A Review of Topical Sirolimus for the Treatment of Facial Angiofibromas in Tuberous Sclerosis Complex.

OBJECTIVE: This article assesses the efficacy, safety, pharmacology, and clinical applications of topical sirolimus 0.2% gel for the treatment of tuberous sclerosis complex (TSC)-associated facial angiofibromas. DATA SOURCES: A review of the literature was conducted using the Medline (PubMed) and EMBASE databases using the keywords topical sirolimus, rapamycin, Hyftor, and tuberous sclerosis. STUDY SELECTION AND DATA EXTRACTION: Articles written in English and relevant to the topic were included. DATA SYNTHESIS: In the phase 2 trial, the mean improvement factor, a composite measure of improved tumor size and redness, was achieved in all patient groups (P < 0.001) with significant responses among the adult and pediatric subgroups at week 12. There were no serious adverse events recorded. In the phase 3 trial, 60% of participants responded to treatment in the sirolimus group compared with 0% in the placebo group with different response rates between the adult and pediatric subgroups at week 12. Sirolimus gel had no serious adverse events, and dry skin was the most common adverse reaction. Patients who had completed the 12-week trials were then enrolled in a long-term trial; angiofibromas had response rates of 78.2% to 0.2% sirolimus gel. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE IN COMPARISON TO EXISTING DRUGS: Topical sirolimus 0.2% is a first-in-class, newly Food and Drug Administration (FDA)-approved, mammalian target of rapamycin (mTOR) inhibitor that is a promising and safe, noninvasive alternative to surgical procedures for TSC-associated angiofibromas. CONCLUSIONS: Topical sirolimus 0.2% gel is a moderately effective treatment for TSC-associated facial angiofibromas with an adequate safety profile.

A Systematic Review of Laser Treatment for Angiofibromas in Tuberous Sclerosis.

BACKGROUND: While mammalian target of rapamycin inhibitors have revolutionized the management of angiofibroma in tuberous sclerosis complex (TS), physical modalities such as laser are still indicated for recalcitrant lesions. OBJECTIVE: The authors performed a systematic review of the efficacy and safety of laser treatment for TS-related facial angiofibroma. METHODS: The electronic databases such as MEDLINE, Embase, PubMed, Cochrane Central Register of Controlled Trials, and Web of Science were searched from inception to October 10, 2023, for eligible records. RESULTS: Forty-seven articles met the inclusion criteria, representing a total of 217 patients with TS-related facial angiofibroma who received laser treatment. Several lasers have been trialed in patients including carbon dioxide ( n = 95, 43.7%), pulsed dye ( n = 21, 9.7%), argon ( n = 16, 7.4%), neodymium-doped: yttrium aluminum garnet ( n = 12, 5.5%), copper vapor ( n = 9, 4.1%), potassium titanyl phosphate ( n = 7, 3.2%), erbium: yttrium aluminum garnet ( n = 2, 0.9%), lasers and various combination therapies ( n = 55, 25.3%). CONCLUSION: Potassium titanyl phosphate, pulsed dye, and neodymium-dopsed:yttrium aluminum garnet lasers are better suited to manage the vascular components of angiofibroma while ablative lasers such as erbium: yttrium aluminum garnet and carbon dioxide lasers may present better options for lesions with a prominent fibrous component. While several lasers have been trialed with broadly favorable results, the low level of evidence precludes definitive conclusions, and no single laser appears superior.

The cutaneous manifestations of tuberous sclerosis complex.

Tuberous sclerosis complex (TSC) is a genetic multisystem disease with variable manifestations that can prominently involve the skin. The diagnosis of this disorder has evolved over the past two centuries. The 2012 TSC criteria emphasizes the importance of dermatological findings; orocutaneous manifestations account for 4 of 11 major criterion and 3 of 6 minor criterion. A detailed clinical dermatological evaluation is recommended for both pediatric and adult patients undergoing initial evaluation for TSC. Comprehensive dermatologic evaluation is extremely helpful when assessing these lesions and constructing a differential diagnosis.

Comparative Effects of Topical 0.2% Sirolimus for Angiofibromas in Adults and Pediatric Patients with Tuberous Sclerosis Complex.

