spontaneous life-threatening haemorrhage, large AML (10-20 cm), pain and visceral compressive symptoms., Results: Selective arterial embolization (SAE) was performed in 19 patients; 10 received operative management and four had a radiofrequency ablation (RFA). SAE was effective in controlling haemorrhage from AMLs in the acute setting (six) but some patients required further intervention (four) and there was a significant complication rate. The reduction in tumour volume was only modest (28%). No complications occurred after surgery (median follow-up 5.5 years) or RFA (median follow-up 9 months). One patient was entered into a trial and treated with sirolimus (rapamycin)., Conclusions: The management of AML is both complex and challenging, especially in those with TSC, where tumours are usually larger and multiple. Although SAE was effective at controlling haemorrhage in the acute setting it was deemed to be of limited value in the longer term management of these tumours. Thus novel techniques such as focused ablation and pharmacological therapies including the use of anti-angiogenic molecules and mTOR inhibitors, which might prove to be safer and equally effective, should be further explored.

Objective: The goal of the work described here was to assess the efficacy and safety of vagus nerve stimulation in a cohort of patients with tuberous sclerosis complex with refractory epilepsy. Furthermore, we examined the impact of vagus nerve stimulation failure on the ultimate outcome following subsequent intracranial epilepsy surgery., Methods: A retrospective review was performed on 19 patients with refractory epilepsy and TSC who underwent vagus nerve stimulator (VNS) implantation. There were 11 (58%) females and 8 (42%) males aged 2 to 44 years when the VNS was implanted (mean: 14.7+/-12 years). Twelve patients underwent primary VNS implantation after having failed a mean of 7.1 antiepileptic drugs. Two patients (17%) had generalized epilepsy, one had a single seizure focus, three (25%) had multifocal epilepsy, and six (50%) had multifocal and generalized epilepsy. Seven patients were referred for device removal and evaluation for intracranial procedures. One patient in the primary implantation group was lost to follow-up and excluded from outcome analysis., Results: All implantations and removals were performed without permanent complications. The duration of treatment for primary VNS implants varied from 8.5 months to 9.6 years (mean: 4.9 years). Mean seizure frequency significantly improved following VNS implantation (mean reduction: 72%, P<0.002). Two patients had Engel Class I (18%), one had Class II (9%), seven had Class III (64%), and one had Class IV (9%) outcome. Three patients with poor response to vagus nerve stimulation therapy at our center underwent resection of one or more seizure foci (Engel Class I, two patients; Engel Class III, one patient). Seven patients referred to our center for VNS removal and craniotomy underwent seizure focus resection (6) or corpus callosotomy (1) (Engel Class II: 2, Engel III: 2; Engel IV: 3). In total, 8 of 10 (80%) patients experienced improved seizure control following intracranial surgery (mean reduction: 65%, range: 0-100%, P<0.05)., Conclusions: VNS is a safe and effective treatment option for medically refractory epilepsy in patients with tuberous sclerosis complex. Nine of 11 patients (82%) experienced at least a 67% reduction in seizure burden. Lack of response to vagus nerve stimulation does not preclude subsequent improvement in seizure burden with intracranial epilepsy surgery.

Background: An emerging literature on behavioural phenotypes has highlighted apparent associations between autism spectrum disorders (ASDs) or ASD-related phenomenology and a number of different genetically determined syndromes., Method: A systematic review of the current literature regarding the association with ASD and ASD characteristics was conducted in the following syndrome groups: Fragile X, Rett, Tuberous Sclerosis Complex, Down, Angelman, CHARGE and Phenylketonuria. Specific consideration was given to the role of intellectual disability in assessing the association between ASD and these syndrome groups., Results: The review highlights that while formal diagnostic assessments may indicate an association between ASD and specific syndrome groups, detailed investigation has revealed subtle but qualitative differences in the presentation of ASD-like phenomenology in particular syndrome groups. The degree of ID of the individual clearly has a role to play with regard to the development and presentation of ASD-like characteristics, and caution should be taken when assessing ASD symptomatology in genetically determined syndromes associated with severe ID. However, degree of ID cannot solely account for the heightened prevalence of ASD characteristics in some specific syndrome groups., Conclusions: There is a need for caution in interpreting the significance of superficial similarities between ASD and the behavioural phenotypes of certain genetically determined syndromes. However, recognition of ASD-like characteristics (even where a true diagnosis of ASD may not be relevant) in individuals with genetic syndromes is crucial in ensuring that individuals receive appropriate behavioural management and educational placement. Further research in this field requires fine-grained investigation of behavioural phenomenology within individual syndrome groups.

