Dravet Syndrome (DS), Helsmoortel-Van Der Aa Syndrome (HVDAS) and Tuberous Sclerosis Complex (TSC) are rare genetic syndromes, sharing intellectual disability (ID) and motor delay. In DS, two distinct gait patterns, crouch and non-crouch, have been described using instrumented 3D gait analysis (i3DGA). This cross-sectional study measures gait in participants with TSC and HVDAS. The findings are compared to the known crouch and non-crouch gait patterns observed in DS and to typical gait.

Participants (6-22 years) with DS (n = 37; 19 crouch and 18 non-crouch), HVDAS (n = 12) or TSC (n = 8) were compared with typically developing (TD) peers (n = 33). All participants underwent i3DGA (Plugin Gait model processed with Vicon Nexus and MATLAB®) to investigate spatiotemporal and lower-limb kinematics.

All three genetic syndromes showed increased step width. Participants with HVDAS and DS, but not participants with TSC walked with decreased step length and velocity compared to TD. HVDAS demonstrated increased knee flexion during the stance phase, lack of hip extension during pre-swing, and increased ankle dorsiflexion during some phases of the gait cycle (p < 0.001). Additionally, HVDAS showed similar kinematic deviations to DS-NonCrouch. No significant differences were found in terms of kinematics between TSC and TD peers (p > 0.05).

The current study reveals differences in gait characteristics from typical functional gait in rare genetic disorders. DS-Crouch, DS-NonCrouch and HVDAS display a more impaired gait from a biomechanical perspective than TSC. The variability of clinical and genetic features might explain heterogeneity in gait deviations and should be further explored.

The development of novel targeted therapies is opening new perspectives in the treatment of pediatric brain tumors. Their precise role in therapeutic protocols still needs still to be defined. Thus, these novel pharmacological approaches in pediatric neurosurgery were the topic of the European Society for Pediatric Neurosurgery (ESPN) Consensus Conference held in Lyon (France) in January 25-27, 2024.

The paper reviews the current knowledge about targeted therapy as well as the current literature published on the topic. The conference aimed for an interdisciplinary consensus debate among pediatric oncologists and pediatric neurosurgeons on the following questions. Question 1: What is the current role for targeted therapies as neoadjuvant treatments before pediatric brain tumor removal? Question 2: What are the benefits, cost/efficiency, and long-term side effects of targeted therapies in the treatment of pediatric brain tumors? Question 3: Based on contemporary data, at which stage and in which pathologies do targeted therapies play a significant role?

Ninety-two participants answered consensus polls on the state of the art of targeted therapies, the ethical issues related to their use, and the evolving change in the role of pediatric neurosurgeons. The neoadjuvant role of targeted therapies is difficult to define as there are many different entities to consider. Despite the recently reported potential benefits, questions regarding the use of targeted therapies are manifold, in particular regarding sustainable benefits and long-term side effects. Additionally, challenging cost issues is a limiting factor for the broader availability of these drugs. Studies have demonstrated superiority of targeted therapy compared to chemotherapy both in randomized trials and compared to historical cohorts in the management of a subset of low-grade gliomas. The same drug combinations, BRAFi and MEKi, may be effective in HGG that have relapsed, progressed, or failed to respond to first-line therapy. Similar conclusions on efficacy may be drawn for mTORi in TSC and selumetinib in plexiform neurofibromas. For other tumors, the picture is still obscure due to the lack of data or even the lack of suitable targets. In conclusion, targeted treatment may not always be the best option even when a target has been identified. Safe surgery remains to be a favorable option in the majority of cases.

The constantly evolving drug technology and the absence of long-term safety and efficacy studies made it difficult to reach a consensus on the predefined questions. However, a report of the conference is summarizing the present debate and it might serve as a guideline for future perspectives and ongoing research.

Tuberous sclerosis complex (TSC) is classified among developmental epileptic encephalopathies, where epilepsy is often associated with comorbidities such as intellectual disability and autistic behavior. The recently introduced term TAND (TSC-associated neuropsychiatric disorders) encompasses the wide range of cognitive, behavioral, psychiatric, and psychosocial manifestations seen in TSC. The severity of these comorbidities is influenced by several factors, including the TSC1/TSC2 genotype, the age of epilepsy onset, the number, volume and type of cortical tubers, the interval between epilepsy onset and treatment initiation, and the presence of infantile spasms, hypsarrhythmia, or drug-resistant epilepsy. Clinical, genetic, EEG, and neuroimaging biomarkers enable the early identification of infants at high risk of developing intellectual disability or autism spectrum disorder. Early preventive intervention targeting seizures and tailored strategies during a sensitive developmental window may modify these contributing factors, leading to improved neurodevelopmental outcomes in infants with TSC.

Subependymal giant cell astrocytomas (SEGAs) are one of the predominant features of the tuberous sclerosis complex (TSC). Before the use of mTOR inhibitors (mTORi; everolimus and sirolimus) in TSC, many patients had to undergo surgical operations (both preemptively and emergently). However, with mTORis gaining increased use, the role of medical and surgical therapy in SEGA is unclear.

The authors have based this review on publications listed in PubMed that delve into the role of surgery and mTORi in the treatment of SEGAs.

There is no sizable head-to-head comparison of surgery and medical therapy in treating SEGA. Factors that reduce the ability to do these types of studies are the lack of uniform diagnosis of SEGA, provider preference for treatment, and variability in each treatment group (dosing of mTORis and various surgical providers). However, with the safety of mTORi, the authors recommend starting mTORi therapy for any growth in a nodule on serial scans and relying on surgery only for failed mTORi therapy.

Tuberous Sclerosis Complex (TSC) is a rare autosomal dominant disorder that is characterized by multisystem involvement and significant neurological manifestations. TSC1 and TSC2 pathogenic variants lead to hyperactivation of the mammalian target of rapamycin (mTOR) pathway, which disrupts cellular growth and differentiation. Epilepsy, affecting 85-90% of individuals with TSC, often presents within the first year of life and is commonly resistant to conventional therapies. This paper provides a comprehensive overview of the diagnostic criteria, pathophysiology, and current treatment strategies for TSC-associated epilepsy, including pharmacological approaches such as vigabatrin, cannabidiol, and mTOR inhibitors, as well as non-pharmacological interventions such as ketogenic diet and epilepsy surgery. Preventive strategies, highlighted by robust trials, delay seizure onset and reduce its severity but have a limited impact on neurodevelopmental outcomes. Challenges include the heterogeneity of cortical tubers, suboptimal seizure control with existing therapies, and underutilization of neuropsychiatric care for TSC-associated neuropsychiatric disorders. Advances in biomarkers, precision medicine, and surgical techniques have paved the way for personalized treatment approaches. Future research providing earlier detection strategies and integrating therapies targeting both the neurological and behavioral dimensions of TSC is ongoing. By addressing these needs, clinicians and researchers can enhance the quality of life and developmental outcomes of individuals with TSC.

