Tuberous sclerosis

INTRODUCTION: Whilst most patients with PLGG will survive, varying morbidities derived from patient,tumour & treatment characteristics can afflict life-long disabling functional impairments. No PLGG studies have evaluated potential prognostic factors for important functional outcomes. METHODS: We performed retrospective analysis of all children diagnosed with PLGG at GOSH 1980-2021.Review of medical notes recorded patient demographics,tumour characteristics & treatment data.Functional outcomes included endocrine,educational,visual (in OPG),auditory & physical function.Multivariate regression analysis(p<0.05) examined associations between biological prognostic variables & functional outcomes. RESULTS: 814 patients were diagnosed with PLGG.731(90%) had 5-years follow-up from diagnosis & were included for functional analysis.Median age at diagnosis 7 years(0-17.9); 50.6%Male,12.2% NF1.Tumours were cerebral(2 7%),cerebellar(27%),hypothalamo-chiasmatic(19%),brainstem(7%),or other(20%);with disseminated disease in 5%.Pilocytic Astrocytoma constituted 46%.Molecular profiling of 133 revealed 5%BRAFV600E mutation,42%BRAF-KIAA1549 fusion.Treatments included: Surgery(7 0%),Chemotherapy(20%),& Radiotherapy(21%).20-year-OS 94%,PFS 76%;median follow-up 16 years(5-38). Documented neurocognitive deficiency(30%) associated with chemotherapy(HR2.36,95%CI 1.49-3.75,P<0.001), radiotherapy(HR 2.25,95%CI1.5-3.36,P<0.001) & male gender(HR 0.68,95%CI 0.49-0.95,P0.02)as independent poorprognostic risk-factors.Chemotherapy (HR 5.7,95%CI1.4-22.3,P0.01) & radiotherapy(HR6.77,95%CI2.1-22.0,P0.001) were independent riskfactors for requirement of Educational-Health-Care-Plans(25%).9% attended specialised schools. Combined-limb-MRC-grade <18/20(6.4%) was independently-associated with receiving chemotherapy(HR 2.77,95%CI1.29-5.93,P0.01),& radiotherapy(HR 6.28,95%CI3.25-12.15,P<0.001).6% mobilised by wheelchair.Resolution of seizures occurred in 68% of 176 following PLGG treatment. Single/multiple endocrinopathies occurred in 9.3%/11%.Presence of 2+Endocrinopathies was associated with chemotherapy(HR6.

This case report describes an uncommon benign neoplasm named Abrikossoff’s tumour or granular cell tumour. Its histological origin is controversial, since several studies have shown that different cells are involved. Granular cell tumour was initially described as myoblastoma, but, at present, a neural origin is supported by most Authors, due to the immunohistochemical pattern. The case presented were unique nodule on tongue mucosa, occurring in young boy of 19 years old. Histopathological features, differential diagnosis and therapeutic implications of granular cell tumour are discussed, together with a brief review of the recent literature.

Lymphangioleiomyomatosis (LAM) is a cystic lung disease that can be included in the wide group of proliferative lesions named PEComas (perivascular epithelioid cell tumors). These proliferative tumors are characterized by the coexpression of myogenic and melanogenesis-related markers. In all these lesions, genetic alterations related to the tuberous sclerosis complex (TSC) have been demonstrated. Striking improvements in the understanding of the genetic basis of this autosomal dominant genetic disease are coupled to the understanding of the mechanisms that link the loss of TSC1 (9q34) or TSC2 (16p13.3) genes with the regulation of the Rheb/m-TOR/p70S6K pathway. These data have opened a new era in the comprehension of the pathogenesis of LAM and have also suggested new therapeutic strategies for this potentially lethal disease. To present and discuss the pathologic and molecular features of LAM within the spectrum of PEComas, providing a rational approach to their diagnosis. The publ...

The perivascular epithelioid cell (PEC) is a cell type constantly present in a group of tumors called PEComas. PEC expresses myogenic and melanocytic markers, such as HMB45 and actin. Recently, recurrent chromosomal alterations have been demonstrated in PEC. At present, PEComa is a widely accepted entity. In the past 10 years, the use of this term has allowed to report and describe numerous cases permitting to start highlighting the biology of this group of lesions. PEComas are related to the genetic alterations of tuberous sclerosis complex (TSC), an autosomal dominant genetic disease due to losses of TSC1 (9q34) or TSC2 (16p13.3) genes which seem to have a role in the regulation of the Rheb/mTOR/p70S6K pathway. There are some open questions about PEComas regarding its histogenesis, the definition of epithelioid angiomyolipoma and the identification of the histological criteria of malignancy. An innovative therapeutic trial using rapamycin is under way for tumors occurring in TSC such as renal angiomyolipoma and lymphangioleiomyomatosis. Its success could provide the rationale for the use of the same drug in other lesions composed of PECs, especially in the malignant ones.