BACKGROUND: Recent reports have suggested that the topical formulation of sirolimus is effective in treating facial angiofibromas in tuberous sclerosis complex (TSC). Here, we determined the safety and efficacy of 0.2% topical sirolimus for the treatment of facial angiofibroma and compared its effects based on age. METHOD: This was a retrospective study which involved 36 TSC patients with facial angiofibromas who were treated with 0.2% sirolimus ointment. Its effect was evaluated using the Facial Angiofibroma Severity Index (FASI). In order to observe its comparative effect based on patient age, a subgroup analysis was performed, between the adult group (> 18 years old) and the pediatric group (≤18 years old). RESULTS: The total FASI as well as its subcategories (erythema, size, and extent) showed statistically significant improvements after the topical treatment with 0.2% sirolimus ointment (FASI before treatment: 7.2 ± 1.1, FASI after treatment: 4.4± 1.4, p < 0.001). Among the subcategories of FASI, the erythema was most significantly reduced with the fastest response to the treatment. In a subgroup analysis, the pediatric group showed significantly greater improvements in FASI (improvement of FASI in the pediatric group = 49.7 ± 12.2%, adult group = 27.9 ± 15.6%, p < 0.001). The serial improvement analysis also showed that the pediatric group achieved a consistently greater improvement in FASI at all visits. Its 1-year application in 3 patients demonstrated a continuous maintenance effect. No significant adverse effects were observed. CONCLUSION: 0.2% sirolimus ointment is safe and effective for facial angiofibromas. Considering its higher efficacy in younger patients, an early initiation of the treatment is recommended.

Sun exposure causes somatic second-hit mutations and angiofibroma development in tuberous sclerosis complex.

Tuberous sclerosis complex (TSC) is characterized by the formation of tumors in multiple organs and is caused by germline mutation in one of two tumor suppressor genes, TSC1 and TSC2. As for other tumor suppressor gene syndromes, the mechanism of somatic second-hit events in TSC tumors is unknown. We grew fibroblast-like cells from 29 TSC skin tumors from 22 TSC subjects and identified germline and second-hit mutations in TSC1/TSC2 using next-generation sequencing. Eighteen of 22 (82%) subjects had a mutation identified, and 8 of the 18 (44%) subjects were mosaic with mutant allele frequencies of 0 to 19% in normal tissue DNA. Multiple tumors were available from four patients, and in each case, second-hit mutations in TSC2 were distinct indicating they arose independently. Most remarkably, 7 (50%) of the 14 somatic point mutations were CC>TT ultraviolet 'signature' mutations, never seen as a TSC germline mutation. These occurred exclusively in facial angiofibroma tumors from sun-exposed sites. These results implicate UV-induced DNA damage as a cause of second-hit mutations and development of TSC facial angiofibromas and suggest that measures to limit UV exposure in TSC children and adults should reduce the frequency and severity of these lesions.

Systemic disease manifestations associated with epilepsy in tuberous sclerosis complex.

OBJECTIVE: Epilepsy is one of the most disabling symptoms of tuberous sclerosis complex (TSC) and is a leading cause of morbidity and mortality in affected individuals. The relationship between systemic disease manifestations and the presence of epilepsy has not been thoroughly investigated. This study utilizes a multicenter TSC Natural History Database including 1,816 individuals to test the hypothesis that systemic disease manifestations of TSC are associated with epilepsy. METHODS: Univariate analysis was used to identify patient characteristics (e.g., age, gender, race, and TSC mutation status) associated with the presence of epilepsy. Individual logistic regression models were built to examine the association between epilepsy and each candidate systemic or neurologic disease variable, controlling for the patient characteristics found to be significant on univariate analysis. Finally, a multivariable logistic regression model was constructed, using the variables found to be significant on the individual analyses as well as the patient characteristics that were significant on univariate analysis. RESULTS: Nearly 88% of our cohort had a history of epilepsy. After adjusting for age, gender, and TSC mutation status, multiple systemic disease manifestations including cardiac rhabdomyomas (odds ratio [OR] 2.3, 95% confidence interval [CI] 1.3-3.9, p = 0.002), retinal hamartomas (OR 2.1, CI 1.0-4.3, p = 0.04), renal cysts (OR 2.1, CI 1.3-3.4, p = 0.002), renal angiomyolipomas (OR 3.0, CI 1.8-5.1, p < 0.001), shagreen patches (OR 1.7, CI 1.0-2.7, p = 0.04), and facial angiofibromas (OR 1.7, CI 1.1-2.9, p = 0.03) were associated with a higher likelihood of epilepsy. In the multivariable logistic regression model, cardiac rhabdomyomas (OR 1.9, CI 1.0-3.5, p = 0.04) remained significantly associated with the presence of epilepsy. SIGNIFICANCE: The identification of systemic disease manifestations such as cardiac rhabdomyomas that confer a higher risk of epilepsy development in TSC could contribute to disease prognostication and assist in the identification of individuals who may receive maximal benefit from potentially novel, targeted, preventative therapies.