Proliferations of neoplastic perivascular epithelioid cells (PECs) may occur within the lung and extrathoracic sites. The term "PEComatosis" is applied to multiple or diffuse microscopic proliferations of neoplastic PECs. Pulmonary diffuse PEComatosis is extremely rare, with only one case documented in the literature to date. We herein report a novel sclerosing variant of diffuse PEComatosis in a 68-year-old woman with clinical tuberous sclerosis complex (TSC), who underwent lung resection for evaluation of persistent, bilateral ground glass opacities. The patient had no respiratory complaints or ventilatory defects in pulmonary function tests. The morphologic features resembled the previous description of pulmonary diffuse PEComatosis, showing interstitial nodular and diffuse proliferation of predominantly clear epithelioid cells with PEC differentiation by immunohistochemistry. The PEComatous proliferation was accompanied by a pattern of sclerosis that overlapped with the sclerosing variant of PEComa. There was no evidence of lymphangioleiomyomatosis. The changes were complicated by neuroendocrine cell hyperplasia, which has not previously been reported in the lungs of patients with TSC.

A 55-year-old man with tuberous sclerosis complex (TSC) was diagnosed with left renal angiomyolipoma (AML), a group of perivascular epithelioid cell tumors called PEComas. He had received the mTOR inhibitor everolimus, which resulted in a complete response. However, a left renal mass relapsed in two years, followed by the occurrence of a hepatic mass five months later. Renal biopsy yielded no diagnosis because of massive necrosis in the tumor cells of the left kidney; however, pathological evaluation of the hepatic mass revealed a PEComa with pleomorphic cells. Even with continuous everolimus therapy, hepatic PEComa progressed aggressively and occupied the entire liver within a year from the first detection. An autopsy revealed pleomorphic cells with nuclear atypia spreading in the liver, kidney, and lung, which were not present in the renal AML sample prior to the initiation of everolimus therapy. This finding raises the possibility of a malignant transformation of the PEComa under the mTOR inhibitor therapy. While PEComas often present with benign characteristics, there are rare instances where the tumor exhibits malignant behavior. This highlights the importance of careful monitoring and long-term follow-up to ensure early detection and effective management of potential malignancies.

Although pancreatic neuroendocrine tumors (PanNETs) are less common than other pancreatic tumors, they show significant differences in clinical behavior, genetics, and treatment responses. The understanding of the molecular pathways of PanNETs has gradually improved with advances in sequencing technology. Mutations in MEN1 (the most frequently varied gene) may result in the deletion of the tumor suppressor menin, affecting gene regulation, DNA repair, and chromatin modification. Changes in ATRX and DAXX involve chromatin remodeling, telomere stability and are associated with the alternative lengthening of telomeres (ALT) pathway and aggressive tumors. VHL mutations emphasize the roles of hypoxia and angiogenesis. Mutations in PTEN, TSC1/TSC2, and AKT1-3 often disrupt the mTOR pathway, complicating the genetic landscape of PanNETs. Understanding these genetic alterations and their impact on the PI3K/AKT/mTOR axis help to investigate new targeted therapies, which in turn can improve patient prognosis. This review aims to clarify PanNET pathogenesis through key mutations and their clinical relevance.

Tuberous sclerosis complex (TSC) is an autosomal dominant inherited disease characterized by systemic hamartomas, neuropsychiatric symptoms known as TAND (TSC-associated neuropsychiatric disorders), and vitiligo. These symptoms are attributed to the constant activation of mechanistic target of rapamycin complex 1 (mTORC1) caused by genetic mutations in the causative genes TSC1 or TSC2. The elucidation of the pathogenesis of this disease and advances in diagnostic technologies have led to dramatic changes in the diagnosis and treatment of TSC. Diagnostic criteria have been created at a global level, and mTORC1 inhibitors have emerged as therapeutic agents for this disease. Previously, the treatment strategy was limited to symptomatic treatments such as surgery. Inhibitors of mTORC1 are effective against all symptoms of TSC, but they also have systemic side effects. Therefore, the need for a cross-disciplinary, collaborative medical care system has increased, resulting in the establishment of a practice structure known as the "TSC Board." Furthermore, to reduce the side effects of systemic administration of mTORC1 inhibitors, a topical formulation of mTORC1 inhibitor was developed in Japan for the treatment of skin lesions caused by TSC. This report summarizes the pathogenesis and current status of TSC and the contribution of the Neurocutaneous Syndrome Policy Research Group to the policies of the Ministry of Health, Labor, and Welfare with respect to this rare, intractable disease.

Tuberous Sclerosis Complex (TSC) is a genetic neurodevelopmental disorder associated with early onset epilepsy, intellectual disability and neuropsychiatric disorders. A hallmark of the disorder is cortical tubers, which are focal malformations of brain development containing dysplastic cells with hyperactive mTORC1 signaling. One barrier to developing therapeutic approaches and understanding the origins of tuber cells is the lack of a model system that recapitulates this pathology. To address this, we established a genetically mosaic cortical organoid system that models a somatic "second-hit" mutation, which is thought to drive the formation of tubers in TSC. With this model, we find that loss of TSC2 cell-autonomously promotes the differentiation of astrocytes, which exhibit features of a disease-associated reactive state. TSC2 -/- astrocytes have pronounced changes in morphology and upregulation of proteins that are risk factors for neurodegenerative diseases, such as clusterin and APOE. Using multiplexed immunofluorescence in primary tubers from TSC patients, we show that tuber cells with hyperactive mTORC1 activity also express reactive astrocyte proteins, and we identify a unique population of cells with expression profiles that match those observed in organoids. Together, this work reveals that reactive astrogliosis is a primary feature of TSC that arises early in cortical development. Dysfunctional glia are therefore poised to be drivers of pathophysiology, nominating a potential therapeutic target for treating TSC and related mTORopathies.

Tuberous Sclerosis Complex (TSC) is a rare autosomal dominant genetic disorder primarily characterized by neurological symptoms. This study aimed to evaluate the current disease burden in Chinese patients with TSC and to identify the potential influencing factors.

A cross-sectional study design was employed using an online questionnaire survey. The questionnaire covered demographics, diagnosis and treatment status, medication use, and disease burden. Descriptive statistics were used to summarize the data, and multivariate logistic regression analysis was performed to examine factors influencing the disease burden in pediatric and adult patients with TSC.