The neurobiological basis of attention-deficit hyperactivity disorder (ADHD) in tuberous sclerosis complex is still largely unknown. Cortical tubers may disrupt several brain networks that control different types of attention. Frontal lobe dysfunction due to seizures or epileptiform electroencephalographic discharges may perturb the development of brain systems that underpin attentional and hyperactive functions during a critical early stage of brain maturation. Comorbidity of attention-deficit hyperactivity disorder (ADHD) with mental retardation and autism spectrum disorders is frequent in children with tuberous sclerosis. Attention-deficit hyperactivity disorder (ADHD) may also reflect a direct effect of the abnormal genetic program. Treatment of children with tuberous sclerosis complex with combined symptoms of attention-deficit hyperactivity disorder (ADHD) and epilepsy may represent a challenge for clinicians, because antiepileptic therapy and drugs used to treat attention-deficit hyperactivity disorder (ADHD) may aggravate the clinical picture of each other.

Background: A 17-year-old girl, who was diagnosed with tuberous sclerosis in infancy, presented with multiple bilateral renal masses, the largest of which was 6.0 cm in diameter on the left side., Investigations: History and physical examination, ultrasonography, MRI, CT, magnetic resonance angiography, and measurement of serial creatinine levels., Diagnosis: Bilateral angiomyolipomas.Management Observation, serial imaging, embolization and infarction.

Pancreatic endocrine tumors (PETs) can occur as part of 4 inherited disorders, including Multiple Endocrine Neoplasia type 1 (MEN1), von Hippel-Lindau disease (VHL), neurofibromatosis 1 (NF-1) (von Recklinghausen disease), and the tuberous sclerosis complex (TSC). The relative frequency with which patients who have these disorders develop PETs is MEN1>VHL>NF-1>TSC. Over the last few years, there have been major advances in the understanding of the genetics and molecular pathogenesis of these disorders as well in the localization and the medical and surgical treatment of PETs in such patients. The study of PETs in these disorders not only has provided insights into the possible pathogenesis of sporadic PETs but also has presented several unique management and treatment issues, some of which are applicable to patients with sporadic PETs. Therefore, the study of PETs in these uncommon disorders has provided valuable insights that, in many cases, are applicable to the general group of patients with sporadic PETs. In this article, these areas are reviewed briefly along with the current state of knowledge of the PETs in these disorders, and the controversies that exist in their management are summarized briefly and discussed.

Tuberous sclerosis complex (TSC) is an autosomal-dominant disorder characterized by the formation of hamartomatous lesions in multiple organ systems. It is the second most common neurocutaneous syndrome after neurofibromatosis type 1 and has been recognized since the late 1800s. Although the disease has complete penetrance, there is also high phenotypic variability: some patients have obvious signs at birth, while others remain undiagnosed for many years. In addition to skin lesions, TSC patients develop numerous brain lesions, angiomyolipoma (AMLs), lymphangiomyomatosis (LAM) in the lungs, cardiac rhabdomyomas, skeletal lesions, and vascular anomalies, all of which are well seen with medical imaging. Our knowledge of TSC genetics and pathophysiology has expanded dramatically in recent years: two genetic loci were discovered in the 1990s and recent elucidation of TSC's interaction with the mTOR pathway has changed how we manage the disease. Meanwhile, medical imaging is playing an increasingly important role in the diagnosis, management, and treatment of TSC. We provide an update on the genetics and pathophysiology of TSC, review its clinical manifestations, and explore the breadth of imaging features in each organ system, from prenatal detection of cardiac rhabdomyomas to monitoring rapamycin therapy to treatment of AMLs by interventional radiology.

