Features Of Tuberous Sclerosis Complex Research Articles

#2242 mTORi: edging closer to targeted therapy in tuberous sclerosis complex

Abstract Background and Aims Tuberous sclerosis complex (TSC) is an autosomal dominant condition with an estimated incidence of 1 in 6000 births. TSC is caused mostly by mutations in either TSC1 or TSC2 genes, with 70–80% of cases resulting from sporadic mutations; however in 10-15% of cases no mutations are identified. A dysregulation of these genes that encode the hamartin and tuberin proteins, respectively, results in an aberrant signaling of the mammalian target of the rapamycin (mTOR) pathway and subsequent tumor growth. Indeed, the clinical features of TSC are characterized by the proliferation of different types of hamartomas in various organs, including brain, heart, skin, lungs, eyes, bone, kidneys and less frequently pancreas. TSC is mainly diagnosed clinically according to diagnostic criteria with genetic testing performed in cases of diagnostic uncertainty or/and to support the clinic diagnosis. Renal angiomyolipomas (AMLs), observed in more than 80% of patients with TSC, are benign, mostly bilateral tumors, composed of immature smooth muscle cells, abnormal blood vessels and fat cells in variable portions. Their size and the prevalence of their vascular component are directly associated with risk of acute bleeding that in 25% of cases may require embolization or nephrectomy. As a consequence, renal complications are the leading cause of death in adult TSC patients and AML-related surgery is performed in a high percentage of these patients. In the last decade, mTOR inhibitor (mTOR-i) therapy has demonstrated to be a potential alternative to embolization and nephrectomy for managing TSC-AML. The aim of this study was to evaluate over time, potential changes in the relative tissue composition of renal AMLs and their overall size following the initiation of mTOR-i therapy based on MRI measurements. Method From August 2011 to May 2023, 86 potentially eligible adult TSC patients with AML, across a great part of Italy were referred for assessment and monitoring at our center. 14 of these patients were eligible for mTOR-i therapy. An ethics committee approved its use as a compassionate therapy as mTOR-is are not approved as a conventional therapy for renal AMLs in Italy. These patients underwent baseline renal magnetic resonance imaging (MRI) assessment and a regular follow-up with MRI scan every 6-9 months after initiation of therapy. Dose titration was guided by trough levels, side effects and lesion radiological responsiveness on MRI. Results No AML bleeding events were documented during the study. None of the 14 patients on treatment discontinued therapy. Overall, 5 of them (35.7%) required dose adjustments during the course of treatment due to adverse events (40%), sub-optimal trough levels (40%) or minimal radiological response (20%). Radiologic assessment with MRI confirmed a halted growth trend in all treatment-naive cases (100%) and in 64% of them, a regression in AML volume and a reduction of their vascular component within the first year of treatment. Conclusion Our experience confirmed results that emerged from different clinical studies evaluating mTOR inhibition in TSC patients conducted in the last decade. For renal angiomyolipoma, mTOR-i treatment, carefully monitored, fundamentally changed the approach from preventive embolization or even partial nephrectomy to pharmacological treatment; drastically limiting the number of urgent interventional procedures that TSC patients often might undergo. In conclusion, mTOR-i therapy represents a valid and important therapeutic strategy to arrest the growth or regress of renal AMLs.

The Evolving Landscape of Therapeutics for Epilepsy in Tuberous Sclerosis Complex.