The survey involved a total of 840 patients or their caregivers, comprising 691 pediatric and 149 adult patients, with an average age at diagnosis of 1.77 years for pediatric patients and 15.28 years for adult patients. The most prevalent clinical manifestations were seizures (75.1% in pediatric, 43.6% in adult), brain calcification spots/nodules (87.8% pediatric, 82.5% adult), and hypomelanotic macules (89.5% pediatric, 72.4% adult). Intellectual disability (ID) was reported in 29.6% of pediatric patients and 19.4% of adult patients. Catastrophic health expenditure (CHE) was reported by 29.6% of patients. Factors influencing the disease burden included ID, misdiagnosis, and use of anti-seizure medications (ASMs) and mammalian target of rapamycin (mTOR) inhibitors for pediatric patients or educational attainment, medication use (such as ASMs and mTOR inhibitors), and ID for adult patients.

The study demonstrated that Chinese patients with TSC are confronted with a considerable disease burden. Comprehensive care strategies, tailored educational support for pediatric patients, and multidisciplinary approaches for early diagnosis are crucial for managing TSC.

This editorial discusses a case report recently published in the World Journal of Clinical Cases. The report describes the clinical presentation, imaging, diagnosis, and treatment of a patient with tuberous sclerosis complex (TSC) combined with primary lymphedema (PLE). Additionally, it retrospectively analyzes the data of 16 previously reported cases of children with TSC combined with PLE to summarize the epidemiology, genetic diagnosis, and current main treatments of these patients. The report also speculates on the pathological and physiological mechanisms underlying TSC combined with PLE. TSC combined with PLE is rare; therefore, the report provides a theoretical basis for understanding the pathophysiological mechanisms and treatment options for patients with TSC and PLE. Comprehensive clinical management of TSC is essential due to the diverse and multiorgan nature of its manifestations, often requiring a multidisciplinary approach for newly diagnosed cases.

Subependymal giant cell astrocytomas (SEGA) are present in patients with tuberous sclerosis complex (TSC), occasionally requiring surgical removal. The study aimed to analyze the results from our series of children undergoing surgery for SEGA.

We retrospectively identified children with TSC undergoing resection of SEGA at Oslo University Hospital between 1982 and 2016. Patient charts, radiological images, epilepsy, and neuropsychological reports were reviewed.

Out of 208 patients with TSC, 18 (9%) underwent resection of SEGA. Due to missing data, we could only analyze results from 14 surgeries in 11 children (median age 6 years, range 0-19; male/female ratio 2.7:1). The tumours were bilateral in four (36%) patients. The tumour diameter was a median of 19 mm (10-104 mm). The surgical approach was transcortical in eight (57%) and transcallosal in six surgeries (43%). Gross total resection was achieved in 12 (86%) of surgeries. There was no mortality or major morbidity related to surgery except for one case of chronic subdural hematoma, but out of two patients with ventriculoperitoneal shunts, one developed shunt infection, and both experienced shunt failures during the follow-up. During the follow-up (median 11 years, range 1-21), three patients (27%) underwent repeated surgery. We could not document any significant impact of the surgery on patients' cognitive functioning or the grade of epilepsy.

Resection of SEGA in children with TSC was associated with a low complication rate. We could not document any impact of surgery on patients' cognitive functioning or grade of epilepsy. However, the neuropsychological data were limited in most cases. Neuropsychological assessment should be performed before the surgery and be a part of follow-up after surgery.

Tuberous sclerosis complex (TSC)-associated seizures result in a significant burden for caregivers. To quantify time spent and describe activities undertaken by caregivers of individuals with TSC-associated seizures in Sweden, primary caregivers participated in a cross-sectional, non-interventional online survey. Questions comprised patient/caregiver characteristics, care provision, time, and activities associated with generalized seizures or non-seizure-related care. Twenty-three primary caregivers participated; 96 % parents, 100 % female. Median number of caregivers per individual was three. In the last month, median (interquartile range [IQR]) hours for caregiving per week was 52.0 (25.7-100.0; n = 21); median (IQR) hours for non-seizure-related care was 46.7 (20.0-93.3; n = 21) and for generalized seizure-related care was 4.7 (1.7-15.8; n = 12). Beyond the last month, hours/week of generalized seizure-related care varied from 1.9 (0-8.8) to 14.0 (0.5-77.0). Professional/paid carers contributed 99.2 (73.5-127.5) hours/week of care. Non-seizure-related care activities included assisting with routine medical care (n = 22, 96 %) and daily activities (n = 22, 96 %). Activities relating to generalized seizures included assessing the need for (n = 16, 84 %) and giving (n = 17, 89 %) rescue medication, providing physical support (n = 16, 84 %), and clearing the individual's environment during generalized seizures (n = 13, 68 %). During generalized seizure recovery, activities included taking the individual to bed (n = 18, 95 %), emotional support (n = 14, 74 %), and managing behavioral issues (n = 14, 74 %). In Sweden, despite contributions of paid caregivers, individuals with TSC-associated seizures require substantial time from unpaid primary caregivers, including seizure- and non-seizure-related care. Generalized seizures have a considerable impact on time spent caregiving and the care activities undertaken.

Vigabatrin (VGB) is intended for use by caregivers of infants (1 month to 2 years old) diagnosed with infantile spasms (IS). Commercially available vigabatrin powders require caregiver reconstitution prior to oral administration. This study compared the ability of caregivers to accurately provide a targeted dose of vigabatrin using a ready-to-use (RTU) vigabatrin oral solution (VGB-RTU solution) and SABRIL® (vigabatrin) powder for oral solution, Lundbeck LLC, (vigabatrin powder) without instruction from a healthcare professional.

A crossover comparative usability study with 30 lay users (15 caregivers with vigabatrin powder experience and 15 oral-syringe/medication preparation naïve users) which required users to deliver a single dose of both VGB-RTU surrogate solution and vigabatrin powder to a sample collection bottle was performed. Doses were measured analytically with a primary endpoint to deliver doses within ± 10% of the target dose of 1125 mg.

All 30 participants administered VGB-RTU solution doses within ± 5% of the target, while only 23/30 of the vigabatrin powder doses were within ± 10%. All naïve users delivered vigabatrin doses using VGB-RTU solution within ± 5% of the target; whereas only 13/15 delivered doses within ± 10% for vigabatrin powder. All experienced vigabatrin users delivered calculated vigabatrin doses using VGB-RTU solution within ± 3%; whereas only 10/15 delivered doses within ± 10% for vigabatrin powder. Users were equally able to accurately deliver the prescribed volumes of both products. Calculated doses of VGB-RTU solution (mg) were significantly less variable (p < 0.0001) and more accurate (p < 0.01) than doses of vigabatrin powder.

Caregivers delivered more accurate and less variable doses of the ready-to-use solution compared to solutions prepared from vigabatrin powders for oral solution. These differences were shown to be due to caregiver errors in reconstituting vigabatrin powders for oral solution.

