Tuberous Sclerosis Research Articles

Neuropsychiatric Manifestations of Tuberous Sclerosis in a young adult male in a Psychiatry Hospital in Botswana: a case report

IntroductionTuberous sclerosis complex (TSC) is a disorder that affects multiple systems and was first described in 1880. Its symptoms include seizures, intellectual disability, and adenoma sebaceum. TSC is caused by mutations in the TSC1 and TSC2 genes and is inherited in an autosomal dominant manner.ObjectivesThis report highlights a case of a patient with an unusual psychological presentation evaluated in a psychiatric hospital.MethodsThe patient presented with psychotic features and abnormal behavior. A physical examination showed neurocutaneous lesions. After assessment a diagnosis of Tuberous sclerosis complex was confirmed through MRI Brain and genetic testing. Some of his relatives also showed similar neuropsychiatric symptoms.ResultsTuberous sclerosis complex is diagnosed based on TSC Clinical Consensus Group guidelines of 2012. Our patient fulfilled 4 of the major criteria and genetic testing also yielded a pathogenic variant. A TAND checklist (TSC-Associated Neuropsychiatric Disorders) is used to guide clinicians on areas to prioritize when managing TSC patients.Image:Image 2:Image 3:ConclusionsGiven that psychiatry may be the first contact for TSC patients, especially in low-resource settings. Patients referred to psychiatry, therefore, need to be thoroughly examined to exclude neuropsychiatric disorders, and a multidisciplinary team approach is vital in investigating and managing these cases.Disclosure of InterestNone Declared

A quantitative cross-sectional study of the burden of caring for patients with Lennox-Gastaut syndrome, Dravet syndrome, and tuberous sclerosis complex-associated epilepsy in Japan

IntroductionLennox-Gastaut syndrome (LGS), Dravet syndrome (DS), and tuberous sclerosis complex (TSC)-associated epilepsy are rare conditions associated with severe childhood-onset epilepsy. Caregivers play a critical role in the patients’ care and may experience significant psychosocial and socioeconomic burden. This cross-sectional study determined the burden of caring for patients with these rare epilepsy conditions in Japan. MethodsA quantitative online survey was used to assess patients’ and caregivers’ characteristics and the caregivers’ emotional state, among others. Several validated questionnaires were used: the Hospital Anxiety and Depression Scale (HADS; 0–21 score) assessed the caregivers’ emotional wellbeing, the Pediatric Quality of Life Inventory Family Impact Module (PedsQL FIM; 0–100 score) assessed the health-related quality of life (HRQoL) of the caregivers and their families, and the Work Productivity and Activity Impairment General Health (WPAI:GH; 0–100 % score) questionnaire assessed work productivity. ResultsA total of 36 caregivers responded (median [interquartile range (IQR)] age 43.5 [39.5, 48.3] years; 33/36 [92 %] female; 13/36 [36 %] working part-time and 13/36 [36 %] not working). Participants cared for 7/36 (19 %), 19/36 (53 %), and 10/36 (28 %) patients with LGS, DS, and TSC, respectively (median [IQR] age, 11.0 [6.8, 16.3] years; age at first seizure, 0 [0, 0] years). Patients received a median (IQR) of 4 (3, 5) treatment drug types. Patients experienced median (IQR) 3.0 (0, 21.0) epileptic seizures in the previous week; 28/36 (78 %) had severe intellectual disabilities, and 34/36 (94 %) had developmental delays. Caregivers reported stress (17/36 [47 %]), sleep problems (13/36 [36 %]), and anxiety (12/36 [33 %]). They spent a median (IQR) of 50.0 (17.5, 70.0) hours caregiving in the previous week, with 3.0 (1.0, 11.0) hours of seizure-specific care. Caregivers reported that their lives would be easier with a median (IQR) of 1.5 (0, 5.0) hours fewer per week caring for patients during/following seizures. Median HADS scores were 9.5 (‘suspected anxiety diagnosis’) and 7.5 (‘no depression’) for caregivers, and PedsQL FIM Total median score was 60.1, indicating HRQoL impairment for the caregiver and their family. WPAI:GH scores for paid workers indicated important work impairment. Higher caregiving hours (≥ 21 h vs. < 21 h in the previous week) resulted in higher caregiver burden as indicated by the HADS Total score (p = 0.0062) and PedsQL FIM Total score (p = 0.0007). ConclusionsCaregivers of patients with LGS, DS, or TSC in Japan experience a significant time burden, reduced HRQoL, and high level of work/activity impairment. Caregivers provide round-the-clock care to patients and rely on family and specialized caring services to help manage the increased caregiving time, which tends to be associated with greater emotional burden and HRQoL impact.

