Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by the presence of proliferative lesions throughout the body. Management of TSC is challenging because patients have a multifaceted systemic illness with prominent neurological and developmental impact as well as potentially severe kidney, heart and lung phenotypes; however, every organ system can be involved. Adequate care for patients with TSC requires a coordinated effort involving a multidisciplinary team of clinicians and support staff. This clinical practice recommendation was developed by nephrologists, urologists, paediatric radiologists, interventional radiologists, geneticists, pathologists, and patient and family group representatives, with a focus on TSC-associated kidney manifestations. Careful monitoring of kidney function and assessment of kidney structural lesions by imaging enable early interventions that can preserve kidney function through targeted approaches. Here, we summarize the current evidence and present recommendations for the multidisciplinary management of kidney involvement in TSC.

BACKGROUND: Rett syndrome (RTT) and tuberous sclerosis complex (TSC) are two rare disorders presenting with a range of different epileptic seizures. Seizure management requires careful therapy selection, thereby necessitating development of high-quality treatment guidelines. This targeted literature review (TLR) aimed to characterise country-specific and international treatment guidelines available for pharmacological management of seizures in RTT and TSC.
METHODS: A TLR was performed between 25-Jan and 11-Mar 2021. Manual searches of online rare disease and guideline databases, and websites of national heath technology assessment bodies were conducted for the following countries: Australia, Canada, France, Germany, Israel, Italy, Japan, Spain, Switzerland, UK, and US as defined by pre-specified eligibility criteria. Search terms were developed for each condition and translated into local languages where appropriate. Eligible publications were defined as guidelines/guidance reporting pharmacological management of seizures in patients with RTT and TSC. Guideline development methodology, geographical focus, author information and treatment recommendations were extracted from guidelines. An author map was generated using R version 3.5.1 to visualise extent of collaboration between authors.
RESULTS: 24 total guidelines were included, of which three and six contained only recommendations for RTT and TSC, respectively (some provided recommendations for ≥ 1 condition). Guideline development processes were poorly described (50% [12 guidelines] had unclear/absent literature review methodologies); reported methodologies were variable, including systematic literature reviews (SLRs)/TLRs and varying levels of expert consultation. Most (83% [20/24]) were country-specific, with guideline authors predominantly publishing in contained national groups; four guidelines were classified as \'International,\' linking author groups in the US, UK, Italy and France. High levels of heterogeneity were observed in the availability of treatment recommendations across indications, with 13 and 67 recommendations found for RTT and TSC, respectively. For RTT, all treatment recommendations were positive and sodium valproate had the highest number of positive recommendations (Khwaja, Sahin (2011) Curr Opin Pediatr 23(6):633-9). All TSC treatments (21 medications) received either exclusively negative (National Organization for Rare Disorders (2019)) or positive (Chu-Shore et al. (2010) Epilepsia 51(7):1236-41) recommendations; vigabatrin received the highest number of positive recommendations (Kaur, Christodoulou (2019)).
CONCLUSIONS: This review highlights the need for the development of international high-quality and comprehensive consensus-based guidance for the management of seizures with pharmacological therapy in RTT and TSC.
BACKGROUND: Not applicable.

Tuberous sclerosis complex (TSC) is associated with a wide range of physical manifestations for which international clinical recommendations for diagnosis and management have been established. TSC is, however, also associated with a wide range of TSC-Associated Neuropsychiatric Disorders (TAND) that are typically under-identified and under-treated yet associated with a profound burden of disease. The contemporary evidence base for the identification and treatment of TAND is much more limited and, to date, consensus recommendations for the diagnosis and management of TAND have also been limited and non-specific.
The TANDem project was launched with an international, interdisciplinary, and participatory consortium of 24 individuals, including TSC family representatives, from all World Health Organization (WHO) regions but one. One of the aims of the TANDem project was to generate consensus recommendations for the identification and treatment of TAND. At the time of this project, no internationally adopted standard methodology and methodological checklists existed for the generation of clinical practice recommendations. We therefore developed our own systematic procedure for evidence review and consensus-building to generate evidence-informed consensus recommendations of relevance to the global TSC community.
At the heart of the consensus recommendations are ten core principles surrounded by cluster-specific recommendations for each of the seven natural TAND clusters identified in the literature (autism-like, dysregulated behavior, eat/sleep, mood/anxiety, neuropsychological, overactive/impulsive, and scholastic) and a set of wraparound psychosocial cluster recommendations. The overarching recommendation is to \"screen\" for TAND at least annually, to \"act\" using appropriate next steps for evaluation and treatment, and to \"repeat\" the process to ensure early identification and early intervention with the most appropriate biological, psychological, and social evidence-informed approaches to support individuals with TSC and their families.
The consensus recommendations should provide a systematic framework to approach the identification and treatment of TAND for health, educational, social care teams and families who live with TSC. To ensure global dissemination and implementation of these recommendations, partnerships with the international TSC community will be important. One of these steps will include the generation of a \"TAND toolkit\" of \"what to seek\" and \"what to do\" when difficulties are identified in TAND clusters.