Effect of Angiofibromas on Quality of Life and Access to Care in Tuberous Sclerosis Patients and Their Caregivers.

BACKGROUND/OBJECTIVES: Facial angiofibromas (AF) have the potential to cause disfigurement in children with tuberous sclerosis complex (TSC). Facial disfigurement can impact the quality of life (QoL) of individuals and their families, leading to negative psychosocial outcomes. QoL has not been studied in TSC patients with AF. METHODS: We conducted a cross-sectional survey study to investigate QoL of TSC patients with AF and their caregivers and to explore the current state of access to treatment for AF. TSC patients and caregivers in TSC clinic at Boston Children's Hospital and through the Tuberous Sclerosis Alliance were recruited to complete QoL surveys including the CADIS, CDLQI, and Skindex-teen questionnaires, and a survey on access to treatment of AF. RESULTS: Fifty-eight patients with TSC and 161 caregivers participated in the study. Caregivers of patients with AF had significantly poorer QoL scores compared to caregivers of those without AF, as measured by a modified CADIS questionnaire (mean 31.7 vs. 11.7, p = 0.004). Among patients with AF, those who received treatment had significantly better QoL scores compared with those without treatment, as measured by the CDLQI (mean 3.8 vs. 9.5, p = 0.001). Forty-one and two-tenths percent of subjects reported never receiving treatment for AF. Forty-seven and three-tenths percent of subjects were prescribed topical rapamycin, 47.7% of whom experienced difficulty with insurance coverage. CONCLUSIONS: Presence and lack of treatment of AF significantly impacts QoL in TSC patients and their caregivers. Access to care for AF is limited by multiple factors and should be addressed by clinicians working with this patient population.

Analysis of current data on the use of topical rapamycin in the treatment of facial angiofibromas in tuberous sclerosis complex.

BACKGROUND: Tuberous sclerosis complex (TSC) is an autosomal dominant neurocutaneous syndrome causing hamartomatous growths in multiple organs. Facial angiofibromas occur in up to 80% of patients and can be highly disfiguring. Treatment for these lesions has historically been challenging. Recently, topical rapamycin has been proposed as an effective option to treat angiofibromas but a commercially available compound has not yet been developed. OBJECTIVES: The aim of this review is to analyse the current data on the use of topical rapamycin in the treatment of angiofibromas in TSC, focusing on the risk-benefit profile. METHODS: A retrospective review of the English-language literature was conducted. RESULTS: Sixteen reports describing the use of topical rapamycin in the treatment of angiofibromas in TSC were considered, involving a total of 84 patients. An improvement of the lesions has been shown in 94% of subjects, particularly if the treatment was started at early stages. Several different formulations (ointment, gel, solution and cream) with a wide range of concentrations (0.003%-1%) were proposed. Only 4 local adverse side-effects were reported after the use of rapamycin solution. CONCLUSION: Topical rapamycin can be considered a safe option for the treatment and the prevention of facial angiofibromas in younger patients, but the best formulation has not been established. Our review demonstrates that ointment and gel should be preferred, but it is not clear which concentration is optimal. Long-term and comparative studies between topical rapamycin and ablative techniques are required to establish which treatment has a better outcome and lower recurrence rate.

Facial Angiofibroma Severity Index (FASI): reliability assessment of a new tool developed to measure severity and responsiveness to therapy in tuberous sclerosis-associated facial angiofibroma.