Perivascular Epithelioid Cell-Family Tumors in Children, Adolescents, and Young Adults: Clinicopathologic Features in 70 Cases.

Perivascular epithelioid cell tumors (PEComas) are rare mesenchymal tumors of uncertain histogenesis expressing smooth muscle and melanocytic markers. The clinicopathologic spectrum in young patients is not well documented. To describe a multi-institutional series of PEComas in children, adolescents, and young adults. PEComas, not otherwise specified (NOS); angiomyolipomas (AMLs); lymphangioleiomyomatosis; and clear cell sugar tumors were retrospectively identified from 6 institutions and the authors' files. Seventy PEComas in 64 patients (median age, 15 years) were identified. They were more common in females (45 of 64 patients), occurring predominantly in the kidney (53 of 70), followed by the liver (6 of 70). Thirty-four patients had confirmed tuberous sclerosis complex (TSC), 3 suspected TSC mosaicism, 2 Li-Fraumeni syndrome (LFS) and 1 neurofibromatosis type 1. Most common variants were classic (49 of 70) and epithelioid (8 of 70) AML. Among patients with AMLs, most (34 of 47) had TSC, and more TSC patients had multiple AMLs (15 of 36) than non-TSC patients (2 of 13). Two TSC patients developed malignant transformation of classic AMLs: 1 angiosarcomatous and 1 malignant epithelioid. Lymphangioleiomyomatosis (5 of 70) occurred in females only, usually in the TSC context (4 of 5). PEComas-NOS (6 of 70) occurred exclusively in non-TSC patients, 2 of whom had LFS (2 of 6). Three were malignant, 1 had uncertain malignant potential, and 2 were benign. All 4 PEComas-NOS in non-LFS patients had TFE3 rearrangements. Compared to the general population, TSC was more prevalent in our cohort; PEComas-NOS showed more frequent TFE3 rearrangements and possible association with LFS. This series expands the spectrum of PEComas in young patients and demonstrates molecular features and germline contexts that set them apart from older patients.

Поліморфізм клінічних проявів орфанних захворювань у дітей із мутаціями генів ARID1A та ARID1B

The Department of Psychoneurology for Children with Perinatal Pathology and Orphan Diseases at the SI “Institute of Pediatrics, Obstetrics and Gynecology named after academician O.M. Lukyanova of the NAMS of Ukraine” has a multidisciplinary team which provides care to children with orphan diseases from all over Ukraine. Thanks to modern methods of clinical, instrumental and genetic diagnostics, it is possible to establish a definitive diagnosis. Aim - to provide a literature review and a clinical case of a child with pathogenic variants of the ARID family genes, which, in particular, lead to the development of Coffin-Circe syndrome (CCS), autism spectrum disorder and intellectual disability, as well as the development of nervous system tumors in children. The article presents a clinical case of a child with a rare disease - CCS, which is part of the ARID gene mutation spectrum. The general clinical and neurological examination, electroencephalographic sleep monitoring, magnetic resonance imaging, whole-exome sequencing, and pathological examination were performed. The difficulty of diagnosis was that a child with skin manifestations of phacomatosis was diagnosed with subependymal giant cell astrocytoma (SGСA) by magnetic resonance imaging, but there were no mutations characteristic of tuberous sclerosis (TSC1, TSC2). Pathologically, the patient was confirmed to have grade I SGСA according to the World Health Organization classification. Two pathogenic mutations of the ARID1A gene in the compound heterozygous state were detected by whole-exome sequencing. After combining the combined clinical and instrumental signs, the diagnosis of CCS with grade I SGСA was established. Conclusions. The disorders caused by ARID1A and ARID1B mutations belong to a spectrum that includes syndromic and non-syndromic cases of intellectual disability, autism spectrum disorder, and CCS with or without a variety of somatic and neurological symptoms, and are grouped under the general term “ARID-related disorders”. Only a thorough medical history, clinical examination, and modern methods of instrumental and genetic diagnostics can make a diagnosis. The research was carried out in accordance with the principles of the Declaration of Helsinki. Informed consent of the women was obtained for the research. No conflict of interests was declared by the authors.