Tuberous sclerosis complex (TSC) is a rare multisystem genetic disorder characterized by benign tumor growth in multiple organs, including the brain, kidneys, heart, eyes, lungs, and skin. Pathogenesis stems from mutations in either the TSC1 or TSC2 gene, which encode the proteins hamartin and tuberin, respectively. These proteins form a complex that inhibits the mTOR pathway, a critical regulator of cell growth and proliferation. Disruption of the tuberin-hamartin complex leads to overactivation of mTOR signaling and uncontrolled cell growth, resulting in hamartoma formation. Neurological manifestations are common in TSC, with epilepsy developing in up to 90% of patients. Seizures tend to be refractory to medical treatment with anti-seizure medications. Infantile spasms and focal seizures are the predominant seizure types, often arising in early childhood. Drug-resistant epilepsy contributes significantly to morbidity and mortality. This review provides a comprehensive overview of the current state of knowledge regarding the pathogenesis, clinical manifestations, and treatment approaches for epilepsy and other neurological features of TSC. While narrative reviews on TSC exist, this review uniquely synthesizes key advancements across the areas of TSC neuropathology, conventional and emerging pharmacological therapies, and targeted treatments. The review is narrative in nature, without any date restrictions, and summarizes the most relevant literature on the neurological aspects and management of TSC. By consolidating the current understanding of TSC neurobiology and evidence-based treatment strategies, this review provides an invaluable reference that highlights progress made while also emphasizing areas requiring further research to optimize care and outcomes for TSC patients.

Molecular diagnosis of tuberous sclerosis complex in fetuses and infants: an institutional case series

ObjectiveWe describe the clinical and genetic characteristics of fetuses and infants diagnosed with tuberous sclerosis complex (TSC) in our centre, prenatally or neonatally, for a better understanding of the benefits...

Subependymal giant cell astrocytoma in the absence of tuberous sclerosis: illustrative case.

Subependymal giant cell astrocytoma (SEGA) is a benign intraventricular tumor classically arising near the Foramen of Monro. SEGAs almost always present as a component of tuberous sclerosis complex (TSC), an autosomal dominant disorder characterized by lesions in multiple organs. A 22-year-old female with no past medical history presented with new-onset right-eye pressure, floaters in the right visual field, and pulsatile tinnitus. Imaging revealed an avidly enhancing mass abutting the right Foramen of Monro, causing obstructive hydrocephalus. Following resection, histopathological analysis identified the lesion as a SEGA. However, on further workup, the patient was found to have no genetic or clinical findings of TSC, which exemplifies a rare case of SEGA in the absence of a TSC diagnosis. It is essential for physicians to be aware of the possibility of SEGA in the absence of other characteristics of TSC, which has many implications for a patient's clinical course. The authors present the seventh case of SEGA without genetic or clinical features of TSC described in the literature.

Subependymal giant-cell astrocytomas in the absence of tuberous sclerosis.

Tuberous sclerosis is a rare genetic condition caused by TSC1 or TSC2 mutations that can be inherited, sporadic, or the result of somatic mosaicism. Subependymal giant-cell astrocytoma (SEGA) is a major diagnostic feature of tuberous sclerosis complex (TSC). This study aimed to present a series of cases in which a pathological diagnosis of SEGA was not diagnostic of tuberous sclerosis. The authors retrospectively reviewed a clinical case series of 5 children who presented with a SEGA tumor to Johns Hopkins All Children's Hospital and St. Louis Children's Hospital between 2010 and 2022 and whose initial genetic workup was negative for tuberous sclerosis. All patients were treated with craniotomy for SEGA resection. TSC genetic testing was performed on all SEGA specimens. The children underwent open frontal craniotomy for SEGA resection from the ages of 10 months to 14 years. All cases demonstrated the classic imaging features of SEGA. Four were centered at the foramen of Monro and 1 in the occipital horn. One patient presented with hydrocephalus, 1 with headaches, 1 with hand weakness, 1 with seizures, and 1 with tumor hemorrhage. Somatic TSC1 mutation was present in the SEGA tumors of 2 patients and TSC2 mutation in 1 patient. Germline TSC mutation testing was negative for all 5 cases. No patient had other systemic findings of tuberous sclerosis on ophthalmological, dermatological, neurological, renal, or cardiopulmonary assessments and thus did not meet the clinical criteria for tuberous sclerosis. The average follow-up was 6.7 years. Recurrence was noted in 2 cases, in which 1 patient underwent radiosurgery and 1 was started on a mammalian target of rapamycin (mTOR) inhibitor (rapamycin). There may be intracranial implications of somatic mosaicism associated with tuberous sclerosis. Children who are diagnosed with SEGA do not necessarily have a diagnosis of tuberous sclerosis. Tumors may carry a TSC1 or TSC2 mutation, but germline testing can be negative. These children should continue to be followed with serial cranial imaging for tumor progression, but they may not require the same long-term monitoring as patients who are diagnosed with germline TSC1 or TSC2 mutations.