Lymphangioleiomyomatosis is a rare and progressive lung cystic disease, caused by the infiltration of lung parenchyma by mesenchymal cells characterized by co-expression of contractile proteins and melanocytic markers. The pathogenesis of lymphangioleiomyomatosis is determined by mutations affecting tuberous sclerosis complex (TSC) genes, with eventual deregulation of the Rheb/mTOR/p70S6K pathway, and the potential therapeutic activity of mTOR inhibitors is currently under investigation. To better understand the molecular mechanisms involved in the pathogenesis of lymphangioleiomyomatosis, we investigated the expression of cathepsin-k (a papain-like cysteine protease with high matrix-degrading activity). The rationale of this choice was based on the recent demonstration that mTOR inhibitors can regulate major functional activities of osteoclasts, including the expression of cathepsin-k. The immunohistochemical study included 12 cases of lymphangioleiomyomatosis. Twelve angiomyolipomas and several lung diseases (sarcoidosis, organizing pneumonia, usual interstitial pneumonia, emphysema) were investigated as controls. In all lymphangioleiomyomatosis cases, strong cathepsin-k immunoreactivity was demonstrated, restricted to lymphangioleiomyomatosis cells. Similar expression levels were observed in renal angiomyolipomas. These observations extend the knowledge regarding the immunophenotypic profile of lymphangioleiomyomatosis cells, and provide a useful new marker for diagnosis in difficult cases (eg, in small transbronchial biopsies). The strong expression of such a potent papain-like cysteine protease in lymphangioleiomyomatosis cells can significantly contribute to the progressive remodelling of lung parenchyma observed in this deadly disease, with eventual formation of lung cysts. It is possible to speculate that mTOR inhibitors may exert part of their action by limiting the destructive remodelling of lung structure.

Perivascular epithelioid cell tumors (PEComas) are mesenchymal tumors composed of histologically, immunohistochemically, ultrastructurally, and genetically distinctive cells. PEComas have been described in different organs and are considered ubiquitous tumors. In this review we discuss recent informations related to PEComas in the genitourinary tract.

In this manuscript, we summarize the main features of angiomyolipoma highlighting the recognition of epithelioid angiomyolipoma and the discovery of immunohistochemical expression of HMB45 in a group of tumors that now are referred to as as PEComas. In this scenario, Dr. Rosai believed in our intuition, demonstrating his intellectual honesty and motivated us with his experience ("when a tumor seems malignant it is malignant") and enthusiasm for the new entities ("in Verona, you use HMB45 instead of H&E"). He really pushed the improvement of the knowledge in this field.

The manuscript is a retrospective patient record-based study that compares the effectiveness of two types of brain surgeries in controlling temporal lobe epilepsy. The findings are conclusive and are very useful to the neurosurgeon in making decision about the choice of type of surgery. The study nevertheless ignores comparison of important aspects of neurologic function like cognition, memory and learning. Although the objective of the study was to compare effectiveness of temporal lobe epilepsy control, it is important for the neurosurgeon to know the comparison of the side effects of each procedure on the language and cognitive function. The manuscript is well written and the results it presents are significant. I suggest adjusting the title to indicate that the study only compared the two procedures regarding their effectiveness in control of temporal lobe epilepsies.

Stwardnienie guzowate (SG) jest schorzeniem polegającym na powstawaniu zmian typu hamartoma w różnych narządach: skórze, mózgu, sercu, płucach, nerkach i wątrobie. Dziedziczy się autosomalnie dominująco. 70% przypadków stanowią mutacje sporadyczne, 30% przypadki rodzinne. Za występowanie objawów choroby odpowiedzialna jest mutacja jednego z dwóch genów supresorowych nowotworów TSC1 lub TSC2. Artykuł omawia kryteria diagnostyczne, zwracając szczególną uwagę na najwcześniej pojawiające się zmiany i możliwości diagnostyki prenatalnej. W części poświęconej leczeniu nacisk położono na skuteczne leczenie padaczki i zapobieganie rozwojowi upośledzenia umysłowego oraz próby leczenia zmian narządowych za pomocą rapamycyny.