Lymphangioleiomyomatosis in patients with tuberous sclerosis: a national centre audit

BackgroundLymphangioleiomyomatosis (LAM) is common in tuberous sclerosis complex (TSC) yet under recognised with management mostly based upon evidence obtained from patients with sporadic LAM. We performed a prospective audit of patients with TSC-LAM attending a national referral centre to inform management guidelines.MethodsThe UK LAM Centre was established in 2011 and conducts a prospective audit of pre-defined quality outcomes for all subjects. Audit data are reported on all patients with TSC-LAM and a comparator population of patients with sporadic LAM.ResultsBetween 2011 and 2022, 73 patients were seen with TSC-LAM. All were women with a mean (SD) age of 39 (12) years. Referral rates were similar over the study period including after the introduction of CT screening. Median age of diagnosis with TSC was 11 years (range 0–70) with one third diagnosed with TSC as adults. Compared with all TSC patients in the ‘TOSCA’ registry, TSC-LAM patients tended to have been diagnosed with TSC at an older age, had fewer neuro-cognitive manifestations and were more likely to have angiomyolipoma. The most common presentations of TSC-LAM were following workup for angiomyolipoma, pneumothorax or dyspnoea with only one fifth detected after CT screening. Baseline FEV1 and DLCO at first assessment were reduced to 77 and 63% predicted respectively and were similar to patients with sporadic LAM. During follow-up, FEV1 fell by a mean of 81 ml/year and DLCO fell by 0.309 mmol/ml/kPa/year in patients not being treated with an mTOR inhibitor. 55% required treatment with either sirolimus or Everolimus for LAM or angiomyolipoma respectively. For those treated with an mTOR inhibitor, mean FEV1 fell by 3 ml/year and DLCO increased by 0.032 mmol/ml/kPa/year and was similar to sporadic LAM. Risk of death due to LAM or need for lung transplant in patients with TSC-LAM was 0.67%/year.ConclusionsDespite screening recommendations, LAM is often diagnosed in TSC after symptoms develop which may delay treatment. Complications including pneumothorax and loss of lung function are significant and similar to sporadic LAM. Work is needed to implement the recommended CT screening for LAM and improve respiratory care for TSC-LAM.

Neuropsychiatric comorbidities in tuberous sclerosis complex patients with epilepsy: results of the TAND checklist survey.

In addition to epilepsy, individuals with tuberous sclerosis complex (TSC) experience a wide range of behavioral, psychiatric, intellectual, academic, and psychosocial problems. They usually exert a large psychological burden on individuals with these illnesses. This cross-sectional study used TSC-associated neuropsychiatric disorders (TAND) checklist interviews conducted at a single medical center. The enrollment of all subjects was > 6years, and the comorbidities of neurodevelopmental disorders were assessed by clinical psychologists before enrollment. To assess the spectrum of TAND, the TAND checklist was applied as stated in the protocol, and the responses to the TAND checklist were evaluated by clinical psychologists. In the behavioral concerns of patients with TSC without epilepsy, those with epilepsy had excessive shyness, language delay, lack of eye contact, rigid behavior, inattentiveness, and restlessness. In psychiatric disorders, autism spectrum disorder and attention-deficit/hyperactivity disorder are significantly correlated with epilepsy history. Diminished academic skills, including reading, writing, and mathematics skills, are significantly associated with epilepsy history. For intellectual ability, TSC patients without epilepsy is associated normal intelligence level. Among neuropsychological skills, deficits in attention, dual tasking/multi-tasking, visuospatial tasking, and executive skills are significantly associated with epilepsy history. Epilepsy in patients with TSC contributes to comorbid neuropsychiatric disorders. In addition to epilepsy evaluation, it is crucial to evaluate the heterogeneous spectrum of neuropsychiatric disorders using a standard checklist during the annual clinical follow-up of patients with TSC.

Single-Center Experience of Pediatric Cystic Kidney Disease and Literature Review.