Astrocyte-derived complement C3 is activated in patients with tuberous sclerosis complex and mediates immune injury: an integrated bioinformatics analysis.

Tuberous sclerosis complex (TSC) is a genetic disorder associated with multiple neurological manifestations. Cortical tubers (CT) are recognized as the hallmark brain lesions of TSC and contribute to neurological and psychiatric symptoms. To understand the molecular mechanism of neuropsychiatric features of TSC, the differentially expressed genes (DEGs) in CT from patients with TSC and those in normal cortex (NC) from participants acting as healthy controls were investigated. The dataset of GSE16969, which had already been published and described (https://onlinelibrary.wiley.com/doi/10.1111/j.1750-3639.2009.00341.x), was downloaded from the Gene Expression Omnibus (GEO), including samples of 4 CT and 4 NC. The R package "limma" was used to screen DEGs in CT and NC. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways enrichment analyses of the DEGs were conducted using the R package "clusterProfiler". The online software Ingenuity Pathway Analysis (IPA) was used to explore activation/inaction of canonical pathways. The hub gene was selected based on the protein-protein interaction (PPI) network constructed using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database and Cytoscape software. Subsequently, the hub genes at messenger (mRNA) and transcriptional levels were tested. We also explored immune cell-type enrichment using the online database xCell, and assessed the correlation between cell types and C3 expression. Then, we verified the source of C3 by constructing TSC2 knockout cells in the U87 astrocyte cell line. The human neuronal cell line SH-SY5Y was used to examine the effects of excessive complement C3 levels. A total of 455 DEGs were identified. A large number of pathways were involved in the immune response process based on the results of GO, KEGG, and IPA. C3 was identified as a hub gene. Complement C3 was also upregulated in the human CT and peripheral blood. Furthermore, based on the enrichment of functions and signaling pathways, complement C3 played a critical role in immune injury in CT of TSC. In the in vitro experiments, we found that excessive complement C3 was derived from TSC2 knockout U87 cells, and there was an increased intracellular reactive oxygen species (ROS) level in SH-SY5Y cells. Complement C3 is activated in patients with TSC and can mediate immune injury.

Impact of facial angiofibromas in tuberous sclerosis complex and reported efficacy of available treatments.

Tuberous Sclerosis Complex (TSC) is a genetic condition which leads to a loss of inhibition of cellular growth. Facial angiofibromas (FAs) are hamartomatous growths associated with TSC that appear as multiple small, erythematous papules on the skin of the face and may resemble more severe forms of acne vulgaris. FAs have been reported in up to 74.5% of pediatric TSC patients, rising to up to 88% in adults >30 years old. They have not been closely studied, potentially overshadowed by other, systemic features of TSC. To investigate the impact of FAs, a common clinical feature for patients with TSC, we performed a non-interventional study in the form of a survey, completed by people living with TSC and FAs, or their caregiver as a proxy, if necessary. Patients were recruited via patient organizations in the UK and Germany. Data was received from 108 families in the UK (44 patients, 64 caregivers) and 127 families in Germany (50 patients, 64 caregivers). Exclusion criteria were those outside of 6-89 years, those without FAs, or those enrolled in a clinical trial. Where caregivers reported on behalf of an individual unable to consent, they were required to be adults (>18 years). Patient experience in the design of the survey was considered from practical and logistical perspectives with survey questions assessing multiple aspects relating to FAs including age of onset, perceived severity, treatments, perceived efficacy of treatments and perceived psychosocial impacts of the FAs. The psychosocial impacts of FAs for the individuals as well as for caregivers were explored in terms of social, occupational and leisure activities. Results of the survey demonstrated that for those with TSC-related moderate or severe FAs, there is an impact on quality of life and psychosocial impacts in the form of anxiety and depression. This finding was also noted by caregivers of TSC individuals in these categories. The treatment most frequently received to improve FAs, topical rapamycin/sirolimus, was found to be successful in the majority of those who received it.