This study evaluates the utility of word embeddings, generated by large language models (LLMs), for medical diagnosis by comparing the semantic proximity of symptoms to their eponymic disease embedding ("eponymic condition") and the mean of all symptom embeddings associated with a disease ("ensemble mean").

Symptom data for 5 diagnostically challenging pediatric diseases-CHARGE syndrome, Cowden disease, POEMS syndrome, Rheumatic fever, and Tuberous sclerosis-were collected from PubMed. Using the Ada-002 embedding model, disease names and symptoms were translated into vector representations in a high-dimensional space. Euclidean and Chebyshev distance metrics were used to classify symptoms based on their proximity to both the eponymic condition and the ensemble mean of the condition's symptoms.

The ensemble mean approach showed significantly higher classification accuracy, correctly classifying between 80% (Cowden disease) to 100% (Tuberous sclerosis) of the sample disease symptoms using the Euclidean distance metric. In contrast, the eponymic condition approach using Euclidian distance metric and Chebyshev distances, in general, showed poor symptom classification performance, with erratic results (0%-100% accuracy), largely ranging between 0% and 3% accuracy.

The ensemble mean captures a disease's collective symptom profile, providing a more nuanced representation than the disease name alone. However, some misclassifications were due to superficial semantic similarities, highlighting the need for LLM models trained on medical corpora.

The ensemble mean of symptom embeddings improves classification accuracy over the eponymic condition approach. Future efforts should focus on medical-specific training of LLMs to enhance their diagnostic accuracy and clinical utility.

Fetal cardiac tumors are often the first clinical manifestation of tuberous sclerosis (TS) when fetal ultrasound screening is performed. TS is an autosomal dominant disorder caused by the mutations in TSC1 or TSC2 genes. Here we report a case of a patient with a fetal and neonatal cardiac tumor who underwent a genetic analysis for TS after birth. Multiple fetal cardiac tumors were detected on ultrasonography at 24 weeks, gestation with no other manifestation. Neither epilepsy nor mental retardation was seen after birth. Once the parents were provided careful genetic counseling, a genetic analysis for TS was performed when the patient was 2 years old that demonstrated a novel pathogenic missense variant: c.1072T>C, p.Trp358Arg in the TSC2 gene with 30% mosaicism. This pathogenic variant is located on exon 10 of the TSC2 gene, which encodes the hamartin binding domain, leading to impair inhibitory function of the hamartin-tuberin complex, which activates mammalian target of rapamycin(mTOR) activity. The cardiac tumors were diagnosed as rhabdomyomas, a major clinical feature of TS, since the penetrance of this gene variants are thought to be 100%. We speculate that this new missense variant in TSC2 gene with 30% mosaicism will be associated to the milder phenotype of TS since the regression of the rhabdomyomas is the only manifestation in this patient. We hope that this case report might help clinicians and genetic counselors manage individualized surveillance plans for patients with TS.

This study employed advanced MRI diffusion imaging techniques to identify cortical tubers in Tuberous Sclerosis Complex (TSC) patients and compared the diagnostic efficacy of various diffusion model parameters in predicting TSC genotypes.

From July 2019 to April 2024, a prospective study was conducted at our Hospital. Participants meeting specific criteria underwent genetic testing and Diffusion Spectrum Imaging (DSI) data collection. The Dipy toolbox calculated parameters for Diffusion Tensor Imaging (DTI), Diffusion Kurtosis Imaging (DKI), Neurite Orientation Dispersion and Density Imaging (NODDI), and Mean Apparent Propagator (MAP) models. Lesion visibility and contrast were scored by two neuroradiologists. Significant parameters were identified through univariate logistic regression, and predictive models were developed using multivariate logistic regression and backward stepwise regression, resulting in a nomogram.

Eighty-three TSC patients were included (49 females, median age 5 years, IQR 3-9 years). Significant differences were found in lesion visibility and contrast among different diffusion model parameter maps (p < 0.001), with NODDI-ICVF and MAP-QIV showing clear advantages. The DTI, DKI, and MAP models struggled to distinguish small lesions near cerebral sulci from cerebrospinal fluid, while NODDI-ICVF performed well. The combined model using ICVF, QIV, and RTOP parameters demonstrated potentially better diagnostic performance compared to single diffusion models, with the nomogram indicating strong discrimination (AUC of 0.89, 95 % CI: 0.86-0.92). Clinical decision curves indicated significant net benefits at probability thresholds of 15 %-95 %.

NODDI and MAP models reveal cortical tubers more clearly. The combined model based on advanced diffusion parameters offers the best predictive efficiency for TSC genotypes.

Tuberous sclerosis complex is a multisystem genetic disorder caused by variant of TSC1 or TSC2, which were defined as an independent diagnostic criterion for TSC.

We present a novel hereditary variant in a family. The family showed a phenomenon of familial aggregation in the Tuberous sclerosis complex.

The proband had the c.3974del (exon 33) (p.Gly1325Alafs*58) loss of heterozygosity frameshift in the TSC2 gene (chr16), which was 1 base deletion on the coding sequence of TSC2, leading to a frameshift mutation. Moreover, the novel variant occurred in the grandchildren (generation 3) also can be detected in the grandparental (generation 1) and parental (generation 2).

The proband had taken antiepileptic drugs (oxcarbazepine [30 mg/(kg·day)], depakine [28 mg/(kg·day)], levetiracetam [38 mg/(kg·day)], and lamotrigine [2 mg/(kg·day)]) and performed a right parietal resection of the epileptic lesion.

The treatment received by the proband was ineffective.

The novel gene mutation sites to be found provide more research entry points for genetic diagnosis, providing new clinical data for tuberous sclerosis complex research.

Tuberous sclerosis complex (TSC) is a genetic disease characterised by the growth of benign tumours. The Tuberous sclerosis Associated Neuropsychiatric Disorders (TAND) Checklist is used to identify patient-reported neurocognitive deficits. Patients may, however, under-recognise mild cognitive impairment. We aimed to determine the frequency of abnormal scores on three objective tests of cognitive function in people with and without diagnosed intellectual disability and examine associations between scores on these tests with self-reported TAND Checklist symptoms.

We conducted a cross-sectional study where people with TSC (PwTSC; n=46) completed the TAND Checklist and three cognitive tests: Symbol Digit Modalities Test (SDMT), Montreal Cognitive Assessment test and Trail Making Test-Parts A and B. We examined associations between cognitive test scores and the TAND Checklist using Pearson's correlations (95% CI). Receiver operating characteristics (ROC) curves were plotted to determine the screening accuracy of each measure in identifying physician-diagnosed neurocognitive disorders.