Pediatric cystic kidney disease (CyKD) includes conditions characterized by renal cysts. Despite extensive research in this field, there are no reliable genetics or other biomarkers to estimate the phenotypic consequences. Therefore, CyKD in children heavily relies on clinical and diagnostic testing to predict the long-term outcomes. A retrospective study aimed to provide a concise overview of this condition and analyze real-life data from a single-center pediatric CyKD cohort followed during a 12-year period. Medical records were reviewed for extensive clinical, laboratory, and radiological data, treatment approaches, and long-term outcomes. During the study period, 112 patients received a diagnosis of pediatric CyKD. Male patients were more involved than female (1:0.93). Fifty-six patients had a multicystic dysplastic kidney; twenty-one of them had an autosomal dominant disorder; fifteen had an isolated renal cyst; ten had been diagnosed with autosomal recessive polycystic kidney disease; three had the tuberous sclerosis complex; two patients each had Bardet-Biedl, Joubert syndrome, and nephronophthisis; and one had been diagnosed with the trisomy 13 condition. Genetic testing was performed in 17.9% of the patients, revealing disease-causing mutations in three-quarters (75.0%) of the tested patients. The most commonly presenting symptoms were abdominal distension (21.4%), abdominal pain (15.2%), and oligohydramnios (12.5%). Recurrent urinary tract infections (UTI) were documented in one-quarter of the patients, while 20.5% of them developed hypertension during the long-term follow-up. Antibiotic prophylaxis and antihypertensive treatment were the most employed therapeutic modalities. Seventeen patients progressed to chronic kidney disease (CKD), with thirteen of them eventually reaching end-stage renal disease (ESRD). The time from the initial detection of cysts on an ultrasound (US) to the onset of CKD across the entire cohort was 59.0 (7.0-31124.0) months, whereas the duration from the detection of cysts on an US to the onset of ESRD across the whole cohort was 127.0 (33.0-141.0) months. The median follow-up duration in the cohort was 3.0 (1.0-7.0) years. The patients who progressed to ESRD had clinical symptoms at the time of initial clinical presentation. This study is the first large cohort of patients reported from Croatia. The most common CyKD was the multicystic dysplastic kidney disease. The most common clinical presentation was abdominal distention, abdominal pain, and oliguria. The most common long-term complications were recurrent UTIs, hypertension, CKD, and ESRD.

Generation of a TSC2 knockout embryonic stem cell line by CRISPR/Cas9 editing

Tuberous Sclerosis Complex (TSC) is a severe developmental disorder with various clinical effects, primarily caused by TSC2 gene mutations, often involving loss of function(Henske,et al., 2016).To explore role of TSC2 in human heart development, we successfully developed a TSC2 knockout (TSC2-/-) human embryonic stem cells (hESCs) line using CRISPR/Cas9 gene editing. This TSC2-/- hESC line maintained a normal karyotype, expressed pluripotency markers strongly, and could differentiate into all three germ layers in vivo. This cell line will be a valuable tool for future research on the role of TSC2 in heart development.

The effect of pregnancy on renal angiomyolipoma; a world of knowledge to gain, specifically in women with TSC

BackgroundWomen are counseled preconceptionally about the potential risks of rAML progression and chance of complications during and due to pregnancy. However, a systematic search investigating the evidence on which this advice is based does not exist. The aim of this systematic review is to determine the effect of pregnancy on renal angiomyolipoma (rAML) size and risk of haemorrhage in patients with tuberous sclerosis complex (TSC).MethodsWe searched PubMed, EMBASE, Medline and ClinicalTrials.gov using terms for “renal angiomyolipoma” and “pregnancy”. English-language articles published between January 1st 2000, and December 31st 2020 of which full-text was available were included. The initial search resulted in 176 articles. After the screening process we included 45 case reports and 1 retrospective study. For the retrospective study we assessed the risk of bias using the Newcastle–Ottawa Scale. We included articles about renal AML and pregnancy with and without an established diagnosis of TSC. From these articles we recorded the rAML sizes and rAML complications.ResultsSeven case reports, from a total of 45 case reports, provided follow-up data on renal AML size (these were all cases of renal AML without a known diagnosis of TSC). Of these cases, renal AML size decreased in one patient, was stable in one patient, increased in three patients and fluctuated in two others. Renal AML size of women who suffered a haemorrhage were significantly larger (12.1 ± 4.6 cm) than rAMLs of women who did not suffer a haemorrhage (8.3 ± 3.2 cm). Data from the retrospective study showed no difference in renal complications between the women with and without a history of pregnancy. Haemorrhage occurred in 30% of the women with a history of pregnancy (n = 20) and in 11% in the patients without a history of pregnancy (n = 2), however this retrospective study had methodological limitations.ConclusionThe effect of pregnancy on renal AML size and complications in patients with TSC is unclear. More research is needed to determine the risk of pregnancy on TSC-associated kidney disease in TSC patient.