New clinical issues have been raised through an interval of 7 years from the previous version (2016). In this study, we update the \"Clinical Practice Guidelines for tuberous sclerosis complex-associated renal angiomyolipoma\" as a 2023 version under guidance by the Japanese Urological Association. The present guidelines were cooperatively prepared by the Japanese Urological Association and Japanese Society of Tuberous Sclerosis Complex; committee members belonging to one of the two societies or specializing in the treatment of this disease were selected to prepare the guidelines in accordance with the \"Guidance for preparing treatment guidelines\" published by Minds (2020 version). The \"Introduction\" consisted of four sections, \"Background Questions (BQ)\" consisted of four sections, \"Clinical Questions (CQ)\" consisted of three sections, and \"Future Questions (FQ)\" consisted of three sections (total: 14 sections). Concerning CQ, an agreement was confirmed through voting by the committee members based on the direction and strength of recommendation, accuracy of evidence, and recommendation comments. The present guidelines were updated based on the current evidence. We hope that the guidelines will provide guiding principles for the treatment of tuberous sclerosis complex-associated renal angiomyolipoma to many urologists, becoming a foundation for subsequent updating.

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Tuberous sclerosis complex (TSC) is a rare autosomal dominant genetic disorder associated with mutations in TSC1 and TSC2 genes, upregulation of mammalian target of rapamycin signaling, and subsequent tumor formation in various organs. Due to the many manifestations of TSC and their potential complications, management requires the expertise of multiple medical disciplines. A multidisciplinary care approach is recommended by consensus guidelines. Use of multidisciplinary teams (MDTs) has been shown to be beneficial in treating other complex diseases, such as cancer. In a lifelong disease such as TSC, an MDT may facilitate the transition from pediatric to adult care. However, little guidance exists in the literature regarding how to organize an MDT in TSC.
To discuss the best approach to assembling an MDT, this project was initiated in October 2017 with a meeting of 12 physicians from various specialties and various countries. Following this first meeting, the experts generated statements on the most important aspects to implement in establishing an MDT for TSC by 3 rounds of selection using a Delphi process via electronic correspondence. Finally, TSC patient advocates reviewed the findings and provided additional insights from a patient perspective.
A 3-step roadmap was recommended, starting with identifying a single individual to begin organizing care (Step 1), then establishing a small core team (Step 2), and finally, establishing a larger multi-disciplinary team (Step 3). Because of the multisystemic nature of TSC, the MDT should include specialists such as a neurologist, a neurosurgeon, a nephrologist, a urologist, a pulmonologist, an ophthalmologist, a cardiologist, a dermatologist, a geneticist, and a psychiatrist/psychologist. The MDT should recommend a care plan for each patient based on the individual\'s needs and in consultation with him/her or his/her family. Some of the most important aspects of an MDT that were agreed upon included identifying a case manager to help coordinate care, providing access to health care professionals of varying specialties, and including a lead physician who takes medical responsibility for patients\' overall care.
The results of our consensus provide guidance to support the initiation of an MDT in TSC.

BACKGROUND: The severity of Tuberous Sclerosis Complex (TSC) can vary among affected individuals. Complications of TSC can be life threatening, with significant impact on patients\' quality of life. Management may vary dependent on treating physician, local and national policies, and funding. There are no current UK guidelines. We conducted a Delphi consensus process to reach agreed guidance for the management of patients with TSC in the UK.
METHODS: We performed a literature search and reviewed the 2012/13 international guideline for TSC management. Based on these, a Delphi questionnaire was formed. We invited 86 clinicians and medical researchers to complete an online survey in two rounds. All the people surveyed were based in the UK. Clinicians were identified through the regional TSC clinics, and researchers were identified through publications. In round one, 55 questions were asked. In round two, 18 questions were asked in order to obtain consensus on the outstanding points that had been contentious in round one. The data was analysed by a core committee and subcommittees, which consisted of UK experts in different aspects of TSC. The Tuberous Sclerosis Association was consulted.
RESULTS: About 51 TSC experts took part in this survey. Two rounds were required to achieve consensus. The responders were neurologists, nephrologists, psychiatrist, psychologists, oncologists, general paediatricians, dermatologist, urologists, radiologists, clinical geneticists, neurosurgeons, respiratory and neurodisability clinicians.
CONCLUSIONS: These new UK guidelines for the management and surveillance of TSC patients provide consensus guidance for delivery of best clinical care to individuals with TSC in the UK.