BACKGROUND: Tuberous sclerosis complex (TSC) is an autosomal dominant neurocutaneous disorder characterized by the development of multisystem hamartomatous tumours. Topical sirolimus has recently been suggested as a potential treatment for TSC-associated facial angiofibroma (FA). AIM: To validate a reproducible scale created for the assessment of clinical severity and treatment response in these patients. METHODS: We developed a new tool, the Facial Angiofibroma Severity Index (FASI) to evaluate the grade of erythema and the size and extent of FAs. In total, 30 different photographs of patients with TSC were shown to 56 dermatologists at each evaluation. Three evaluations using the same photographs but in a different random order were performed 1 week apart. Test and retest reliability and interobserver reproducibility were determined. RESULTS: There was good agreement between the investigators. Inter-rater reliability showed strong correlations (> 0.98; range 0.97-0.99) with inter-rater correlation coefficients (ICCs) for the FASI. The global estimated kappa coefficient for the degree of intra-rater agreement (test-retest) was 0.94 (range 0.91-0.97). CONCLUSIONS: The FASI is a valid and reliable tool for measuring the clinical severity of TSC-associated FAs, which can be applied in clinical practice to evaluate the response to treatment in these patients.

Topical rapamycin for angiofibromas in paediatric patients with tuberous sclerosis: follow up of a pilot study and promising future directions.

One of the most visible and potentially disfiguring cutaneous manifestations of tuberous sclerosis complex is the development of multiple facial angiofibromas, present in over 80% of patients. Topical rapamycin has been shown in many reports to be a safe and effective treatment for facial angiofibromas. In February 2012 we reported the results of a pilot study of four patients undertaken at a paediatric tertiary hospital in Australia. Since then, we have continued to refine the optimal formulation and concentration of topical rapamycin and expanded our selection of patients. We present an update on our current cohort of treated patients, discuss the optimal formulation of topical rapamycin and include a literature review on all published cases to date. Although topical rapamycin is not a curative treatment, we have demonstrated that its early institution significantly reduces both the vascularity and palpability of angiofibromas and prevents their progression with age. It is well tolerated and now a cost effective option.

Morbus Bourneville: a case report and review of the literature.

Tuberous sclerosis (TS) or tuberous sclerosis complex (TSC), also known as Bourneville disease or Bourneville-Pringle disease, is an autosomal dominant disorder classically characterized by the presence of hamartomatous growths in multiple organs. A combination of symptoms may include seizures, developmental delay, behavioral problems, skin abnormalities, and lung and kidney diseases. The authors present a case of a 18 year-old female patient with a history of TS, epileptic episodes, mental retardation, and papillary formations in multiple organs located at the abdominal, axillary, cervical, facial, and genital region.

Targeted topical and combination laser surgery for the treatment of angiofibromas.

BACKGROUND AND OBJECTIVE: The angiofibromas of Tuberous sclerosis (TS) is well described manifestation. Due to the progressive nature of the skin lesion, a safe and effective technique for treating these disfiguring skin lesions is needed. STUDY DESIGN/PATIENTS AND METHODS: We report a targeted topical and combination laser technique for treating the angiofibromas of TS in one patient. This includes treatment with topical sirolimus, pinpoint electrosurgery, pulsed-dye laser treatment, and ablative fractional resurfacing (AFR). RESULTS: Improvement in the number and appearance of facial angiofibromas and erythema is noted, without scarring or adverse events. CONCLUSION: The technique of targeted therapy with sirolimus with electrosurgery, pulsed dye laser treatment, and AFR represents an innovative, safe therapeutic option for treating facial angiofibromas associated with TS.

Angiofibroma of inferior turbinate as an unusual complication of CO2 laser turbinoplasty.

Angiofibroma is a benign vascular tumor that usually occurs in the nasopharynx, and extranasopharyngeal angiofibromas are rarely reported. We report the first case of an angiofibroma arising from the inferior turbinate after CO2 laser turbinoplasty. Endoscopic excisional biopsy was performed, but the tumor recurred after 2 months of surgery. The mass was excised by endoscopic approach including surrounding normal mucosal tissue. Histologic examination suggested the diagnosis of angiofibroma. The patient was asymptomatic, and there was no evidence of recurrence after 1 year of the second surgery.

Tuberous Sclerosis Complex in a 17-month-old: A Case Report.