Measurement of Developmental and Behavioral Concerns in Toddlers With Tuberous Sclerosis Complex

BackgroundThe TAND (Tuberous Sclerosis Complex [TSC]-Associated Neuropsychiatric Disorders) Checklist was developed as a clinical screener for neurodevelopmental disorders in TSC. Most studies have described patterns in older children and adults. This study sought to better understand behavioral concerns as measured by the TAND Checklist in young children with TSC. MethodsWe examined patterns of caregiver responses to the TAND Checklist in 90 toddlers with TSC (12 to 23 months n = 60; 24 to 36 months n = 30) through data collected during baseline visits across two TSC early intervention studies. ResultsOver 90% of caregivers reported at least one behavioral concern related to TAND. The number of concerns increased with age. Delayed language was the most frequently reported concern across ages (12 to 23 months: 58.3%, 24 to 36 months: 86.7%). Questions related to behavioral concerns were largely relevant in this age range, but questions in other areas, such as neuropsychological or academic function, were not. ConclusionsTAND symptoms are very common in toddlers with TSC, and these symptoms may increase with age. The TAND Checklist is a useful tool for identifying behavioral concerns efficiently, but several items and sections are not suited to younger children. Results support the development of an abbreviated form of the TAND Checklist for toddlers.

Stereoelectroencephalography and surgical treatment of TSC-associated epilepsy in children: preliminary results

Introduction. The most prevalent symptom of central nervous system involvement in tuberous sclerosis complex is epilepsy, predominantly of a drug-resistant nature. In such cases, surgical treatment methods become a focal point for consideration. Purpose of the study: to analyze the outcomes of surgical treatment for drug-resistant epilepsy in children with tuberous sclerosis following stereoelectroencephalography. Materials and methods. A retrospective analysis of surgical outcomes for epilepsy in children with tuberous sclerosis after stereo-EEG was conducted. From April 2017 to December 2021, 23 patients underwent prolonged stereo-EEG monitoring. Based on the results of invasive EEG, resective surgery was performed on 14 patients. Primary resection of the epileptogenic zone was carried out in 11 cases (79 %), and repeated resection was performed in 3 cases (21 %). Tuberectomy was conducted in three cases, tuberectomy plus — in six patients, lobectomy — in three patients, multilobar resection — in three cases, and one patient had an extension of the previous resection area with cor ticoectomy. Results. In the follow-up period ranging from 12 to 78 months, ILAE I outcome was observed in 64 % of cases, ILAE IV in 29 % of children, and ILAE V in 7 % of cases. Antiepileptic therapy was discontinued in one patient, a decrease in drug load was noted in four patients, and an increase in drug load was obser ved in one patient. Conclusion. Surgical treatment of TSC-associated epilepsy in children requires a comprehensive pre-surgical examination in specialized centers, incorporating the invasive electroencephalography method. Given the multifocal nature of epilepsy, along with the combination of generalized and focal seizures, resective surgeryis worth considering as palliative treatment in some cases.

Abstract 630: The role of AKT pathway in β-catenin mutated hepatocellular carcinoma

Abstract The Wnt/β-catenin and PI3K/AKT pathways are pivotal contributors to the development of the malignant phenotype in cancer. The activated Wnt/β-catenin pathway synergizes with various signaling cascades to propel HCC formation, operating through its downstream effectors. It has been well-established that the mammalian target of rapamycin complex 2 (mTORC2) serves as an upstream regulator of AKT, orchestrating the phosphorylation and activation of AKT. Once activated, AKT phosphorylates and inhibits canonical downstream targets like forkhead box O protein (FOXO) and tuberous sclerosis complex 2 (TSC2). Studies indicated that AKT-mediated phosphorylation of TSC2 activates mTORC1, subsequently suppressing autophagy. However, there are limited data exist on the interplay between Wnt/β-catenin and AKT pathways in HCC. In this study, we sought to explore the role of the AKT pathway in β-catenin activated HCC tumors. Sleeping beauty-mediated hydrodynamic transfection was used to overexpress constitutively active forms of β-catenin (N90-β-catenin) and c-MET in the livers of mice to establish the HCC model (c-Met/β-catenin model). Notably, the knockout of Rictor, a component of the mTORC2 complex, significantly impeded tumor growth, underscoring the pivotal role of AKT in c-Met/β-catenin tumor development. AKT1 and AKT2 are the two main isoforms expressed in the liver. We determined that both AKT1 and AKT2 isoforms are critical for c-Met/β-catenin tumor growth. Intriguingly, simultaneous knockout of Rictor and activation of mTORC1 in the c-Met/β-catenin model resulted in delayed tumor growth, indicating that mTORC1 is not the sole downstream determinant of AKT signaling during c-Met/β-Catenin tumor development. Furthermore, overexpression of the activated FOXO1 (FOXO1AAA) significantly delayed the tumor growth, which highlighted the importance of FOXO1. Given the limited understanding of FOXO1 in HCC, we extended our investigation on FOXO1 to human HCC cell lines. Overexpression of FOXO1AAA notably delayed tumor growth in vitro. RNAseq analysis of FOXO1AAA-overexpressed human HCC cell lines revealed a significant upregulation of "metabolic pathways", suggesting metabolic reprogramming post FOXO1 activation. This study, for the first time, unveils the role of the AKT pathway in β-catenin-mutated HCC growth and highlights the potential therapeutic value of targeting the AKT pathway in patients with β-catenin-mutated HCC. Citation Format: Xue Wang, Xin Chen. The role of AKT pathway in β-catenin mutated hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 630.