There were minimal correlations between the cognitive test scores and the TAND Checklist. More than 20% of PwTSC reported no cognitive issues on the TAND Checklist but had abnormal performance on at least one cognitive test. The ROC curves demonstrated similar results, with areas under the curve of 0.93 (95% CI 0.79 to 1.00) for the SDMT but only 0.70 (95% CI 0.45 to 0.95) for the TAND Checklist.

Objective tests of cognitive function are useful in identifying unrecognised neurocognitive deficits in PwTSC. Deficits likely have multifactorial origins, including undiagnosed intellectual disability and the impact of chronic epilepsy.

Background/Objectives: Tuberous sclerosis complex (TSC) is a rare, autosomal dominant genetic disorder caused by mutations in the TSC1 and TSC2 genes, which disrupt the regulation of the mammalian target of rapamycin (mTOR) pathway, a critical regulator of cellular growth. The disorder presents as a multisystem condition, with benign tumors (hamartomas) developing in organs such as the brain, skin, heart, kidneys, and lungs, leading to significant clinical variability and impact on quality of life. This review aims to summarize recent advances in the understanding of TSC pathogenesis and clinical variability and evaluate the therapeutic breakthroughs in targeted treatments. Methods: A narrative review was conducted using various available databases. We applied objective evaluation metrics, such as the impact factor of the journals and the citation count, to assess the quality of the studies. Results: Targeted therapies, particularly mTOR inhibitors (mTORis), have shown efficacy in reducing hamartoma size, improving neuropsychiatric symptoms, and enhancing patient outcomes. Despite these advances, variability in disease expression poses challenges in diagnosis and individualized management strategies. Conclusions: Challenges such as early diagnosis, optimizing long-term outcomes, and addressing residual unmet needs remain critical. Future research should prioritize precision medicine approaches and patient-centered care models within centers of expertise to improve treatment efficacy and quality of life for individuals with TSC.

A case of tuberous sclerosis (TSC) caused by a previously unreported mutation, with epilepsy responding well to phenytoin (PHT) and multilocular benign tumors regressing with everolimus, has not been documented before, to the best of our knowledge. The patient is a 24-year-old female who was diagnosed with tuberous sclerosis complex (TSC) at the age of seven due to epilepsy and the presence of multiple hamartomas, including angiofibromas, angiomyolipomas, lymphangioleiomyomas, rhabdomyomas, and astrocytomas, throughout her body. She also has a history of developmental delay, mild cognitive impairment, adjustment disorder, claustrophobia, recurrent depressive episodes, anxiety disorder, and autism spectrum disorder. Genetic testing confirmed a deletion of exons 4-8 in the TSC2 gene. At the age of 10, monotherapy with PHT was started, which had such a favorable effect that no more seizures occurred until the age of 19. From the age of 19, she also received everolimus, as a result of which the multi-organ hamartomas regressed significantly. This case shows that epilepsy in TSC is not intractable, that phenytoin could be an option for epilepsy in TSC patients, and that everolimus is very effective in terms of regression of benign tumors.

Diffuse cystic lung diseases (DCLDs) represent a group of pathophysiologically heterogeneous entities that share a common radiologic phenotype of multiple thin-walled pulmonary cysts. DCLDs differ from the typical fibroinflammatory interstitial lung diseases in their epidemiology, clinical presentation, molecular pathogenesis, and therapeutic approaches, making them worthy of a distinct classification. The importance of timely and accurate identification of DCLDs is heightened by the impact on patient management including recent discoveries of targeted therapeutic approaches for some disorders.

This article offers a practical framework for evaluating patients with DCLD, indicating the most appropriate and current diagnostic and management approaches. We focus on the DCLDs that are most likely to be encountered by practicing pulmonologists: lymphangioleiomyomatosis, pulmonary Langerhans cell histiocytosis, Birt-Hogg-Dubé syndrome, and lymphoid interstitial pneumonia. Chest CT scan is the most informative noninvasive diagnostic modality to identify DCLDs. Thereafter, instituting a structured approach to high-yield associated factors (eg, medical, social, and family history; renal and dermatologic findings) increases the likelihood of identifying DCLDs and achieving a diagnosis.

Although the individual diseases that comprise the DCLD family are rare, taken together, DCLDs can be encountered more frequently in clinical practice than commonly perceived. An increased eagerness among general pulmonary physicians to recognize these entities, coupled with a practical and systematic clinical approach to examinations and investigations, is required to improve case findings, allow earlier intervention, and reduce morbidity and mortality.

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder caused by mutations in either the TSC1 or TSC2 genes. Though TSC causes the formation of nonmalignant tumors throughout multiple organs, the most frequent causes of mortality and morbidity are due to neurological complications. In two-thirds of cases, TSC occurs sporadically and TSC2 pathogenic variants are approximately three times more prevalent than TSC1 pathogenic variants. Here, we utilized CRISPR-Cas9-mediated homology directed repair in patient induced pluripotent stem cells (iPSCs) to correct two types of TSC2 pathogenic variants generating two isogenic lines. In one line, we corrected a splice acceptor variant (c.2743-1G>A), which causes the skipping of coding exon 23 and subsequent frameshift and introduction of a stop codon in coding exon 25. In the second line, we corrected a missense variant in coding exon 40 within the GTPase-activating protein domain (c.5228G>A, p.R1743Q). The generation of TSC2 patient iPSCs in parallel with their corresponding CRISPR-corrected isogenic lines will be an important tool for disease modeling applications and for developing therapeutics.

This study aims to improve genetic diagnosis in childhood onset epilepsy with neurodevelopmental problems by utilizing RNA sequencing of fibroblasts to identify pathogenic variants that may be missed by exome sequencing and copy number variation analysis.

We enrolled 41 individuals with childhood onset epilepsy and neurodevelopmental problems who previously had inconclusive genetic testing. Fibroblast samples were cultured and analyzed using RNA sequencing to detect aberrant expression, aberrant splicing, and monoallelic expression using the Detection of RNA Outlier Pipeline (DROP) pipeline. Detected events were correlated with phenotypes, and long-read genome sequencing was performed on individuals with strong candidate events to identify the causal genomic variant. A systematic literature review on RNA sequencing in rare disorders was conducted to contextualize our findings.

RNA sequencing identified five strong candidate events in four individuals, affecting the genes QRICH1, TSC1, SMARCA1, GNAI1, and PTEN. (Likely) pathogenic genomic variants affecting expression of QRICH1, TSC1, and SMARCA1 were detected, resulting in a diagnostic yield of 7% (3/41). Two variants were not covered in the initial exome sequencing data but were revealed through long-read sequencing. The identification of a pathogenic TSC1 variant led to a previously unrecognized diagnosis of tuberous sclerosis complex. This prompted guideline-based screening, which revealed tuberous sclerosis lesions in the brain and lung, directly impacting clinical care. Notably, two of the three pathogenic events would not have been detected using whole blood due to the lack of expression of the involved genes. The lower yield of this study compared to studies in other rare disorders reflects the genetic heterogeneity of epilepsy and neurodevelopmental disorders, and the inaccessibility of affected tissue.