Identification of a Novel Canonical Splice Site Variant TSC2 c.2967-1G>T That is Not Associated With Tuberous Sclerosis Pathogenesis

Tuberous sclerosis, also known as tuberous sclerosis complex (TSC), is an autosomal dominant defect characterized by hamartomas in multiple organ systems. Inactivating variants cause this defect in either the TSC1 gene or the TSC2 gene, leading to hamartin or tuberin protein dysfunction, thus resulting in TSC. The diagnostic criteria for TSC suggest that it can be diagnosed by identifying a heterozygous pathogenic variant of TSC1 or TSC2, even in the absence of clinical signs. In a 4-year-old girl, we identified a splicing variant (NM_000548.4: c.2967-1G>T) that she inherited from her father. Neither the girl (patient) nor her father showed typical features of TSC. This variant is located in a NAGNAG acceptor, which can produce mRNA isoforms that differ by a three-nucleotide indel. Reverse transcription polymerase chain reaction analysis of the patient and both parents’ blood RNA samples suggested two different splicing patterns, and these two splicing patterns differed in the presence or absence of the first codon of exon 27, thus providing two splicing products designated as isoforms A and B, respectively. Furthermore, the proportions of these two patterns varied between the patient and either parent. A minigene assay further confirmed that the c.2967-1G>T variant led to the absence of isoform A (including the first codon of exon 27). The finding of our study demonstrates this variant, c.2967-1G>T, disrupts the balance of an alternative splice event which involves the use of two tandem alternatives acceptors and is not associated with typical symptoms of tuberous sclerosis. Our finding is of importance for genetic counseling and suggests that we need to be vigilant to avoid misdiagnosis when we encounter such a site.

A mechanistic target of rapamycin inhibitor, everolimus safely ameliorated lupus nephritis in a patient complicated with tuberous sclerosis.

A 26-year-old woman with tuberous sclerosis complex (TSC) received outpatient treatment for the complication of systemic lupus erythematosus (SLE) at our hospital. She visited our hospital with a chief complaint of pitting oedema in bilateral lower legs for 3 days. The urinalysis showed massive proteinuria with a lot of white blood cell casts. The blood tests revealed hypoalbuminaemia, hypercholesterolaemia, hypocomplementaemia, and elevated anti-double-stranded DNA antibody titre. Renal biopsy was not performed because of multiple renal angiomyolipomas, which was one of the features of TSC. She was diagnosed with a nephrotic state due to lupus nephritis. Although she had a standard therapy with high-dose corticosteroid and mycophenolate mofetil and tacrolimus, complete remission had not been achieved leading to a steroid-dependent nephrotic syndrome. During the follow-up, the angiomyolipomas became larger and had a risk of rupture at the age of 29 years. Everolimus, a mechanistic target of rapamycin (mTOR) inhibitor, was started for the treatment of angiomyolipomas, and mycophenolate mofetil and tacrolimus were terminated instead. The activity of lupus nephritis was surprisingly ameliorated, and the amount of corticosteroid successfully tapered. Everolimus has been continued for 6 years without severe side effects. Accumulating evidence suggests that the activated mTOR pathway plays a key role in the pathogenesis of SLE. We reported the long-term efficacy and safety of everolimus for refractory SLE in a patient with TSC for the first time. This case suggests that everolimus can be a promising option for the treatment of lupus nephritis.