In the study we reassessed the clinical features of 22 patients diagnosed with tuberous sclerosis complex but with no mutation in TSC1 or TSC2 gene found, and compared them with the phenotypes of TSC1 and TSC2 patients, characterized in our previous study. Material and Methods: In a cohort of over 230 patients with tuberous sclerosis complex (TSC) diagnosed at the Children's Memorial Health Institute mutational analysis of the TSC1 and TSC2 genes has been carried out. In this group we identified 22 subjects (17 sporadic, 5 familial cases) in whom there were no definite mutational findings (the NMI -no mutation identified group). Results: Epilepsy, hypomelanotic macules, facial angiofibroma, shagreen patches, ungual fibroma, SEGA, cortical tubers and kidney cysts were less common in the NMI group than in TSC1 or TSC2. Mental retardation was seen at similar frequency in the NMI and TSC2 groups. Frequency of other features: forehead plaque, SENs, kidney AMLs, liver AMLs and cardiac rhabdomyomas remained lower in the NMI than in TSC2, but higher than in TSC1 group. Conclusions: NMI patients had milder clinical features than patients with defined mutations in either TSC1 or TSC2 genes. Mosaicism is a likely explanation for this observation among sporadic TSC patients. In familial cases, however, the possibility of a distinct mutational spectrum or even mutation in a third TSC gene must be considered. Cel: W pracy przeprowadzono analizę objawów klinicznych 22 pacjentów ze stwardnieniem guzowatym (SG), ale bez znalezionej mutacji w genach TSC1 lub TSC2, oraz porównano ich fenotypy do opisanych we wcześniejszym badaniu fenotypów pacjentów ze stwierdzonymi mutacjami w TSC1 i TSC2. Materiał i metoda: W grupie 230 pacjentów ze zdiagnozowanym w Instytucie "Pomnik-Centrum Zdrowia Dziecka" SG (ang. TSC) wykonano badanie genetyczne poszukując mutacji w genach TSC1 i TSC2. Wśród tych pacjentów u 22 (17 przypadków sporadycznych, 5 rodzinnych) nie znaleziono mutacji w żadnym z genów (grupa NMI -no mutation identified). Wyniki: Padaczka, plamy odbarwieniowe, angiofibroma twarzy, skóra szagrynowa, włókniaki okołopaznokciowe, SEGA, guzki podkorowe i torbiele nerek występowały rzadziej w grupie NMI niż w grupach z mutacją w TSC1 lub TSC2. Upośledzenie umysłowe stwierdzano równie często w grupie NMI i u pacjentów z TSC2. Częstość innych cech SG: płaskie włókniaki czoła, guzki okołokomorowe (SEN), angiomiolipoma (AML) nerek i rabdomioma serca pozostawała niższa w grupie NMI niż TSC2, ale wyższa niż w TSC1. Wnioski: Pacjenci z grupy NMI prezentują łagodniejsze objawy kliniczne niż pacjenci ze stwierdzoną mutacją w genach TSC1 lub TSC2. Mozaikowatość może tłumaczyć to zjawisko u pacjentów ze sporadyczną postacią SG. W postaciach rodzinnie występujących można jednak brać pod uwagę obecność mutacji modyfikujących ekspresję TSC1 lub TSC2, a nawet obecność mutacji w trzecim, nieznanym jeszcze genie SG.

Background: Epilepsy develops in 70-90% of children with Tuberous Sclerosis Complex (TSC) and is often resistant to medication. Treatment with mTOR pathway inhibitors is an important therapeutic option in drug-resistant epilepsy associated with TSC. Our study evaluated the antiepileptic effect of rapamycin in the pediatric population of patients diagnosed with TSC. Methods: This single center, open-label study evaluated safety and anti-epileptic efficacy of 12 months of rapamycin treatment in 32 patients aged from 11 months to 14 years with drug-resistant TSC-associated epilepsy. Results: After the first 6 months of treatment, the improvement in seizure frequency, defined as at least a 50% reduction in the number of seizures per week compared to baseline, was seen in 18 individuals (56.25%). We observed no change in 12 individuals (37.5%) and worsening, defined as increase in the number of seizures-in 2 patients (6.25%). The overall improvement defined as at least a 50% reduction in seizure frequency was found in 65.6% of all patients after 12 months with 28% of patients obtaining complete remission. Another five patients experienced at least an 80% reduction in the frequency of seizures. Concomitant treatment with vigabatrin, and to a much lesser extent topiramate and levetiracetam, was an additional favorable prognostic factor for the success of the therapy. A linear relationship between the cumulative dose of rapamycin and its therapeutic effect was observed. The safety profile of the drug was satisfactory. In none of the observed cases did the adverse events reach the level that required withdrawal of the rapamycin treatment. The reason for dropouts was insufficient drug efficacy in 3 cases. Conclusions: Long-term use of rapamycin, especially in combination with vigabatrin, might be a beneficial therapeutic option in the treatment of drug-resistant epilepsy in children with TSC.

Purpose Subependymal giant cell astrocytoma (SEGA) is a brain tumor associated with tuberous sclerosis complex (TSC). It usually grows in a second decade of life, but may develop in the first months of life. The aim of this work was to establish the incidence, clinical features, and outcome of congenital SEGA in TSC patients. Methods Cohort of 452 TSC patients was reviewed to identify cases with growing or hydrocephalus producing SEGAs in the first 3 months of life. Clinical presentation, size of the tumor, growth rate, mutational analysis, treatment applied, and outcome were analyzed. Results Ten (2.2 %) patients presented with SEGA in the first 3 months of life. All of them had documented SEGA growth and all developed hydrocephalus. In eight patients, mutational analysis was done, and in all of them, TSC2 gene mutations were identified. Mean maximum SEGA diameter at baseline was 21.8 mm. Mean SEGA growth rate observed postnatally was 2.78 mm per month and tended to be higher (5.43 mm per month) in patients with TSC2/PKD1 mutation than in other cases. Seven patients underwent SEGA surgery and surgeryrelated complications were observed in 57.1 % cases. One patient was successfully treated with everolimus as a primary treatment. Conclusions Congenital SEGA develops 2.2 % of TSC patients. Patients with TSC2 mutations, and especially with TSC2/PKD1 mutations, are more prone to develop SEGA earlier in childhood and should be screened for SEGA from birth. In young infants with SEGA, both surgery and mTOR inhibitor should be considered as a treatment option.