The autism spectrum disorder phenotype in children with tuberous sclerosis complex: A systematic review and meta-analysis.

https://onlinelibrary.wiley.com/doi/10.1111/dmcn.15307

Recurrent Tuberous Sclerosis Complex/Mammalian Target of Rapamycin Mutations Define Primary Renal Hemangioblastoma as a Unique Entity Distinct From Its Central Nervous System Counterpart.

Renal hemangioblastoma (HB) is a rare subset of HBs arising outside of the central nervous system (CNS), with its molecular drivers remaining entirely unknown. There were no significant alterations detected in previous studies, including von Hippel-Lindau gene alterations, which are commonly associated with CNS-HB. This study aimed to determine the real molecular identity of renal HB and better understand its relationship with CNS-HB. A cohort of 10 renal HBs was submitted for next-generation sequencing technology. As a control, 5 classic CNS-HBs were similarly analyzed. Based on the molecular results, glycoprotein nonmetastatic B (GPNMB) immunohistochemistry was further performed in the cases of renal HB and CNS-HB. Mutational analysis demonstrated that all 10 renal HBs harbored somatic mutations in tuberous sclerosis complex 1 ( TSC1 , 5 cases), TSC2 (3 cases), and mammalian target of rapamycin (2 cases), with the majority classified as pathogenic or likely pathogenic. The CNS-HB cohort uniformly demonstrated somatic mutations in the von Hippel-Lindau gene. GPNMB was strong and diffuse in all 10 renal HBs and completely negative in CNS-HBs, reinforcing the molecular findings. Our study reveals a specific molecular hallmark in renal HB, characterized by recurrent TSC/mammalian target of rapamycin mutations, which defines it as a unique entity distinct from CNS-HB. This molecular finding potentially expands the therapeutic options for patients with renal HB. GPNMB can be considered for inclusion in immunohistochemical panels to improve renal HB identification.

Nutritional status as a predictive factor for paediatric tuberous sclerosis complex-associated kidney angiomyolipomas: a retrospective analysis

The purpose of this study is to determine the predictive factors of tuberous sclerosis complex (TSC)-associated kidney disease and its progression in children. Retrospective review of children with TSC in a tertiary children’s hospital was performed. Relevant data were extracted, and Cox proportional hazards regression was used to establish predictors of kidney lesions. Logistic regression was conducted to identify factors predicting chronic kidney disease (CKD) and high-risk angiomyolipomas (above 3 cm). Kidney imaging data were available in 145 children with TSC; of these, 79% (114/145) had abnormal findings. The only significant predictive factor for cyst development was being female (HR = 0.503, 95% CI 0.264–0.956). Being female (HR = 0.505, 95% CI 0.272–0.937) and underweight (HR = 0.092, 95% CI 0.011–0.800) both lowers the risk of having angiomyolipomas, but TSC2 mutations (HR = 2.568, 95% CI 1.101–5.989) and being obese (HR = 2.555, 95%CI 1.243–5.255) increases risks. Ten (12%) of 81 children with kidney function tested demonstrate CKD stages II–V, and only angiomyolipomas above 3 cm predict CKD. Additionally, 13/145 (9%) children had high-risk angiomyolipomas, whereby current age (adjusted odds ratio (aOR) 1.015, 95% CI 1.004–1.026) and being overweight/obese (aOR 7.129, 95% CI 1.940–26.202) were significantly associated with angiomyolipomas above 3 cm.Conclusions: While gender and genotype are known predictors, this study includes the novel finding of nutritional status as a predictor of TSC-associated kidney disease. This study sheds light on a possible complex interplay of hormonal influences, obesity, and kidney angiomyolipomas growth, and further investigations focusing on the impact of nutritional status on TSC-associated kidney disease are warranted.What is Known:• Gender and genotype are well-studied predictive factors in TSC kidney disease.What is New:• Nutritional status may influence the development and the progression of kidney lesions in children with TSC and should not be overlooked.• Management guidelines of TSC-associated kidney disease can address nutritional aspects.