The genetics and diagnosis of pediatric neurocutaneous disorders: Neurofibromatosis and tuberous sclerosis complex

Neurofibromatosis (NF) and tuberous sclerosis complex (TSC) are the two most common neurocutaneous disorders, both transmitted as autosomal dominant or, in the case of NF, also as a mosaic condition. The causative genetic mutations in these neurocutaneous disorders can lead to benign skin changes or uninhibited growth and proliferation in multiple organ systems due to the loss of tumor suppression in mitogen-activated protein kinase and mammalian target of rapamycin signaling pathways. Common clinical features in NF include pigmented lesions, known as café au lait patches, neurofibromas, intertriginous freckles (Crowe's sign), and benign fibrous growths, such as hamartomas in multiple organ systems. Common clinical features in TSC include hypopigmented macules, known as ash leaf spots, in addition to neurologic sequelae, such as autism, seizures, and developmental delays. Advances in genetic sequencing technologies have allowed an exponential expansion in the understanding of NF and TSC.Consensus criteria have been established for both diagnoses that can be confirmed in most cases through gene testing. Once diagnosed, the clinical and diagnostic value of disease-specific surveillance include early identification of benign and malignant tumors. Genetic counseling is important for informed reproductive decision-making for patients and at-risk family members. The improvement in understanding of pathways of pathogenic disease development and oncogenesis in both conditions have produced a new series of therapeutic options that can be used to control seizures and tumor growth. Tremendous advances in life expectancy and quality of life are now a reality due to early introduction of seizure control and novel medications. While we lack cures, early institution of interventions, such as seizure control in tuberous sclerosis, appears to be disease-modifying and holds immense promise to offer patients better lives.

Expanding Our Knowledge of Menstrual Irregularities Reported by Females With Tuberous Sclerosis Complex.

PurposeThe purpose of our study is to expand the knowledge regarding intrinsic reproductive dysfunction in females with TSC and to explore the impact of mTOR inhibitors (mTORi) on menstrual irregularity in the Tuberous Sclerosis Complex (TSC) community.MethodsAn electronic survey composed of author-designed questions set out to evaluate reproductive history, presence of menstrual irregularities, mTORi use, as well as maternal reproductive history among females with TSC.ResultsOf the 68 responses from females with TSC regarding age of menarche, the average age was 12.3 years. 56.5% (n = 48) of respondents reported irregular menstrual cycles and noted a total of 102 menstrual irregularities. There was a cohort of 35 women with a reported history of mTORi use. Of these women, 68.6% (n = 24) reported irregular menstrual cycles after taking mTORi. In comparison, among the females with no history of mTORi use (n = 50) only 48% reported irregular menstrual cycles (n = 24).ConclusionsOur data expands the knowledge regarding intrinsic menstrual dysregulation present in women with TSC, demonstrates a rate of menstrual irregularities among females taking mTORi, and identifies a tendency toward early menarche that may be a previously unrecognized feature of TSC.

Evaluation of the Relationship Between Cranial Magnetic Resonance Imaging and Epileptic Features in Tuberous Sclerosis Complex

Evaluation of the Relationship Between Cranial Magnetic Resonance Imaging and Epileptic Features in Tuberous Sclerosis Complex

Tale of a Teenager: A Case Report of Tuberous Sclerosis

Tuberous sclerosis complex is an unusual neurocutaneous syndrome with autosomal-dominant inheritance. It is characterized by the development of benign tumors involving the brain, skin, retina, heart, kidneys, lungs, and liver. The classic triad of clinical features comprises learning disability, epilepsy and skin lesions but there is marked heterogeneity in clinical features. Here, we present a case report of a 17-old-year male with characteristic clinical and radiological features of tuberous sclerosis complex. Bangladesh J Medicine July 2022; 33(1) : 99-103

Neuro-encephalic features of tuberous sclerosis complex

Tuberous sclerosis is a phacomatosis resulting from an autosomal dominant inheritance. It is characterized by the presence of multiple hamartomas in various organs, especially the brain, the skin, the kidneys and the heart. The aims of this study is to focus on neuro-encephalic features of tuberous sclerosis complex.