Backgroud: Drug-resistant epilepsy is the main risk factor for future intellectual disability in patients with tuberous sclerosis complex. Clinical epileptic seizures are often preceded by electroencephalographic changes, which provide an opportunity for preventive treatment. We evaluated the neuropsychologic and epilepsy outcomes at school age in children with tuberous sclerosis complex who received preventive antiepileptic treatment in infancy. Methods: We performed a prospective, nonrandomized clinical trial with 14 infants diagnosed with tuberous sclerosis complex in whom serial electroencephalographic recordings were performed and preventive treatment with vigabatrin initiated when active epileptic discharges were detected. An agematched control group consisted of 31 infants with tuberous sclerosis complex in whom treatment with vigabatrin was given only after onset of clinical seizures. Results of clinical assessment of epilepsy and cognitive outcomes were analyzed. Results: All patients in the preventive group (n ¼ 14) and 25 of 31 patients in the standard treatment group were followed through minimum age five years, median 8.8 and 8.0 years in the preventive and standard groups, respectively. The median intelligence quotient was 94 for the preventive group when compared with 46 for the standard group (P < 0.03). Seven of 14 patients (50%) in the preventive group never had a clinical seizure when compared with one of 25 patients (5%) in the standard treatment group (P ¼ 0.001). Conclusions: This study provides evidence that preventive antiepileptic treatment in infants with tuberous sclerosis complex improves long-term epilepsy control and cognitive outcome at school age.

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introduction. Epilepsy that is associated with neurocutaneous disorders seriously deteriorates quality of life and cognitive outcome of affected children. Recent advances in epilepsy pathophysiology raise hopes for better treatment results in this difficult group of patients. Aim. The aim of this review is to present recent treatment recommendations as well as current research progress in the most frequent neurocutaneous disorders. Material and methods. We analyzed PubMed database to select the most prominent and recent (up to 2014 year) publications on the treatment and mechanisms of epilepsy in selected neurocutaneous disorders. We aimed to emphasize evidence-based medicine recommendations as well as basic experimental studies dealing with molecular mechanisms of epileptogenesis. discussion and conclusions. Recent advances in disease-modifying treatment options such as mTOR inhibitors in patients with tuberous sclerosis complex open up new perspectives for neurologists. Traditional resective surgery has still a major role as a treatment of choice in carefully selected cases. key words: epilepsy • neurocutaneous disorders • tuberous sclerosis • pathogenesis • treatment recommendation ities of the central nervous system may result in epilepsy which is a major factor affecting quality of life and cognitive outcome of the affected children. This review summarizes scientific progress as well as recent recommendations and advances in the treatment of seizures in the most common neurocutaneous disorders, in which epilepsy is a major symptom. The aim of the study is to present in an orderly way state-of-the art knowledge concerning pathogenesis and treatment of epilepsy in the most frequent neurocutaneous syndromes. Neurocutaneous disorders are a broad term for a group of congenital and hereditary multisystem disorders with characteristic central nervous system and cutaneous lesions of variable severity. Although each condition is distinct and characterized by a unique pathophysiology, the concept unifies these neurological disorders whose preliminary identification depends predominantly on simple visual diagnosis. Historically this category included tuberous sclerosis, neurofibromatosis, encephalotrigeminal angiomatosis (Sturge-Weber disease) and retino-cerebellar angiomatosis (von Hippel-Lindau disease). Up to now neurocutaneous disorders include about 80 different conditions. Abnormal-