Tuberous sclerosis complex is a rare autosomal dominant genetic disorder that affects multiple organ systems, primarily affecting the central nervous system. It develops with a pathogenic mutation in tumour suppressor genes i.e. Tuberous Sclerosis Complex 1 or Tuberous Sclerosis Complex 2 which codes for protein hamartin and tuberin leading to unopposed hyperactivation of the mammalian target of the rapamycin signalling pathway. It presents with a triad of facial angiofibroma, intellectual disability, and epilepsy. We present a case of a 17-month female toddler with abnormal body movement with loss of consciousness and later developing into generalised jerky movements. On magnetic resonance imaging, a diagnosis of tuberous sclerosis was made. The patient underwent symptomatic management with anti-epileptic. As seizures in these cases are subtle, they remain undiagnosed for a long time leading to delays in management and developing refractory seizures. Keywords: angiofibroma; case reports; seizures; tuberous sclerosis; tumor suppressor gene.

Giant angiofibromas in tuberous sclerosis complex: a possible role for localized lymphedema in their pathogenesis.

BACKGROUND: Giant angiofibromas in patients with tuberous sclerosis complex (TSC) are rare. OBJECTIVE: We sought to report two patients who had TSC with unusually large and disfiguring facial angiofibromas and to identify underlying histopathologic changes that may possibly explain the clinical features. METHODS: We performed a clinicopathologic, immunohistochemical, and molecular biologic study using 42 lesional specimens and peripheral blood from one of the two patients. The immunohistochemical investigations were mainly focused on the vascular moiety of the lesions. TSC1 and TSC2 alterations were studied using multiplex ligation-dependent probe amplification for large deletion/duplication mutations, whereas screening for small mutations was performed using polymerase chain reaction amplification of individual coding exons and exon-intron junctions of both genes followed by an analysis on denaturation gradient gel electrophoresis. RESULTS: Histopathologic examination revealed, in addition to findings typical of angiofibroma, several unusual features including multinucleated giant cells containing multiple intracytoplasmic vacuoles, Touton-like cells, emperipolesis, pagetoid dyskeratosis, vacuolar alteration at the dermoepidermal junction, Civatte bodies, and melanophages in the subjacent dermis. Numerous dilated lymphatic vessels were detected indicating localized lymphostasis, probably caused by secondary lymphedema. The lymphatic nature of the vessels was confirmed by immunohistochemical study. Genetic testing for TSC1 and TSC2 gene mutations revealed a substitution on position c.2251C>T resulting in a nonsense mutation R751X in fragment 20.2. LIMITATIONS: Histopathologic specimens and peripheral blood were available from only one patient. CONCLUSION: Localized lymphedema may contribute to the formation of large disfiguring angiofibromas in patients with TSC.

Sustained clinical effectiveness and favorable safety profile of topical sirolimus for tuberous sclerosis - associated facial angiofibroma.

BACKGROUND: Tuberous sclerosis complex (TSC) is an autosomal dominant neurocutaneous disorder characterized by the development of multisystem hamartomatous tumours. Facial angiofibroma appears in up to 80% of patients and has a considerable psychological impact. Various invasive procedures have been used, although they show limited effectiveness and potential adverse effects. OBJECTIVES: To evaluate the sustained clinical benefits and safety profile of topical sirolimus applied to treat facial angiofibromas. METHODS: This study was a non-blinded, uncontrolled case-series comprising 10 patients with TSC-associated facial angiofibroma that was treated with 0.4% sirolimus ointment 3 times a week for 9 months. Patients were clinically evaluated at baseline and at 6, 12, 24 and 36 weeks. Plasma levels of sirolimus were determined. RESULTS: A sustained improvement was observed in erythema and in the size and extension of the lesions as early as the first weeks of treatment. Sirolimus plasma levels remained below detection limits (0.3 ng/mL) in all cases. The formula was well-tolerated with no local or systemic adverse effects. CONCLUSIONS: Topical sirolimus seems to be an effective and safe medical alternative to surgery or laser-based treatments in patients with TSC-associated facial angiofibromas.

Intraoral desmoplastic fibroma: a manifestation of tuberous sclerosis.

Desmoplastic fibroma (DF) is a benign but locally aggressive tumor usually recognized as an intraosseous counterpart of soft tissue fibromatosis in both gnathic and extra-gnathic sites. The most common site is mandible followed by pelvis and long bones. Maxilla has been reported to be involved very rarely. Desmoplastic fibroma is recently being considered to be one of the oral manifestations of tuberous sclerosis rather than a coincidental finding. We report an unusual case of a girl with a previous diagnosis of tuberosclerosis who presented at 8 years with an oral lesion diagnosed as desmoplastic fibroma.