Objectives: The aim of the study described here was to characterize the efficacy and safety of vagus nerve stimulation in a population of patients with tuberous sclerosis complex (TSC) and intractable epilepsy., Methods: This retrospective study comprised 16 patients with TSC who underwent implantation of a vagus nerve stimulator for treatment of intractable epilepsy., Results: The average age at vagus nerve stimulator implantation was 15 years (range: 2-44, SD: 12.5) and the average duration of follow-up on VNS was 4 years (range: 0.5-8.6, SD: 2.3). Outcome was rated class I (>80% seizure frequency reduction) in 3 (19%), class II (50-79% reduction) in 5 (31%), class III (<50% reduction) in 2 (13%), class IV (magnet benefit only) in 1 (6%), and class V (no improvement) in 5 (31%) patients. Intermittent magnet use was effective in aborting seizures in 8 (50%). Five (31%) patients reported an improved level of functioning., Conclusion: The findings suggest that the vagus nerve stimulation can be an effective and safe therapy for patients with TSC with intractable epilepsy.

Lymphangioleiomyomatosis (LAM) is a rare multisystemic disease of women of child-bearing age and affects mainly the lungs, promoting cystic destruction of lung parenchyma or leading to abdominal tumor formation (e.g., angiomyolipomas, lymphangioleiomyomas). LAM can arise sporadically or in association with tuberous sclerosis complex (TSC), an autosomal inherited syndrome characterized by hamartoma-like tumor growth and pathologic features that are distinct from manifestations of pulmonary LAM. A substantial body of evidence has now been gathered suggesting that the two diseases share a common genetic origin. TSC is caused by mutations in two genes, TSC1 on chromosome 9q34 and TSC2 on 16p13. Both of these genes are tumor suppressor genes encoding hamartin (TSC1) and tuberin (TSC2). Sporadic LAM is correlated with a mutation in the TSC2 gene and tuberin appears to play a central role in the pathogenesis of the disease. A TSC2 loss or mutation leads to disruption of the tuberin-hamartin heteromer and dysregulation of S6K1 activation leading to aberrant cell proliferation seen in LAM disease. The extremely diverse clinical and radiologic features of the disease and the complex therapeutic approach are reviewed in detail. Although new therapeutic agents have been tested, to date no effective treatment has been proposed and the prognosis of patients with LAM remains poor. As long as newer therapeutic agents do not change this picture, lung transplantation remains the last hope for patients with respiratory failure at the advanced stage of the disease.

Objective: The purpose of this article is to present neuroimaging findings in tuberous sclerosis complex, including recently developed imaging techniques that have demonstrated clinical benefit to this patient population., Conclusion: Neuroimaging advances have improved the diagnosis of tuberous sclerosis complex and the treatment of children with this condition. Superimposition of functional information from PET onto MRI allows accurate and noninvasive identification of epileptogenic tubers, improving surgical cure rates. Magnetic source imaging can also be used to localize epileptiform activity arising from tubers.