Tuberous Sclerosis: Current Update.

Tuberous sclerosis complex (TSC) is a relatively rare autosomal dominant neurocutaneous disorder secondary to mutations in the TSC1 or TSC2 tumor suppressor genes. Although manifestation of the classic triad of seizures, intellectual disability, and facial angiofibromas may facilitate timely diagnosis of TSC, the multisystem features that may indicate TSC in the absence of these manifestations remain highly variable. In addition, patients with TSC are at risk of developing multiple benign and malignant tumors in various organ systems, resulting in increased morbidity and mortality. Thus, imaging plays a critical role in diagnosis, surveillance, and management of patients with TSC. It is crucial that radiologists be familiar with TSC and the various associated imaging features to avoid a delayed or incorrect diagnosis. Key manifestations include cortical dysplasias, subependymal nodules, subependymal giant cell astrocytomas, cardiac rhabdomyomas, lymphangioleiomyomatosis, and angiomyolipomas. Renal angiomyolipomas in particular can manifest with imaging features that mimic renal malignancy and pose a diagnostic dilemma. Other manifestations include dermatologic and ophthalmic manifestations, renal cysts, renal cell carcinomas, multifocal micronodular pneumocyte hyperplasia, splenic hamartomas, and other rare tumors such as perivascular epithelioid tumors. In addition to using imaging and clinical features to confirm the diagnosis, genetic testing can be performed. In this article, the molecular pathogenesis, clinical manifestations, and imaging features of TSC are reviewed. Current recommendations for management and surveillance of TSC are discussed as well. ©RSNA, 2021.

Co-existence of ESC-RCC, EVT, and LOT as synchronous and metachronous tumors in six patients with multifocal neoplasia but without clinical features of tuberous sclerosis complex

Renal cell tumors with oncocytic phenotypes represent a daily challenge, with several novel, emerging, and provisional entities enriching the diagnostic repertoire. Eosinophilic solid and cystic renal cell carcinoma (ESC-RCC), low-grade oncocytic tumor (LOT), and eosinophilic vacuolated tumor (EVT) have been recognized as unique entities, although their distinctive nature remains controversial. Although most of these tumors are sporadic, rare reports of similar tumors in tuberous sclerosis complex (TSC) have been published. We describe multifocal, often bilateral, tumors in six patients without personal or family history of syndromic diseases. More than 60 tumors in various combinations were identified in 10 nephrectomies and one biopsy encompassing ESC-RCC (n=6), LOT (n=14), EVT (n=1), clear cell RCC with fibromyomatous stroma (n=12), clear cell RCC (n=2), angiomyolipomas (AMLs; n>20), unclassified renal cell tumors (n=2), papillary adenomas (n=4), and renomedullary interstitial cell tumor (n=1). TSC1 germline pathogenic mutations were confirmed in two patients. A tumor without germline testing in a third patient revealed TSC1 biallelic inactivation. Two additional patients had molecular testing, which excluded common renal mutations and syndromes. We provide the first evidence of co-existence in the same organ and unequivocal relatedness of ESC-RCC, EVT, and LOT. End-stage renal disease was present in three of six patients with precursor lesions to all above tumors within adjacent renal parenchyma. In conclusion, identification of multifocal tumors with TSC-like morphology, especially in association with AMLs, could be the first manifestation of clinically silent TSC guiding clinical recommendations for further genetic testing and/or treatment recommendations.

New imaging features of tuberous sclerosis complex: A 7 T MRI study.

