TuberOus SClerosis registry to increAse disease awareness (TOSCA) Post-Authorisation Safety Study of Everolimus in Patients With Tuberous Sclerosis Complex

This non-interventional post-authorisation safety study (PASS) assessed the long-term safety of everolimus in patients with tuberous sclerosis complex (TSC) who participated in the TuberOus SClerosis registry to increase disease Awareness (TOSCA) clinical study and received everolimus for the licensed indications in the European Union. The rate of adverse events (AEs), AEs that led to dose adjustments or treatment discontinuation, AEs of potential clinical interest, treatment-related AEs (TRAEs), serious AEs (SAEs), and deaths were documented. One hundred seventy-nine patients were included in the first 5 years of observation; 118 of 179 patients had an AE of any grade, with the most common AEs being stomatitis (7.8%) and headache (7.3%). AEs caused dose adjustments in 56 patients (31.3%) and treatment discontinuation in nine patients (5%). AEs appeared to be more frequent and severe in children. On Tanner staging, all patients displayed signs of age-appropriate sexual maturation. Twenty-two of 106 female (20.8%) patients had menstrual cycle disorders. The most frequent TRAEs were stomatitis (6.7%) and aphthous mouth ulcer (5.6%). SAEs were reported in 54 patients (30.2%); the most frequent SAE was pneumonia (>3% patients; grade 2, 1.1%, and grade 3, 2.8%). Three deaths were reported, all in patients who had discontinued everolimus for more than 28 days, and none were thought to be related to everolimus according to the treating physicians. The PASS sub-study reflects the safety and tolerability of everolimus in the management of TSC in real-world routine clinical practice.

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Enhancing Disease Awareness for Tuberous Sclerosis Complex in Patients with Radiologic Diagnosis of Renal Angiomyolipoma: An Observational Study

10.21203/rs.3.rs-103693/v1 ◽

2020 ◽

Author(s):

Kathrin Bausch ◽

Christian Wetterauer ◽

Julian Diethelm ◽

Jan Ebbing ◽

Daniel T. Boll ◽

...

Keyword(s):

Tuberous Sclerosis ◽

Tuberous Sclerosis Complex ◽

Genetic Disorder ◽

Binary Logistic Regression ◽

Binary Logistic Regression Analysis ◽

Renal Angiomyolipoma ◽

Radiologic Diagnosis ◽

Disease Awareness ◽

Younger Age ◽

Age Range

Abstract BackgroundTuberous Sclerosis Complex (TSC) is a genetic disorder, with renal manifestations like angiomyolipoma (AML) occurring in 70-80% of patients. AML usually cause more complications in TCS patients than in non-TSC patients. However, AML patients are not routinely investigated for TSC. Our aim was to retrospectively assess the correlation between radiologically diagnosed AML and TSC.MethodsAll patients were stratified into AML related vs. unrelated to TSC. Correlations were calculated to determine the association between age, AML, and TSC. ResultsComplete data were available for 521 patients with renal AML, in 7 of which the concurrent diagnosis of TSC was found. Younger age significantly positively correlated with the prevalence of TSC in AML patients (p<0.01). 37 (7%) of the 521 patients were within the age-range of 18-40 years, in which TSC occurred in 6 cases, 4 (66.7%) of which presented with multiple, bilateral renal AML (p<0.05), and 2 (33.3%) of which with a single, unilateral AML (p<0.05). In patients with AML but without TSC, unilateral AML was found in 83.9% and bilateral AML in 16.1% (p<0.05). Simple binary logistic regression analysis revealed bilateral AML (OR 33.0; 95% CI 3.2–344.0; p=0.003) (but not unilateral AML (OR 0.09; 95% CI 0.01–0.88; p=0.04)) to be a risk factor for TSC. ConclusionsThe presence of bilateral AML in patients within the age-range of 18-40 years should raise suspicion for TSC as the underlying cause. Therefore, our advice is to refer patients with multiple bilateral renal AML for further investigations regarding TSC.

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Enhancing disease awareness for tuberous sclerosis complex in patients with radiologic diagnosis of renal angiomyolipoma: an observational study

BMC Nephrology ◽

10.1186/s12882-021-02253-w ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Kathrin Bausch ◽

Christian Wetterauer ◽

Julian Diethelm ◽

Jan Ebbing ◽

Daniel T. Boll ◽

...

Keyword(s):