Background: Tuberous sclerosis is an autosomal-dominant inherited disease involving many organs of the body. Oral manifestations include gingival enlargement, fibromas, and dental enamel pitting. The report presents a case of tuberous sclerosis with gingival enlargement histologically consistent with angiofibroma, describes its successful periodontal management, and reviews the literature associated with oral manifestations of tuberous sclerosis., Methods: A 26-year-old white male presented to the Department of Periodontics and Implant Dentistry, New York University College of Dentistry, with a diagnosis of tuberous sclerosis and a chief complaint of gingival enlargement affecting mastication and esthetics. Following a complete medical history review, consultation with the patient's medical team at New York University Medical Center, and a thorough oral and periodontal examination, a treatment plan was developed that included oral hygiene instructions, mechanical debridement, and periodontal reevaluation. This was followed by gingivectomy, which provided improved function and esthetics. Excised tissue was submitted for histologic examination. The patient was followed every 2 months for assessment of the outcome of the surgical treatment. An extensive search of the dental and dermatologic literature was performed on MEDLINE., Results: Histologic examination of the gingival tissue revealed features consistent with angiofibroma. Fifteen months following gingivectomy, the contours and gingival surface appearance remained normal., Conclusions: The gingival enlargement was histologically consistent with the characteristic angiofibromas of tuberous sclerosis. The gingival enlargement responded very well to gingivectomy and periodontal maintenance.

Tuberous sclerosis complex (TSC) is an important cause of epilepsy, autism, and renal and pulmonary disease in children and adults. The clinical course of TSC and the prognosis and appropriate therapy for TSC patients are often different than that for individuals with epilepsy, renal tumors, or interstitial lung disease from other causes. This article reviews the current therapeutic recommendations for medical and surgical management of neurologic, renal, and pulmonary manifestations of TSC. In addition, recent clinical trials using inhibitors of the mammalian target of rapamycin (mTOR) have demonstrated regression of astrocytomas, angiofibromas, and angiomyoliomas, as well as improved pulmonary function in persons with TSC.

Background: Tuberous sclerosis complex (TSC), a tumor syndrome caused by mutations in TSC1 or TSC2 genes, is characterized by the development of hamartomas. We previously isolated, from an angiomyolipoma of a TSC2 patient, a homogenous population of smooth muscle-like cells (TSC2(-/-) ASM cells) that have a mutation in the TSC2 gene as well as TSC2 loss of heterozygosity (LOH) and consequently, do not produce the TSC2 gene product, tuberin. TSC2(-/-) ASM cell proliferation is EGF-dependent., Methods and Findings: Effects of EGF on proliferation of TSC2(-/-) ASM cells and TSC2(-/-) ASM cells transfected with TSC2 gene were determined. In contrast to TSC2(-/-) ASM cells, growth of TSC2-transfected cells was not dependent on EGF. Moreover, phosphorylation of Akt, PTEN, Erk and S6 was significantly decreased. EGF is a proliferative factor of TSC2(-/-) ASM cells. Exposure of TSC2(-/-) ASM cells to anti-EGFR antibodies significantly inhibited their proliferation, reverted reactivity to HMB45 antibody, a marker of TSC2(-/-) cell phenotype, and inhibited constitutive phosphorylation of S6 and ERK. Exposure of TSC2(-/-) ASM cells to rapamycin reduced the proliferation rate, but only when added at plating time. Although rapamycin efficiently inhibited S6 phosphorylation, it was less efficient than anti-EGFR antibody in reverting HMB45 reactivity and blocking ERK phosphorylation. In TSC2(-/-) ASM cells specific PI3K inhibitors (e.g. LY294002, wortmannin) and Akt1 siRNA had little effect on S6 and ERK phosphorylation. Following TSC2-gene transfection, Akt inhibitor sensitivity was observed., Conclusion: Our results show that an EGF independent pathway is more important than that involving IGF-I for growth and survival of TSC(-/-) ASM cells, and such EGF-dependency is the result of the lack of tuberin.

Tuberous sclerosis complex (TSC) is an autosomal-dominant phacomatosis that manifests with visceral harmatomas, epilepsy, and mental retardation. Paranasal angiofibromas may cause bleeding and difficulties in nasal breathing and can stigmatise the individual. When treating TSC patients, the otolaryngologist must take patient compliance and the tendency to develop malignancies into account. We report on a 34-year-old woman who was treated successfully by a combination of CO(2) laser treatment and fibrin glue. The cosmetic results were excellent.