Wstęp: Stwardnienie guzowate (SG) jest uwarunkowaną genetycznie chorobą skórno-nerwową dotykającą 1 na 6000 osób. W jej przebiegu dochodzi do rozwoju mnogich, zwykle łagodnych guzów w obrębie wielu narządów. Napady padaczkowe są częstym objawem i występują u 70-90% pacjentów z SG. Padaczka w SG zazwyczaj rozwija się w pierwszych miesiącach życia i często prowadzi do wystąpienia niepełnosprawności umysłowej. W ostatnich latach podejmowane są próby prewencyjnego leczenia padaczki w przebiegu SG. Aby było to możliwe, konieczne jest wczesne rozpoznanie choroby. Najwcześniejszym możliwym do zaobserwowania objawem SG są guzy rhabdomyoma serca, często rozpoznawane już w okresie prenatalnym. Cel pracy: Celem pracy była ocena i porównanie częstości rozpoznania SG u dzieci z pojedynczymi i mnogimi guzami serca. Materiał i metody: Przeprowadzono retrospektywną analizę historii chorób 76 dzieci, które z powodu pojedynczych lub mnogich guzów serca były skierowane do Instytutu "Pomnik -Centrum Zdrowia Dziecka" w Warszawie celem dalszej diagnostyki w kierunku SG. Wyniki: Pojedyncze lub mnogie guzy serca były obecne u odpowiednio 14,5% oraz 85,5% dzieci. W większości przypadków (71,1%) zmiany były wykryte w okresie prenatalnym. Pewne rozpoznanie SG postawiono u 92,1% dzieci. Zaobserwowano istotną korelację między mnogimi guzami serca a pewnym rozpoznaniem SG (p < 0,01), które w tej grupie pacjentów było również znacząco częstsze w porównaniu z dziećmi z pojedynczymi guzami serca (95,4% vs 72,7%, p < 0,05). Wnioski: Stwardnienie guzowate może być rozpoznane zarówno u pacjentów z pojedynczymi, jak i mnogimi rhabdomyoma serca. Występowanie mnogich zmian w sercu znacząco zwiększa jednak prawdopodobieństwo rozpoznania SG i może być traktowane jako jeden z wczesnych biomarkerów choroby.

Background The genetic disorder tuberous sclerosis complex (TSC) is frequently accompanied by the development of neuropsychiatric disorders, including autism spectrum disorder and intellectual disability, with varying degrees of impairment. These co-morbidities in TSC have been linked to the structural brain abnormalities, such as cortical tubers, and recurrent epileptic seizures (in 70–80% cases). Previous transcriptomic analysis of cortical tubers revealed dysregulation of genes involved in cell adhesion in the brain, which may be associated with the neurodevelopmental deficits in TSC. In this study we aimed to investigate the expression of one of these genes – cell-adhesion molecule contactin-3. Methods Reverse transcription quantitative polymerase chain reaction for the contactin-3 gene (CNTN3) was performed in resected cortical tubers from TSC patients with drug-resistant epilepsy (n = 35, age range: 1–48 years) and compared to autopsy-derived cortical control tissue (n = 27, a...

Objectives: Experimental data indicate that activating mutations in the mTOR (mammalian target of rapamycin) pathway may lead to abnormal arterial wall structure. Vascular anomalies like arterial stenoses are reported in pediatric patients with tuberous sclerosis complex (TSC). In addition, large renal lesions (angiomyolipoma—AML and cysts) are risk factors for arterial hypertension in adult patients with TSC. This study aimed to assess blood pressure, including central blood pressure and arterial damage (early vascular aging—EVA) in children with TSC.Materials and Methods: In a group of 33 pediatric patients with TSC (11.13 ± 4.03 years, 15 boys, 18 girls), we evaluated peripheral and central office blood pressure, 24-h ambulatory blood pressure, and arterial damage: aortic pulse wave velocity (aPWV) [m/s], [Z-score], augmentation index (AIx75HR [%]), common carotid artery intima-media thickness (cIMT) [mm], [Z-score], stiffness of common carotid artery (E-tracking), renal lesions ...

A dysmature EEG background was also associated with lower cognitive (p-value = 0.029), language (p-value = 0.001), and motor (p-value = 0.017) developmental quotients at the age of 24 months. Our findings suggest that early EEG characteristics in newborns and infants with TSC can be used to predict neurodevelopmental comorbidities.

Tuberous sclerosis complex (TSC) is a genetic disease presenting with multiple neurological symptoms including epilepsy, mental retardation, and autism. Abnormal activation of various inflammatory pathways has been observed in astrocytes in brain lesions associated with TSC. Increasing evidence supports the involvement of microRNAs in the regulation of astrocyte-mediated inflammatory response. To study the role of inflammation-related microRNAs in TSC, we employed real-time PCR and in situ hybridization to characterize the expression of miR21, miR146a, and miR155 in TSC lesions (cortical tubers and subependymal giant cell astrocytomas, SEGAs). We observed an increased expression of miR21, miR146a, and miR155 in TSC tubers compared with control and perituberal brain tissue. Expression was localized in dysmorphic neurons, giant cells, and reactive astrocytes and positively correlated with IL-1β expression. In addition, cultured human astrocytes and SEGA-derived cell cultures were used...