Neuropsychiatric manifestations in Tuberous Sclerosis Complex (TSC): diagnostic guidelines, TAND concept and therapy with mTOR inhibitors Abstract. Tuberous sclerosis complex (TSC), albeit a rare autosomal-dominant multisystem disease with an incidence of 1:6,000, is one of the most important monogenetic disorders in child and adolescent psychiatry. In up to 90 % of patients, neurological disorders such as epilepsy and psychiatric disorders such as autism spectrum disorder, ADHD, affective disorders, and intellectual disability are observed. In recent years, significant progress has been made in understanding the molecular mechanism as well as in the clinical diagnosis and treatment of the disease. Here, we review these recent developments. In the first part, we describe the need for psychiatric assessment and treatment of patients and analyse challenges in interdisciplinary work between child and adolescent psychiatry, child neurology, and other professional groups. In the second part, we introduce the concept of TSC-associated neuropsychiatric disorders (TAND), developed by the TSC Neuropsychiatry Panel as a guide to help clinical teams, families, and individuals with TSC via screening, assessment, and treatment of neuropsychiatric symptoms and disorders as well as with a novel screening instrument, the TAND Checklist. Finally, we report findings from recent clinical trials of mTOR-inhibitors to treat TAND. The paper includes the German translation of the TAND Checklist as an electronic supplement.
Zusammenfassung. Obwohl insgesamt selten („orphan disease“ mit einer Inzidenz von 1:6000), ist die Tuberöse Sklerose (TSC) eine der häufigsten monogenetisch bedingten Erkrankungen mit Bedeutung für die Kinder- und Jugendpsychiatrie. TSC führt bei bis zu 90 % der Betroffenen zu neurologischen Störungen wie Epilepsie und ebenfalls bei bis zu 90 % zu psychiatrischen Manifestationen wie Autismus-Spektrum-Störungen, Aufmerksamkeitsdefizit-/Hyperaktivitätsstörung, affektiven Störungen und Intelligenzminderung. In den letzten Jahren wurden sowohl zum Verständnis des molekularen Pathomechanismus der Erkrankung als auch zu Diagnostik und Behandlung erhebliche Fortschritte erzielt. Die vorliegende Übersichtsarbeit stellt diese aktuellen Entwicklungen dar. Im ersten Abschnitt zeigen wir den Bedarf an psychiatrischer Diagnostik und Begleitung von Patienten mit TSC auf und behandeln Herausforderungen und Schwierigkeiten in der interdisziplinären Zusammenarbeit zwischen Kinder- und Jugendpsychiatrie, Neuropädiatrie und anderen Berufsgruppen. Im zweiten Teil stellen wir das Konzept der TSC-assoziierten neuropsychiatrischen Störungen (TAND) vor, das von einer internationalen Expertengruppe entwickelt wurde, um Kliniker, Familien und Betroffene in der Diagnostik und Behandlung psychiatrischer Symptome und Störungen zu unterstützen, sowie ein neuartiges Screeninginstrument (TAND-Checkliste). Schließlich geben wir einen Überblick über kürzlich publizierte Studien bezüglich möglicher Krankheitsmodifikation der neuropsychiatrischen Manifestationen mittels mTOR-Inhibitoren. Die deutsche Übersetzung der TAND-Checkliste ist dem Artikel als elektronisches Supplement (ESM) beigefügt.

Renal-related disease is the most common cause of tuberous sclerosis complex (TSC)-related death in adults, and renal angiomyolipomas can lead to complications that include chronic kidney disease (CKD) and hemorrhage. International TSC guidelines recommend mammalian target of rapamycin (mTOR) inhibitors as first-line therapy for management of asymptomatic, growing angiomyolipomas >3 cm in diameter. This review discusses data regarding patient outcomes that were used to develop current guidelines for embolization of renal angiomyolipomas and presents recent data on 2 available mTOR inhibitors - sirolimus and everolimus - in the treatment of angiomyolipoma. TSC-associated renal angiomyolipomas can recur after embolization. Both sirolimus and everolimus have shown effectiveness in reduction of angiomyolipoma volume, with an acceptable safety profile that includes preservation of renal function with long-term therapy. The authors propose a hypothesis for mTORC1 haploinsufficiency as an additional mechanism for CKD and propose that preventive therapy with mTOR inhibitors might have a role in reducing the number of angiomyolipoma-related deaths. Because mTOR inhibitors target the underlying pathophysiology of TSC, patients might benefit from treatment of multiple manifestations with one systemic therapy. Based on recent evidence, new guidelines should be considered that support the earlier initiation of mTOR inhibitor therapy for the management of renal angiomyolipomas to prevent future serious complications, rather than try to rescue patients after the complications have occurred.