Tuberous Sclerosis ◽

Tuberous Sclerosis Complex ◽

Genetic Disorder ◽

Binary Logistic Regression ◽

Binary Logistic Regression Analysis ◽

Renal Angiomyolipoma ◽

Radiologic Diagnosis ◽

Disease Awareness ◽

Younger Age ◽

Age Range

Abstract Background Tuberous Sclerosis Complex (TSC) is a genetic disorder, with renal manifestations like angiomyolipoma (AML) occurring in 70–80% of patients. AML usually cause more complications in TCS patients than in non-TSC patients. However, AML patients are not routinely investigated for TSC. Our aim was to retrospectively assess the correlation between radiologically diagnosed AML and TSC. Methods All patients were stratified into AML related vs. unrelated to TSC. Correlations were calculated to determine the association between age, AML, and TSC. Results Complete data were available for 521 patients with renal AML, in 7 of which the concurrent diagnosis of TSC was found. Younger age significantly positively correlated with the prevalence of TSC in AML patients (p < 0.01). 37 (7%) of the 521 patients were within the age-range of 18–40 years, in which TSC occurred in 6 cases, 4 (66.7%) of which presented with multiple, bilateral renal AML (p < 0.05), and 2 (33.3%) of which with a single, unilateral AML (p < 0.05). In patients with AML but without TSC, unilateral AML was found in 83.9% and bilateral AML in 16.1% (p < 0.05). Simple binary logistic regression analysis revealed bilateral AML (OR 33.0; 95% CI 3.2–344.0; p = 0.003) (but not unilateral AML (OR 0.09; 95% CI 0.01–0.88; p = 0.04)) to be a risk factor for TSC. Conclusions The presence of bilateral AML in patients within the age-range of 18–40 years should raise suspicion for TSC as the underlying cause. Therefore, our advice is to refer patients with multiple bilateral renal AML for further investigations regarding TSC.

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Rare manifestations and malignancies in tuberous sclerosis complex: findings from the TuberOus SClerosis registry to increAse disease awareness (TOSCA)

Orphanet Journal of Rare Diseases ◽

10.1186/s13023-021-01917-y ◽

2021 ◽

Vol 16 (1) ◽

Author(s):

Matthias Sauter ◽

Elena Belousova ◽

Mirjana P. Benedik ◽

Tom Carter ◽

Vincent Cottin ◽

...

Keyword(s):

Tuberous Sclerosis ◽

Tuberous Sclerosis Complex ◽

Malignant Tumors ◽

Significant Proportion ◽

Clinical Manifestations ◽

Thyroid Adenoma ◽

Autosomal Dominant Disorder ◽

Disease Awareness ◽

Pathogenic Variants ◽

Potential Association

Abstract Background Tuberous sclerosis complex (TSC) is a rare multisystem autosomal dominant disorder caused by pathogenic variants in either the TSC1 or TSC2 gene. Common manifestations of TSC have been grouped into major and minor clinical diagnostic criteria and assessed in clinical routine workup. However, case studies point towards the existence of rare disease manifestations and to the potential association of TSC with malignant tumors. In this study we sought to characterize rare manifestations and malignancies using a large cohort of patients. Methods TuberOus SClerosis registry to increAse disease awareness (TOSCA) is a multicenter, international disease registry collecting clinical manifestations and characteristics of patients with TSC, both retrospectively and prospectively. We report rates and characteristics of rare manifestations and malignancies in patients with TSC who had enrolled in the TOSCA registry. We also examined these manifestations by age, sex, and genotype (TSC1 or TSC2). Results Overall, 2211 patients with TSC were enrolled in the study. Rare manifestations were reported in 382 (17.3%) study participants and malignancies in 65 (2.9%). Of these rare manifestations, the most frequent were bone sclerotic foci (39.5%), scoliosis (23%), thyroid adenoma (5.5%), adrenal angiomyolipoma (4.5%), hemihypertrophy and pancreatic neuroendocrine tumors (pNET; both 3.1%). These rare manifestations were more commonly observed in adults than children (66.2% vs. 22.7%), in females versus males (58.4% vs. 41.6%; except for scoliosis: 48.9% vs. 51.1%), and in those with TSC2 versus TSC1 (67.0% vs. 21.1%; except for thyroid adenoma: 42.9% vs. 57.1%). In the 65 individuals with reported malignancies, the most common were renal cell carcinoma (47.7%), followed by breast (10.8%) and thyroid cancer (9.2%). Although malignancies were more common in adult patients, 26.1% were reported in children and 63.1% in individuals < 40 years. TSC1 mutations were over-represented in individuals with malignancies compared to the overall TOSCA cohort (32.1% vs. 18.5%). Conclusion Rare manifestations were observed in a significant proportion of individuals with TSC. We recommend further examination of rare manifestations in TSC. Collectively, malignancies were infrequent findings in our cohort. However, compared to the general population, malignant tumors occurred earlier in age and some tumor types were more common.

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Historical Patterns of Diagnosis, Treatments, and Outcome of Epilepsy Associated With Tuberous Sclerosis Complex: Results From TOSCA Registry

Frontiers in Neurology ◽

10.3389/fneur.2021.697467 ◽

2021 ◽

Vol 12 ◽

Author(s):

Rima Nabbout ◽

Elena Belousova ◽

Mirjana P. Benedik ◽

Tom Carter ◽

Vincent Cottin ◽

...