Electroretinogram as a Screening Tool to Assess Vigabatrin-Induced Retinal Toxicity in Children With Infantile Spasms.

To assess the utility of electroretinogram (ERG) as a screening tool for vigabatrin-induced retinal toxicity in children with infantile spasms. This was an observational cohort study including children with infantile spasms receiving treatment with vigabatrin. A 30-Hz flicker potential ERG, using the RETeval system (LKC Technologies), was done at baseline before starting vigabatrin at 6 months and 1 year. The amplitudes were recorded. Eleven children were included in the study. The most common etiologic factor for infantile spasms was tuberous sclerosis (36.4%) followed by West syndrome (27.3%). The mean age of the children was 7.14 ± 2.9 months, with a range of 3 to 16 months. The mean difference in amplitude was 3.21 ± 2.45 and 5.72 ± 4.18 µV at 6 and 12 months follow-up, respectively (P < .001). Eight of the 11 children (72.7%) showed vigabatrin-induced retinal toxicity, and all 8 children were receiving vigabatrin for more than 6 months. ERG can be used for vigabatrin-induced retinal toxicity monitoring in children with infantile spasms. Vigabatrin-induced retinal toxicity is related to the duration of treatment rather than cumulative dosage. [J Pediatr Ophthalmol Strabismus. 2024;61(4):273-278.].

Cardiac Rhabdomyomas Presenting with Critical Cardiac Obstruction in Neonates and Infants: Treatment Strategies and Outcome, A Single-Center Experience.

Cardiac rhabdomyomas are the most common benign pediatric heart tumor in infancy, which are commonly associated with tuberous sclerosis complex (TSC). Most rhabdomyomas are asymptomatic and spontaneously regress over time. However, some cases especially in neonates or small infants can present with hemodynamic instability. Surgical resection of the tumor, which has been the gold standard in alleviating obstruction, is not always possible and may be associated with significant morbidity and mortality. Recently, mammalian target of rapamycin inhibitors (mTORi) have been shown to be safe and effective in the treatment of TSC. We present the outcomes of neonates and an infant who received treatment for symptomatic rhabdomyomas at a tertiary cardiology center. Medical records were reviewed to obtain clinical, demographic, and outcome data. Six patients received interventions for symptomatic rhabdomyomas, median age at presentation was 1 day old (range from 1 to 121 days old), and 67% of the patients had a pathogenic mutation in TSC gene. One patient underwent surgical resection of solitary tumor at right ventricular outflow tract (RVOT) successfully. In the four patients with left ventricular outflow tract (LVOT) obstruction, two patients received combined therapy of surgical debulking of LVOT tumor, Stage I palliation procedure, and mTORi and two patients received mTORi therapy. One patient with RVOT obstruction underwent ductal stenting and received synergistic mTORi. Four of the five patients had good response to mTORi demonstrated by the rapid regression of rhabdomyoma size. 83% of patients are still alive at their latest follow-up, at two to eight years of age. One patient died on day 17 post-LVOT tumor resection and Hybrid stage one due to failure of hemostasis, in the background of familial factor VII deficiency. Treatment of symptomatic rhabdomyoma requires individualized treatment strategy based on the underlying pathophysiology, with involvement of multidisciplinary teams. mTORi is effective and safe in inducing rapid regression of rhabdomyomas. A standardized mTORi prescription and monitoring guide will ensure medication safety in neonates and infants with symptomatic cardiac rhabdomyoma. Although the majority of tumors responded to mTORi, some prove to be resistant. Further studies are warranted, ideally involving multiple international centers with a larger number of patients.

A real-world disproportionality analysis of Everolimus: data mining of the public version of FDA adverse event reporting system.