Introduction: Mechanistic target of rapamycin (mTOR) inhibitors sirolimus and everolimus are an effective therapy for subependymal giant cell astrocytomas, cardiac rhabdomyomas, renal angiomyolipomas, and lymphangioleiomyomatosis associated with tuberous sclerosis complex (TSC). Everolimus was recently approved in the EU and the USA for the treatment of refractory focal-onset seizures. Despite frequent use of mTOR inhibitors, there are only a few studies on their effect on epilepsy control in children under 2 years of age. This study aims to assess the effect of adjunctive mTOR inhibitor treatment on seizure frequency in this age group. Methods: We performed retrospective data analysis of medical records of patients with TSC who initiated sirolimus or everolimus under the age of 2 years. Participants' antiseizure medication was adjusted according to their epilepsy control independently from mTOR inhibitor administration. The data was assessed separately for patients treated with mTOR inhibitors before and after the onset of seizures. We also compared the treatment group with a matched control group. The follow-up duration was up to 24 months. Results: Twenty-one patients with TSC from two clinical centers were included in the study. Nine participants had no history of seizures before mTOR inhibitor initiation. Twelve reported active epilepsy in the month prior to treatment initiation. Most patients treated preventively with mTOR inhibitors did not report active epilepsy at the end of their follow-up. In the second group, the mean frequency of seizures decreased with time. According to the comparative analysis, seizure control was better in the groups treated with mTOR inhibitors. Conclusion: Patients with TSC treated with mTOR inhibitors demonstrated better seizure control than individuals without this treatment. Adjunctive pharmacotherapy with mTOR inhibitors appears to have a beneficial effect on epilepsy outcome in young children. Further prospective clinical trials should be conducted

Pulmonary Lymphangioleiomyomatosis (LAM) is a rare and female-dominant disease and associated with smooth muscle cell proliferation, (LAM) which presents with diffuse progressive destruction of the pulmonary parenchyma. The incidence is less than 1 per million, which results in cystic lung disease and presente commonly with dyspnea and pneumothorax. Work up for diagnosis and exclusion other disease as: Sjögren's syndrome type A, B and mazement of angiotensin-converting enzyme (ACE) levels, alpha-1-antitrypsin levels, and vascular endothelial growth factor (VEGF) anti bodies. Definitive diagnosis limited only to tissue sampling. No effective treatments are currently proposed for this disease. Two 49 and 39year-old woman who was referred with recurrent pneumothorax, after thoracotomy and resection, diagnosed was made with pulmonary Lymphangioleiomyomatosis. After pulmonary Lymphangioleiomyomatosis was performed, they treated with anti-estrogen therapy and symptomatic supportive care. In follow up pneumothorax was not occurred again. Pulmonary Lymphangioleiomyomatosis is a very rare disease that cannot be effectively cured.

INTRODUCTION: Rhabdomyomas are the most frequent cardiac tumors in children. Furthermore, they are often associated to tuberous sclerosis complex, an autosomal dominant neurocutaneous disorder characterized by tumor-like malformations that involve many organ systems. PRESENTATION OF THE CASE: We describe a rare ECG pattern in a severe case of neonatal tuberous sclerosis complex. DISCUSSION: In the presence of significant rhabdomyomatosis related to tuberous sclerosis, multiple clusters of rhabdomyoma-like cells can infiltrate the myocardium, with increased fibrosis areas. CONCLUSION: Considering the fact that rhabdomyomas often show spontaneous regression, close followup is sufficient in hemodynamically stable cases. Destruction of the conduction system, with arrhythmias as consequence, can be the presenting feature of diffuse rhabdomyomatosis.

INTRODUCTION: Rhabdomyomas are the most frequent cardiac tumors in children. Furthermore, they are often associated to tuberous sclerosis complex, an autosomal dominant neurocutaneous disorder characterized by tumor-like malformations that involve many organ systems. PRESENTATION OF THE CASE: We describe a rare ECG pattern in a severe case of neonatal tuberous sclerosis complex. DISCUSSION: In the presence of significant rhabdomyomatosis related to tuberous sclerosis, multiple clusters of rhabdomyoma-like cells can infiltrate the myocardium, with increased fibrosis areas. CONCLUSION: Considering the fact that rhabdomyomas often show spontaneous regression, close followup is sufficient in hemodynamically stable cases. Destruction of the conduction system, with arrhythmias as consequence, can be the presenting feature of diffuse rhabdomyomatosis.

BackgroundActivating variants in platelet‐derived growth factor receptor beta (PDGFRB), including a variant we have previously described (p.Tyr562Cys [g.149505130T&gt;C [GRCh37/hg19]; c.1685A&gt;G]), are associated with development of multiorgan pathology, including aneurysm formation. To investigate the association between the allele fraction genotype and histopathologic phenotype, we performed an expanded evaluation of post‐mortem normal and aneurysmal tissue specimens from the previously published index patient.Methods and ResultsFollowing death due to diffuse subarachnoid hemorrhage in a patient with mosaic expression of the above PDGFRB variant, specimens from the intracranial, coronary, radial and aortic arteries were harvested. DNA was extracted and alternate allele fractions (AAF) ofPDGFRBwere determined using digital droplet PCR. Radiographic and histopathologic findings, together with genotype expression ofPDGFRBwere then correlated in aneurysmal tissue and compared to non...