This research underscores RNA sequencing of cultured fibroblasts as a valuable tool in genetic diagnostics for childhood onset epilepsy, particularly when conventional methods fail. Expanding the control dataset with age-matched samples and incorporating RNA sequencing with nonsense-mediated decay inhibition could further enhance diagnostic yield.

Tuberous sclerosis complex (TSC) is a multisystem genetic disorder primarily characterized by the development of benign tumors in multiple organs. While cardiovascular involvement is less common than neurological or renal manifestations, it typically presents with cardiac rhabdomyomas (CRs). The co-occurrence of a bicuspid aortic valve (BAV) with TSC is exceedingly rare.

We report the case of a 26-year-old woman with genetically confirmed TSC, harboring a novel pathogenic variant in the TSC2 gene. Cardiovascular characteristics included a history of heart valve disease, a bicuspid aortic valve, and severe aortic regurgitation. multi-system characteristics of TSC were also presented, affecting skin, brain, lung, kidney, and bone. She underwent aortic valve replacement but experienced postoperative complications, including significant pleural and pericardial effusions requiring drainage and subsequent thoracic duct ligation.

This case expands the clinical spectrum of TSC-associated cardiovascular abnormalities, highlighting the rare association of BAV with this disorder. Our finding emphasizes the importance of considering TSC in individuals presenting with these cardiac features, as well reinforce the critical role of molecular genetic testing in confirming the diagnosis of TSC.

This case report presents markedly different clinical and radiological manifestations of the same disease in a family over three consecutive generations with varying treatment strategies. The index case/proband primarily presented with gastrointestinal symptoms, including diarrhoea, bleeding per rectum and seizures. Further evaluation revealed bilateral renal angiomyolipoma and cerebral subependymal nodules, in conjunction with facial adenoma sebaceum, periungual fibromas and hypomelanotic ash-leaf macules. Genetic testing confirmed the diagnosis of tuberous sclerosis complex, identifying a mutation in the TSC2 gene.The entire family was evaluated for inherited disorders, leading to the detection of tuberous sclerosis in three adult offspring and a grandchild. The uncharacteristic neurological and cardiac manifestations in the proband are noteworthy. Another important aspect is the missed diagnosis in patients despite obvious clinical features and interaction with healthcare facilities, reflecting a gap in disease awareness and a lack of clinical vigilance.

Phosphate and tensin homolog hamartoma tumor syndrome, DICER1-related tumor predisposition, and tuberous sclerosis complex are rare conditions, which each increases risk for distinct spectra of benign and malignant neoplasms throughout childhood and adulthood. Surveillance considerations for each of these conditions focus on patient and family education, early detection, and multidisciplinary care. In this article, we present updated surveillance recommendations and considerations for children and adolescents with phosphate and tensin homolog hamartoma tumor syndrome, DICER1-related tumor predisposition, and tuberous sclerosis complex and provide suggestions for further research in each of these conditions.

Cardiac rhabdomyoma (CR), the most frequently occurring fetal cardiac tumor, is often an early marker of tuberous sclerosis complex (TSC). This study evaluates outcomes of fetuses with prenatally diagnosed cardiac tumors managed at a single tertiary center.

Medical records of fetuses diagnosed with cardiac tumors between 2009 and 2024 were retrospectively reviewed.

Sixteen cases were identified, with a median follow-up of 6.7 years. TSC was confirmed in 14 cases (88%). Multiple tumors were observed in 13 cases (81%), while 3 cases (19%) had solitary tumors. Both non-TSC cases involved solitary tumors. Cardiac complications (arrhythmias, conduction disorders, and hemodynamic abnormalities) occurred in 38% of cases prenatally and 69% postnatally, with larger tumor diameters significantly associated with complications (p = 0.02). No fetal hydrops or mortality occurred; however, one child died at age five due to a seizure. Postnatal tumor regression occurred in 56% of cases and complete regression in 38% by a median age of 2.3 years (range: 0.6-4.4). One tumor remained stable. Brain MRI revealed TSC-related changes in all TSC-affected patients except one, who had a developmental brain anomaly. Most TSC patients experienced epilepsy (71%) and developmental delays.

While CRs are typically benign and regress spontaneously, their strong association with TSC highlights the importance of early diagnosis and family counseling. TSC-related epilepsy and psychomotor delays significantly impair the quality of life. Early mTOR inhibitor therapy offers promise in mitigating TSC-related complications and improving outcomes.

Tuberous sclerosis complex (TSC) is a monogenetic disorder associated with sustained mechanistic target of rapamycin (mTOR) activation, leading to heterogeneous clinical manifestations. Epilepsy and renal angiomyolipoma are the most important causes of morbidity in adult people with TSC (pwTSC). mTOR is a key player in inflammation, which in turn could influence TSC-related clinical manifestations. Reliable biomarkers are lacking to monitor and predict evolution and response to treatment for epilepsy in pwTSC. Inflammation has been implicated in epileptogenesis in non-TSC-related epilepsy. We aimed to characterize the relation between markers of neuroglial activation/injury, markers of peripheral inflammation, and active epilepsy in pwTSC to identify accessible biomarkers and potential new therapeutic targets.

We performed a cross-sectional study to investigate markers of central nervous system (CNS) (neurofilament light [NfL] and glial fibrillary acidic protein [GFAP]) and peripheral (45 cytokines) inflammation in the peripheral blood of pwTSC (n = 46) vs age- and sex-matched healthy controls (HCs) (n = 26). In pwTSC, markers associated with active epilepsy (n = 23/46) were compared to non-TSC epilepsy controls (n = 18). Observations on markers of neuroglial activation/injury (GFAP, NfL) were confirmed in an independent TSC cohort (n = 45; 69% with active epilepsy).

We report that TSC is characterized by elevated serum levels of marker of astrogliosis (GFAP), pro-inflammatory molecules (interleukin 1β [IL-1β], CXCL8) and trophic factor (epidermal growth factor [EGF]) compared to HCs and to non-TSC-related epilepsy controls. Among pwTSC, renal angiomyolipoma presence and size was associated with IL-15. It is notable that active epilepsy in pwTSC was associated with higher levels of GFAP compared to pwTSC without epilepsy, which was confirmed in an external validation cohort, and with elevated levels of pro-inflammatory cytokines (IL-17A, IL-17C, tumor necrosis factor α [TNF-α]), not significantly related to seizure activity or treatment with mTOR inhibitor. These associations remained significant after adjusting for age and sex.