Few in vivo studies have focused on the perivenous association of tubers and iron deposition in the deep gray nuclei in patients with tuberous sclerosis complex (TSC). We investigated this possible relationship in TSC patients using susceptibility weighted imaging (SWI) at 7 T. SWI with high spatial resolution and enhanced sensitivity was performed on 11 TSC patients in comparison with 15 age- and sex-matched healthy controls. The relationship between tubers and veins was evaluated. In addition, the phase images of SWI were processed to produce local field shift (LFS) maps to quantify iron deposition. The mean LFS in the deep gray nuclei was compared between the TSC patients and healthy controls using a covariance analysis. Venous involvement was observed in 211 of the 231 (91.3%) cortical tubers on SWI. The slender tubers often oriented around the long axis of penetrating veins, possibly because cortical tubers typically developed and/or migrated along venous vasculatures. A significant difference in LFS of the thalamus was detected between the TSC patients and healthy controls (3.36 ± 0.50 versus 3.01 ± 0.39, p < 0.01). The new in vivo imaging features observed at 7 T provide valuable insights into the possible venous association of TSC lesions and iron accumulation in the deep gray nuclei. Our results may lead to a better understanding of the pathological changes involved in TSC under in vivo conditions.

Frequency, Progression, and Current Management: Report of 16 New Cases of Nonfunctional Pancreatic Neuroendocrine Tumors in Tuberous Sclerosis Complex and Comparison With Previous Reports.

Background: Tuberous sclerosis complex (TSC) is a genetic condition that causes benign tumors to grow in multiple organ systems. Nonfunctional pancreatic neuroendocrine tumors (PNETs) are a rare clinical feature of TSC with no specific guidelines outlined for clinical management at this time. Our purpose is to calculate the frequency of nonfunctional PNETs as well as characterize the presentation, current clinical management, and assess the impact of systemic mammalian target of rapamycin (mTOR) on nonfunctional PNETs in TSC.Methods: This retrospective chart review was performed by a query of the TS Alliance's Natural History Database and the Cincinnati Children's Hospital TSC Database for patients with nonfunctional PNET. Clinical data from these two groups was summarized for patients identified to have a nonfunctional PNET and compared to previously reported cases with TSC and nonfunctional PNETs.Results: Our calculated frequency of nonfunctional PNETs is 0.65%. We identified 16 individuals, nine males and seven females, with a median age of 18.0 years (interquartile range: −15.5 to 25.5). Just over half (56.3%, n = 9) of the patients provided results from genetic testing. Six had pathogenic variants in TSC2 whereas three had pathogenic variants in TSC1. The average age at PNET diagnosis was 15.0 years (range: 3–46 years). Almost all individuals were diagnosed with a PNET during routine TSC surveillance, 56.3% (n = 9) by MRI, 12.5% (n = 2) by CT, 25% (n = 4) by ultrasound, and 6.2% (n = 1) through a surgical procedure. Follow up after diagnosis involved 68.8% (n = 11) having serial imaging and nine of the sixteen individuals proceeding with surgical removal of the PNET. Eight individuals had a history of using systemic mTOR inhibitors. Tumor growth rate was slightly less in individuals taking an mTOR inhibitor (−0.8 mm/yr, IQR: −2.3 to 2.2) than those without (1.6 mm/yr; IQR: −0.99 to 5.01, p > 0.05).Conclusions: Nonfunctional PNETs occurred at younger ages in our TSC cohort and more commonly compared to ages and prevalence reported for the general population. PNETs in patients on systemic mTOR inhibitors had lower rates of growth. The outcome of this study provides preliminary evidence supporting the use of mTOR inhibitor therapy in conjunction with serial imaging as medical management for nonfunctional PNETs as an alternative option to invasive surgical removal.