The authors present an unusual case of a 3-year-old girl who was diagnosed with a fast-growing brachial aneurysm due to tuberous sclerosis. The patient underwent aneurysm resection and microsurgical reconstruction with reversed greater saphenous vein graft at the same time. She had a favorable outcome, without neuromuscular deficits. Doppler ultrasonography was performed for diagnosis, vein graft selection, and postoperative follow-up. The authors believe that such combined approach may be the routine for pediatric vascular reconstructions. Finally, this reconstruction has been rarely reported in tuberous sclerosis patients.

An eighteen-year-old male presented with painless swelling of left lateral malleolus of left ankle for last one year. There was no history of trauma or any significant medical illness. FNAC yielded blood only. Further excision was done and based on histopathological features the diagnosis of synovial hemangioma was rendered. Synovial hemangioma is a rare entity with very few cases reported so far. It is characterized by the presence of normal or abnormal blood vessels, arising from the synovial lining of the tendon sheath or joint space. The clinical presentation is not so specific. Histopathology of the synovectomy specimen plays a very important role in rendering a correct diagnosis. Based on characteristic morphological findings and absence of reactive vessels surrounded by perivascular myxoid change is important in differentiating it from pigmented villonodular synovitis, which has chances of recurrence. The anatomical distributions of these lesions are important in management of these lesions.

Patients with tuberous sclerosis complex (TSC) develop an array of multi-organ disease manifestations, with angiomyolipomas (AML) and cysts in the kidneys being one of the most common and deadly. Early and regular AML/cyst detection and monitoring are vital in lowering TSC patient morbidity and mortality. However, current standard of care for imaging-based methods are not designed for rapid screening, posing challenges for early detection. To identify potential diagnostic screening biomarkers of AML/cysts, we performed global untargeted metabolomics in blood samples from 283 kidney AML/cystpositive or -negative TSC patients using mass spectrometry. We identified seven highly sensitive chemical features, including octanoic acid, that predict kidney AML/cysts in TSC patients. Patients with elevated octanoic acid have lower levels of very long-chain fatty acids (VLCFAs), suggesting that dysregulated peroxisome activity leads to overproduction of octanoic acid via VLCFA oxidation. This study highlights serum metabolites as novel biomarkers for TSC kidney tumor diagnosis and offers valuable metabolic insights into the disease.

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 im...

Lymphangioleiomyomatosis (LAM) is characterized by lung cysts that cause lung deterioration, changes in the lymphatic system, and tumors in the kidneys. It mainly affects women of reproductive age and is a progressive disease. LAM can occur as an isolated disease or coexist with tuberous sclerosis (TSC). The source of LAM cells is unknown. Patients with confirmed LAM should be treated with an mTOR inhibitor, sirolimus, or everolimus. We present a case of LAM with TSC in a patient whose symptoms, including those in the lymph nodes and chyaloperitoneum, mainly concern the abdominal cavity.

Adult cardiac rhabdomyoma (CR) is a rare benign tumor of the heart muscle composed mainly of disorganized myocytes. Cardiac CR is the most common primary cardiac tumor in infants and children but is extremely rare in adults. A cardiac tumor can occur at any site in the myocardium but is predominantly observed in the ventricles. CRs are highly prevalent in tuberous sclerosis complex (TSC) patients, an autosomal dominant syndrome characterized by TSC1 or TSC2 gene mutations. In patients with TSC, CRs are found in more than 50%, part of a spectrum of benign tumors in most organs in this complex. Non-TSC adult CRs are rare benign tumors of uncertain etiology, probably occurring sporadically or due to congenital abnormalities. Their pathophysiology entails hamartomatous cardiac myocyte growths but lacks the genetic or molecular hallmarks seen in TSC-associated cases. As a result, this adult form of CR is still poorly understood because of the condition's rarity. We report the case of a 29-year-old man with adult CR to heighten clinicians' and pathologists' awareness of this rare tumor. We briefly review the pertinent literature, including differential diagnosis, imaging findings, understanding of possible molecular changes, and management that may help to include this tumor in the differential diagnosis of cardiac masses.

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Background: Sleep disturbance is common in children with neurodevelopmental disorders, with high rates identified in children with Smith-Magenis syndrome (SMS), Angelman syndrome (AS), autism spectrum disorder (ASD) and tuberous sclerosis complex (TSC). Phenotypic sleep profiles for these groups may implicate different pathways to sleep disturbance. At present, cross-group comparisons that might elucidate putative phenotypic sleep characteristics are limited by measurement differences between studies. In this study, a standardised questionnaire was administered across groups affording comparison of the prevalence and profile of sleep disturbance between groups and contrast to chronologically age-matched typically developing (TD) peers. The modified version of Simonds and Parraga's sleep questionnaire, adapted for use in children with intellectual disabilities, was employed to assess sleep disturbance profiles in children aged 2-15 years with SMS (n = 26), AS (n = 70), ASD (n = 30), TSC (n = 20) and a TD contrast group (n = 47). Associations between sleep disturbance and age, obesity, health conditions and overactivity/impulsivity were explored for each neurodevelopmental disorder group. Results: Children with SMS displayed severe night waking (81%) and early morning waking (73%). In contrast, children with ASD experienced difficulties with sleep onset (30%) and sleep maintenance (43%). Fewer children with ASD (43%) and AS (46%) experienced severe night waking compared to children with SMS (both p < .01). Higher sleep-disordered breathing scores were identified for children with SMS (p < .001) and AS (p < .001) compared to the TD group. Sleep disturbance in children with AS and TSC was associated with poorer health. Children experiencing symptoms indicative of gastro-oesophageal reflux had significantly higher sleep-disordered breathing scores in the AS, SMS and ASD groups (all p < .01). A number of associations between overactivity, impulsivity, gastro-oesophageal reflux, age and sleep disturbance were found for certain groups.