These results suggest that key inflammatory mediators could contribute to epileptogenesis and represent novel biomarkers and therapeutic targets in TSC.

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder which can have manifestations in the kidneys, along with other organ systems. Children with TSC may develop kidney lesions at any point during childhood, and typically these are angiomyolipomata (AML) and/or kidney cysts. Children may also have hypertension associated with TSC-associated kidney disease, and rarely reduced kidney function. New guidelines for the management of TSC-associated kidney disease in children and adults were published in 2024. This educational review summarises the relevant clinical aspects of these guidelines for paediatric nephrologists through a series of four clinical cases. These cases cover management of hypertension, frequency of follow-up and frequency of kidney imaging. Difficult clinical scenarios are reviewed, such as the management of TSC2-PKD1 contiguous gene syndrome and the management of large AMLs in children with TSC.

Once believed to be the culprits of epileptogenic activity, the functional properties of balloon/giant cells (BC/GC), commonly found in some malformations of cortical development including focal cortical dysplasia type IIb (FCDIIb) and tuberous sclerosis complex (TSC), are beginning to be unraveled. These abnormal cells emerge during early brain development as a result of a hyperactive mTOR pathway and may express both neuronal and glial markers. A paradigm shift occurred when our group demonstrated that BC/GC in pediatric cases of FCDIIb and TSC are unable to generate action potentials and lack synaptic inputs. Hence, their role in epileptogenesis remained obscure. In this review, we provide a detailed characterization of abnormal non-neuronal cells including BC/GC, intermediate cells, and dysmorphic/reactive astrocytes found in FCDIIb and TSC cases, with special emphasis on electrophysiological and morphological assessments. Regardless of pathology, the electrophysiological properties of abnormal cells appear more glial-like, while others appear more neuronal-like. Their morphology also differs in terms of somatic size, shape, and dendritic elaboration. A common feature of these types of non-neuronal cells is their inability to generate action potentials. Thus, despite their distinct properties and etiologies, they share a common functional feature. We hypothesize that, although the exact role of abnormal non-neuronal cells in FCDIIb and TSC remains mysterious, it can be suggested that cells displaying more glial-like properties function in a similar way as astrocytes do, i.e., to buffer K+ ions and neurotransmitters, while those with more neuronal properties, may represent a metabolic burden due to high energy demands but inability to receive or transmit electric signals. In addition, due to the heterogeneity of these cells, a new classification scheme based on morphological, electrophysiological, and gene/protein expression in FCDIIb and TSC cases seems warranted.

Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder affecting multiple organ systems, with a prevalence of 1:6,760-1:13,520 live births in Germany. On the molecular level, TSC is caused by heterozygous loss-of-function variants in either of the genes TSC1 or TSC2, encoding the Tuberin-Hamartin complex, which acts as a critical upstream suppressor of the mammalian target of rapamycin (mTOR), a key signaling pathway controlling cellular growth and metabolism. Despite the therapeutic success of mTOR inhibition in treating TSC-associated manifestations, studies with mTOR inhibitors in children with TSC above two years of age have failed to demonstrate beneficial effects on disease-related neuropsychological deficits. It has thus been hypothesized, that the critical time window for mTOR inhibitors may lie in early infancy, before TSC-related symptoms such as early-onset epilepsy and infantile spasms as sign of disruptive brain maturation occur. No controlled prospective clinical trials have evaluated the effect of pre-symptomatic mTOR inhibitor therapy on neuropsychological manifestations in TSC patients under two years of age.

This two-arm, randomized, observer-blind, phase IIb national multicenter clinical trial aims at investigating the long-term neuropsychologic outcomes of pre-emptive mTOR inhibitor treatment in children diagnosed with TSC under four months of age. Sixty participants will be allocated to the trial with a 1:1 randomization ratio. The primary endpoint will be the neuropsychological outcome assessed by the cognitive scale of the Bayley Scales of Infant and Toddler Development III at 24 months of age compared to Standard of Care. Secondary endpoints include neuropsychologic outcomes at 12 months of age, seizure frequency, cardiac and cerebral tumor load, and safety assessments. Inclusion criteria are a definite TSC diagnosis and an age below four months at enrolment. The investigational medicinal product is sirolimus (Rapamune®), administered orally based on body surface area and surveilled by pharmacokinetic measurements, starting within the first four months of life and continuing until the second birthday.

This study addresses a critical gap in understanding the impact of pre-emptive mTOR inhibitor therapy on neuropsychologic outcomes in young TSC patients, aiming to improve overall patient outcomes and quality of life. EUCT number: 2022-502332-39-00, Registered 22/06/2023, https://euclinicaltrials.eu/search-for-clinical-trials/?lang=en&EUCT=2022-502332-39-00.

The vast majority of neuroendocrine 'neoplasms (NENs) are sporadic, although recent evidence has indicated that a subset of these cancers may also originate as a result of genetic germline mutations. To date, 10% of these cancers can be linked to an inherited genetic syndrome. Genetic diagnosis is crucial for patients with a suspected hereditary NEN syndrome, as it recognizes patients carrying germline mutations and allows for personalized clinical follow-up, considering the higher risk of developing other tumours. The potential for early genetic detection has significant implications for the treatment of patients with hereditary NEN syndrome, as it may facilitate the delivery of precision therapy that differs from that typically provided to other patients. Thus, the integration of genotypic and phenotypic diagnostic methods help clinicians to provide more informed treatment and to extend appropriate prevention to family members.

Epilepsy and intellectual disability are common in tuberous sclerosis complex (TSC). Although early life seizures and intellectual disability are known to be correlated in TSC, the differential effects of age at seizure onset and accumulated seizure burden on development remain unclear.

Daily seizure diaries, serial neurodevelopmental testing, and brain magnetic resonance imaging were analyzed for 129 TSC patients followed from 0 to 36 months. We used machine learning to identify subgroups of patients based on neurodevelopmental test scores at 36 months of age and assessed the stability of those subgroups at 12 months. We tested the ability of candidate biomarkers to predict 36-month neurodevelopmental subgroup using univariable and multivariable logistic regression. Candidate biomarkers included age at seizure onset, accumulated seizure burden, tuber volume, sex, and earlier neurodevelopmental test scores.

Patients clustered into two neurodevelopmental subgroups at 36 months of age, higher and lower scoring. Subgroup was mostly (75%) the same at 12 months. Significant univariable effects on subgroup were seen only for accumulated seizure burden (largest effect), earlier test scores, and tuber volume. Neither age at seizure onset nor sex significantly distinguished 36-month subgroups, although for girls but not boys there was a significant effect of age at seizure onset. In the multivariable model, accumulated seizure burden and earlier test scores together predicted 36-month neurodevelopmental group with 82% accuracy and an area under the curve of .86.