Background: Everolimus is an inhibitor of the mammalian target of rapamycin and is used to treat various tumors. The presented study aimed to evaluate the Everolimus-associated adverse events (AEs) through data mining of the US Food and Drug Administration Adverse Event Reporting System (FAERS). Methods: The AE records were selected by searching the FDA Adverse Event Reporting System database from the first quarter of 2009 to the first quarter of 2022. Potential adverse event signals were mined using the disproportionality analysis, including reporting odds ratio the proportional reporting ratio the Bayesian confidence propagation neural network and the empirical Bayes geometric mean and MedDRA was used to systematically classify the results. Results: A total of 24,575 AE reports of Everolimus were obtained using data from the FAERS database, and Everolimus-induced AEs occurrence targeted 24 system organ classes after conforming to the four algorithms simultaneously. The common significant SOCs were identified, included benign, malignant and unspecified neoplasms, reproductive system and breast disorders, etc. The significant AEs were then mapped to preferred terms such as stomatitis, pneumonitis and impaired insulin secretion, which have emerged in the study usually reported in patients with Everolimus. Of note, unexpected significant AEs, including biliary ischaemia, angiofibroma, and tuberous sclerosis complex were uncovered in the label. Conclusion: This study provided novel insights into the monitoring, surveillance, and management of adverse drug reaction associated with Everolimus. The outcome of serious adverse events and the corresponding detection signals, as well as the unexpected significant adverse events signals are worthy of attention in order to improving clinical medication safety during treatment of Everolimus.

Patients’ and physicians’ awareness of clinical symptoms and disease severity in tuberous sclerosis complex

Tuberous sclerosis complex (TSC) is a rare inherited disease with the potential to affect virtually every organ system. Clinical presentation is age- and partly sex-dependent and varies broadly with respect to disease manifestations including treatment-refractory epilepsy, intellectual disability and TSC-associated neuropsychiatric disorders, chronic kidney disease or progressive lung function decline. Given the complexity of this disease, multidisciplinary care in specialized TSC centres is recommended. We aimed to elucidate the state of knowledge of patients/caregivers and physicians on individual disease manifestations. We further examined whether the association to a TSC centre has an impact on the comprehensive consideration of potential disease manifestations. Therefore, a survey was performed in a cohort of German TSC patients and their physicians. Complete information was available for 94 patients with a median age of 18 years [range 1–55] and a sex distribution of 53.2% (male): 48.8% (female). Using almost identical questionnaires for patients/caregivers and their respective physician, there was a good correlation for disease assessments associated with relevant morbidity and mortality like epilepsy, renal angiomyolipoma, cardiac rhabdomyomas or intellectual disability. Correlation was moderate for several neuropsychiatric disorders and only poor for hypomelanotic macules, dental pits or retinal achromic patches. Estimation of overall disease severity using a numeric rating scale correlated highly significantly (Pearson correlation coefficient = 0.767; p < 0.001) between patients/caregivers and physicians. In general, physicians more likely quoted items as ‘unknown’ than patients (822 answers vs. 435 answers in the respective groups). Questionnaires completed by physicians who were associated with a specialized TSC centre declared a significantly lower proportion of items as unknown (mean 8.7% vs. 20.5%; p < 0.001). These findings indicate that patients treated by specialized TSC centres seem to obtain a more comprehensive surveillance. Furthermore, it shows that there were reasonable surveillance strategies in general and sufficient patient/caregiver interaction and education in the examined cohort. However, for the most prominent disease characteristics there was a good awareness within both the patients/caregivers and the physicians group.

Giant cell angiofibroma of gingiva in tuberous sclerosis complex: a case report and literature review

BackgroundTuberous sclerosis complex (TSC) is a rare, complex genetic disorder characterized by hamartomas and neoplastic lesions in various organ systems. With the development of radiology and gene testing, the diagnostic criteria for TSC were updated in 2012 at the International Consensus Conference. Intraoral fibromas have long been associated with TSC. However, the incidence of giant cell angiofibroma (GCA) in TSC patients is extremely rare. Here, we report the first case of GCA in the gingival tissue of a patient with TSC.Case presentationA 41-year-old woman first visited the Department of Oral and Maxillofacial Surgery, Chonnam National University Dental Hospital, complaining of gingival enlargement. Clinical examination revealed several manifestations associated with TSC, including intraoral fibromas, facial angiofibromas, dental enamel pits, ungual fibromas, “confetti” skin lesions, hypomelanotic macules, and a shagreen patch. Intraoral examination revealed a 6.0 × 5.0 cm gingival overgrowth on the left mandible. Surgical excision was performed, and subsequent histopathological examination confirmed the diagnosis of GCA. There was no evidence of recurrence within the 24- months of surgery.ConclusionsWe report the first case of GCA in the gingival tissue of a patient with TSC. This report would contribute to an improved understanding of this rare disease. However, further case reports are necessary to clarify the relationship between GCA and TSC.