mTOR is a central controller that integrates many inputs to regulate cell growth and ensure cellular homeostasis. The mTORC1 inhibitor TSC (tuberous sclerosis complex) on the peroxisome is found to inhibit mTORC1 in response to endogenous reactive oxygen species. Thus, mTOR may avoid confounding different inputs by sensing them at different cellular locations.

Angiomyolipoma (AML) is a rare benign mesenchymal neoplasm composed of variable admixture of blood vessels, smooth muscle, and adipose tissue; most commonly located in kidney, and is usually associated with tuberous sclerosis. Extrarenal AML has been reported in various sites, although infrequently in female genital tract (FGT). AML in cervix is extremely rare and only six cases have been reported so far. A 46-year-old postmenopausal female presented with lower abdominal pain, bleeding for 4 days and a polypoidal mass protruding through the cervical os. Endometrial curettings were suggestive of endometrial adenocarcinoma—endometrioid type (World Health Organization [WHO]). The subsequent hysterectomy specimen confirmed the diagnosis and the histologic grade was International Federation of Obstetrics and Gynecology (FIGO) grade I and stage was pT1aN0 (American Joint Committee on Cancer [AJCC], 8th edition). Cervical polyp showed AML. CD34 and smooth muscle actin (SMA) showed diffuse ...

Rhabdomyoma is the most common cardiac tumor detected during fetal life and childhood; nevertheless its incidence is very low. This is a histologically benign tumor, but in some cases may cause hemodynamic repercussion with date of low cardiac output, arrhythmias and exceptionally intrauterine death as occurred in our case, which was detected by obstetric ultrasound and fetal echocardiogram and corroborated by histological study.

Background Tuberous sclerosis complex (TSC) is a rare multisystem autosomal dominant genetic disorder caused by pathogenic mutations in either the TSC1 or TSC2 gene. Common manifestations of TSC have been grouped into major and minor clinical diagnostic criteria and assessed in clinical routine workup. However, case studies point towards the existence of rare disease manifestations and to the potential association of TSC with malignant tumors. In this study we sought to characterize rare manifestations and malignancies using a large cohort of patients. Methods TuberOus SClerosis registry to increAse disease awareness (TOSCA) is a multicenter, international disease registry collecting clinical manifestations and characteristics of patients with TSC, both retrospectively and prospectively. We report rates and characteristics of rare manifestations and malignancies in patients with TSC who had enrolled in the TOSCA registry. We also examined these manifestations by age, sex, and genoty...

A patient with tuberous sclerosis and attention deficit hyperactivity disorders is reported. He presented with generalized tonic-clonic seizures, skin lesions, restlessness, irritability, hyperactivity and impulsivity since 4 years. He had also developed hyperactivity and impulsivity for the past 2 years. Examination showed Shagreen patches and multiple hypomelanotic macules. MRI brain revealed multiple cortical tubers and sub-ependymal nodules. The condition is briefly discussed.

of perinephric haematoma (20.5% vs 31.9%, p = 0.03) was detected in the interventional radiologist group. However, they self-report haematoma, whereas ultrasonographers report haematoma for nephrologists. Conclusions: Interventional radiologists obtained significantly larger specimens than nephrologists. There were no significant differences in post procedural complications other than perinephric haematoma.

Background Tuberous sclerosis complex (TSC) is a monogenetic, multisystem disorder characterized by benign growths due to TSC1 or TSC2 mutations. This German multicenter study estimated the costs and related cost drivers associated with organ manifestations in adults with TSC. Methods A validated, three-month, retrospective questionnaire assessed the sociodemographic and clinical characteristics, organ manifestations, direct, indirect, out-of-pocket (OOP), and nursing care-level costs among adult individuals with TSC throughout Germany from a societal perspective (costing year: 2019). Results We enrolled 192 adults with TSC (mean age: 33.4 ± 12.7 years; range: 18–78 years, 51.6% [n = 99] women). Reported TSC disease manifestations included skin (94.8%) and kidney and urinary tract (74%) disorders, epilepsy (72.9%), structural brain defects (67.2%), psychiatric disorders (50.5%), heart and circulatory system disorders (50.5%), and lymphangioleiomyomatosis (11.5%). TSC1 and TSC2 mutat...