These results untangle the contributions of age at seizure onset and accumulated seizure burden to neurodevelopmental outcomes in young children with TSC. Accumulated seizure burden, rather than the age at seizure onset, most accurately predicts neurodevelopmental outcome at 36 months of age. These results emphasize the need to manage seizures aggressively during the first 3 years of life for patients with TSC, not only to promote seizure control but to optimize cognitive function.

Autism spectrum disorder (ASD) is characterized by difficulties in social interaction, communication, and repetitive behavior, typically diagnosed during early childhood and attributed to altered neuronal network connectivity. Several genetic and environmental risk factors contribute to ASD, including pre- or early life immune activation, which can trigger microglial and astroglial reactivity, impacting early neurodevelopment. In ASD, astrocytes show altered glutamate metabolism, directly influencing neuronal network activity, while microglia display impaired synaptic pruning, an essential developmental process for the refinement of neuronal connections. Additionally, reduced myelination in specific cortical and subcortical regions may affect brain connectivity in ASD, with white matter integrity correlating with the severity of the disorder, suggesting an important role for oligodendrocytes and myelin in ASD. This chapter provides an overview of current literature on the role of neuroglia cells in ASD, with a focus on immune activation, glutamate signaling, synaptic pruning, and myelination.

Liver masses in children with underlying systemic disease or a predisposing syndrome can be benign or malignant, ranging from focal fat to hepatocellular carcinoma (HCC). Knowledge of the underlying condition, the pathophysiologic effect on the liver, and the development of liver disease and specific liver lesions allows radiologists to guide imaging with regard to modality and frequency and give recommendations for biopsy when appropriate. In some predisposition disorders, such as Beckwith Wiedemann spectrum, familial adenomatous polyposis syndrome, and tuberous sclerosis complex, established guidelines for imaging screening exist. In many of the syndromes discussed, masses may occur outside of the liver and the liver may not be the primary focus of screening. For other entities, no consensus recommendations exist. Screening recommendations may be based on the risk of development of chronic liver disease. Once cirrhosis occurs, the risk of developing HCC is elevated. The authors summarize the spectrum of liver lesions that may be encountered in children with predisposing syndromes and systemic diseases, the imaging appearance of the lesions with various modalities, and screening guidelines where published. ©RSNA, 2024 See the invited commentary by Rutten and Chavan in this issue.

Tuberous sclerosis complex (TSC) is a rare genetic disorder characterized by the formation of benign tumors in various organs, particularly in the central nervous system. We aimed to delineate the molecular profile of Turkish individuals diagnosed with TSC by analyzing the TSC1 and TSC2 genes using next-generation sequencing (NGS). Sophia Genetics' Sophia Inherited Disease Panel was used to perform NGS on 22 individuals diagnosed with TSC and to identify pathogenic variants in the TSC1 and TSC2 genes. Among the 22 cases, mutations were found in 3 (13.6%) for TSC1 and in 16 (73%) for TSC2, while 3 (13.6%) exhibited no detectable mutations. Notably, one individual with a TSC2 mutation presented with angiofibroma, ungual fibroma, and pitted dental enamel, while another had cardiac rhabdomyoma. Autism spectrum disorders were observed in 6 (27%) with TSC2 mutations, including one with autistic behavior. Abnormal motor development was noted in 3 (13.6%), of which 2 had TSC2 mutations. Severe intellectual disability was found in 3 (13.6%) with TSC2 mutations, and developmental delay was seen in 2 (9%) with TSC2 mutations. Epileptic encephalopathy occurred in 3 (13.6%), with 2 having TSC2 mutations. Additionally, 6 (27%) exhibited drug resistance for focal seizures, with 5 of them having TSC2 mutations. These findings are consistent with other research indicating that TSC2 mutations are associated with a more severe phenotypic range compared to TSC1 mutations. Moreover, our analysis showed that some people with TSC1/TSC2 mutations did not match diagnostic criteria. This highlights the importance of genetic testing and molecular profiling in understanding the clinical variability and aiding in the management of TSC patients.

Renal angiomyolipomas, benign tumors composed of blood vessels, adipose tissue, and smooth muscle, affect approximately 70% to 80% of patients with tuberous sclerosis. Angiomyolipomas smaller than 4 cm are usually asymptomatic, whereas larger ones can cause lumbar pain, anemia, and hematuria. Contrary to its sporadic counterparts, tuberous sclerosis-associated angiomyolipomas often present at a young age, are multicentric and large, and carry a higher risk of life-threatening hemorrhage. Therapeutic strategies include selective tumor embolization, nephrectomy for severe cases, and medical treatment such as everolimus. Despite a correlation between tuberous sclerosis and renal angiomyolipomas and their described high complication rates in literature, disease awareness in clinical practice remains low. This case series describes the management and outcomes of three patients with tuberous sclerosis-associated renal angiomyolipomas treated with selective arterial embolization.

Tuberous sclerosis complex (TSC) is a genetic and multisystemic disorder that affects between 1/6'000 and 1/10'000 of newborns. Clinical criteria and/or genetic analysis establish the diagnosis. The mechanistic target of rapamycin (mTOR) inhibitors everolimus or sirolimus reduce the severity of several TSC-related clinical traits. We report here on the epidemiology and management of TSC patients in a large Swiss canton: the canton of Vaud.

We extracted patient files containing the diagnostic code TSC in 2015 at the Lausanne University hospital (tertiary reference center for a population of about 755'000 people) and in specialized neurological institutions of the same region.

We identified 52 patients with a diagnosis of TSC. The majority of the patients with a pathologic result in genetic testing were positive for a pathogenic variant in the TSC2 gene, including five cases of contiguous gene deletion syndrome of TSC2 and PKD1 causing both polycystic kidney disease and TSC. The most frequent clinical manifestations encountered were affecting the skin (87% of patients), the brain (83%), the heart (46%) and the kidneys (46%). Neuropsychiatric disorders were described in 56% of cases. At the time of data collection (2015), there were 2 patients using systemic mTOR inhibitors and 16 patients using topical mTOR inhibitors for dermatological features. Next, we compared this data with those of large published cohorts. While we found fewer cases than expected for the screened population, demographic as well as genetic data were overall similar to the literature. However, we observed that some clinical manifestations (renal, lung and neuropsychiatric disorders) were less frequently described in our cohort.

This work indicates that TSC and some of its clinical manifestations is under-reported. It raises concern that patients with mild manifestations are often not referred to reference centers with dedicated multidisciplinary group. The follow-up by expert board is instrumental in offering systematic screening of all putatively affected organs and to assess the eligibility for targeted treatment.