Keyword(s):

Tuberous Sclerosis ◽

Tuberous Sclerosis Complex ◽

Infantile Spasms ◽

Line Treatment ◽

Seizure Onset ◽

First Line ◽

Disease Awareness ◽

Focal Seizures ◽

Over Time ◽

First Line Treatment

Background: Epilepsy is the most common neurological manifestation in individuals with tuberous sclerosis complex (TSC). However, real-world evidence on diagnosis and treatment patterns is limited. Here, we present data from TuberOus Sclerosis registry to increase disease Awareness (TOSCA) on changes in patterns of epilepsy diagnosis, treatments, and outcomes over time, and detailed epilepsy characteristics from the epilepsy substudy.Methods: TuberOus Sclerosis registry to increase disease Awareness (TOSCA) was a multicentre, international disease registry, consisting of a main study that collected data on overall diagnostic characteristics and associated clinical features, and six substudies focusing on specific TSC manifestations. The epilepsy substudy investigated detailed epilepsy characteristics and their correlation to genotype and intelligence quotient (IQ).Results: Epilepsy was reported in 85% of participants, more commonly in younger individuals (67.8% in 1970s to 91.8% in last decade), while rate of treatments was similar across ages (>93% for both infantile spasms and focal seizures, except prior to 1960). Vigabatrin (VGB) was the most commonly used antiepileptic drugs (AEDs). Individuals with infantile spasms showed a higher treatment response over time with lower usage of steroids. Individuals with focal seizures reported similar rates of drug resistance (32.5–43.3%). Use of vagus nerve stimulation (VNS), ketogenic diet, and surgery remained low.Discussion: The epilepsy substudy included 162 individuals from nine countries. At epilepsy onset, most individuals with infantile spasms (73.2%) and focal seizures (74.5%) received monotherapies. Vigabatrin was first-line treatment in 45% of individuals with infantile spasms. Changes in initial AEDs were commonly reported due to inadequate efficacy. TSC1 mutations were associated with less severe epilepsy phenotypes and more individuals with normal IQ. In individuals with TSC diagnosis before seizure onset, electroencephalogram (EEG) was performed prior to seizures in only 12.5 and 25% of subsequent infantile spasms and focal seizures, respectively.Conclusions: Our study confirms the high prevalence of epilepsy in TSC individuals and less severe phenotypes with TSC1 mutations. Vigabatrin improved the outcome of infantile spasms and should be used as first-line treatment. There is, however, still a need for improving therapies in focal seizures. Electroencephalogram follow-up prior to seizure-onset should be promoted for all infants with TSC in order to facilitate preventive or early treatment.

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Rare manifestations and malignancies in tuberous sclerosis complex: Findings from the TuberOus SClerosis registry to increAse disease awareness (TOSCA)

10.21203/rs.3.rs-154823/v1 ◽

2021 ◽

Author(s):

Matthias Sauter ◽

Elena Belousova ◽

Mirjana P Benedik ◽

Tom Carter ◽

Vincent Cottin ◽

...

Keyword(s):

Tuberous Sclerosis ◽

Tuberous Sclerosis Complex ◽

Malignant Tumors ◽

Genetic Disorder ◽

Significant Proportion ◽

Clinical Manifestations ◽

Thyroid Adenoma ◽

Disease Awareness ◽

Potential Association ◽

Tumor Types

Abstract Background Tuberous sclerosis complex (TSC) is a rare multisystem autosomal dominant genetic disorder caused by pathogenic mutations in either the TSC1 or TSC2 gene. Common manifestations of TSC have been grouped into major and minor clinical diagnostic criteria and assessed in clinical routine workup. However, case studies point towards the existence of rare disease manifestations and to the potential association of TSC with malignant tumors. In this study we sought to characterize rare manifestations and malignancies using a large cohort of patients. Methods TuberOus SClerosis registry to increAse disease awareness (TOSCA) is a multicenter, international disease registry collecting clinical manifestations and characteristics of patients with TSC, both retrospectively and prospectively. We report rates and characteristics of rare manifestations and malignancies in patients with TSC who had enrolled in the TOSCA registry. We also examined these manifestations by age, sex, and genotype (TSC1 or TSC2). Results Overall, 2211 patients with TSC were enrolled in the study. Rare manifestations were reported in 382 (17.3%) study participants and malignancies in 65 (2.9%). Of these rare manifestations, the most frequent were bone sclerotic foci (39.5%), scoliosis (23%), thyroid adenoma (5.5%), adrenal angiomyolipoma (4.5%), hemihypertrophy and pancreatic neuroendocrine tumors (pNET; both 3.1%). These rare manifestations were more commonly observed in adults than children (66.23% vs. 22.7%), in females versus males (58.4% vs. 41.6%; except for scoliosis: 48.9% vs. 51.1%), and in those with TSC2 versus TSC1 (67.0% vs. 21.1%; except for thyroid adenoma: 42.9% vs. 57.1%). In the 65 individuals with reported malignancies, the most common were renal cell carcinoma (47.7%), followed by breast (10.8%) and thyroid cancer (9.2%). Although malignancies were more common in adult patients, 26.1% were reported in children and 63.1% in individuals < 40 years. TSC1 mutations were over-represented in individuals with malignancies compared to the overall TOSCA cohort (32.1% vs. 18.5%). Conclusion Rare manifestations collectively were observed in a significant proportion of individuals with TSC. We recommend further examination of rare manifestations in TSC. Collectively, malignancies were infrequent findings in our cohort. However, compared to the general population, malignant tumors occurred earlier in age and some tumor types were more common.

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