Sclérose tubéreuse de Bourneville : mise au point

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder that affects different organs and caused by loss-of-function mutations in one of two genes: TSC1 or TSC2. TSC1 or TSC2 gene mutation lead to dysfunction of hamartin or tuberin, respectively. Hamartin and tuberin form a protein complex that helps regulate cellular proliferation. These proteins form a complex that constitutively inhibits the mammalian target of rapamycin (mTOR) signaling pathway, leading to permanent activation of mTOR signaling within all TSC-associated lesions. Major features of TSC include tumors of the brain, skin, heart, lungs and kidneys, seizures and TSC-associated neuropsychiatric disorders, which can include autism spectrum disorder and cognitive disability. These disorders are usually diagnosed in children and adults. Specific guidelines for diagnosis, surveillance, and management have been proposed by the International Tuberous Sclerosis Complex Consensus Group. Several randomized controlled trials led to regulatory approval of the use of mTOR inhibitors for the treatment of renal angiomyolipomas, brain subependymal giant cell astrocytomas, refractory epilepsy and pulmonary lymphangioleiomyomatosis.

POS-429 A RARE VARIANT OF GENETICALLY CONFIRMED TUBEROUS SCLEROSIS COMPLEX PRESENTING WITH BILATERAL RENAL ANGIOMYOLIPOMA IN WUNDERLICH SYNDROME

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder with a prevalence of approximately 1 to 6,000-12,000 worldwide. Renal angiomyolipoma (AML) associated with TSC is often life-threatening due to the greater propensity to develop hemorrhage. A rare condition associated with it is the Wünderlich syndrome (WS), atraumatic renal hemorrhage into the subcapsular and perirenal spaces. We present a case of a patient who presented with the cutaneous and renal features of TSC with bilateral AML in Wünderlich syndrome. Case Report A 28-year-old female was admitted for non-traumatic right flank pain. She presented with the classic cutaneous features of TSC: hyperpigmented skin papules located on the center area of her face, periungual angiomas, and angiofibroma (Figure 1). She was also unable to finish high school. She previously consulted another hospital where a whole abdominal ultrasound was done, revealing a complex retroperitoneal mass on the right measuring 14.9 x 9.3 x 14 cm. She was then advised urologic evaluation and transferred to our institution. She had no dysuria, hypogastric pain, nor hematuria. Physical examination revealed her abdomen was enlarged and a right flank mass (doughy, round, non-tender, measuring 3 cm x 3 cm) was palpated. She was hypotensive on admission and required aggressive resuscitation. Abdominal computed tomography (CT) with contrast showed bilaterally enlarged kidneys and fluid collection (611 mL) in the right perirenal space (Figure 2). The Urology service at the time opted to observe the patient (no surgical plans) at the time since there was no evidence of active hemorrhage. The consideration was an angiomyolipoma in Wünderlich syndrome (shock, flank mass, flank pain). Genetic testing of TSC related genes revealed mutations in the TSC2 gene (loss-of-function variant), consistent with tuberous sclerosis complex. Genetic counseling was rendered to the patient and her immediate family. Furthermore, echocardiography with doppler studies, cranial and chest CT with contrast done were all unremarkable. She opted to be discharged against medical advice and was scheduled for a close outpatient follow-up. She was sent home on sirolimus 2 mg once daily. On her follow-up two weeks post-discharge, she reported improved overall well-being and a subjective decrease in the right flank mass. In summary, the diagnosis of TSC should be considered in young females of Southeast Asian descent presenting with multiple dermatologic lesions and multiple renal masses and development delay. Particularly, in those presenting with renal angiomyolipoma are at high risk for developing life-threatening hemorrhage. Hence, timely and appropriate management is needed (i.e. embolization, nephrectomy, or chemotherapy). Also, a thorough workup must be done to rule out the involvement of vital organs (i.e. cardiac rhabdomyoma, and intracranial space-occupying lesions. Lastly, it should be emphasized that early recognition of the disease and its manifestations is the keystone of the prevention of these fatal complications.