Facial Angiofibromas Research Articles

Topical sirolimus in dermatology: a systematic review.

Topical sirolimus is increasingly utilised off-license to manage various dermatological conditions whilst avoiding typical adverse effects associated with systemic sirolimus. However, widespread use is limited by a highly heterogeneous evidence base of mixed quality. to evaluate the current evidence base for the indications, efficacy and safety profile for topical sirolimus in dermatology. A literature search was conducted from 2005 to July 4th, 2023, of English language studies, with the following databases consulted: MEDLINE, PubMed, Embase, CENTRAL and EBSCO. Key words included 'topical', 'rapamycin', 'sirolimus' and 'dermatology'. Data on drug efficacy, concentration, side effects, co-interventions and follow up were extracted. The search identified 202 studies; 71 studies met the inclusion criteria. Efficacy of topical sirolimus was demonstrated in facial angiofibromas (799 patients) compared to placebo across multiple randomised controlled trials with a predominant concentration of 0.1%. Evidence was mixed for sirolimus use in port-wine stains (61 patients), with evidence of effectiveness in combined sirolimus and pulsed-dye laser. Multiple case reports demonstrated clinical improvement with topical sirolimus use in cutaneous vascular abnormalities (33 patients) at a higher concentration of 1%. Other applications of topical sirolimus were predominantly case reports demonstrating generally favourable outcomes. Topical sirolimus was generally well tolerated - most reported adverse effects were localised irritation and pruritus. Ointment-based preparations and once-daily dosing appeared to confer a better side effect profile. Most high-quality data pertain to the efficacy of topical sirolimus in treating facial angiofibromas in tuberous sclerosis. Outcomes are generally promising in other indications and good tolerability, but data quality is mixed.

Multiple unilateral angiofibromas with a hypopigmented patch as a possible presentation of tuberous sclerosis complex (TSC)

Tuberous sclerosis complex (TSC), known as Bourneville’s disease or epiloia, is an autosomal dominant inherited disorder that may affect numerous organ systems. TSC has many forms of clinical presentation. The cutaneous features of TSC include facial angiofibromas, shagreen patches, ash leaf hypopigmented macules, periungual fibromas, forehead fibrous plaques, confetti hypopigmentation, and poliosis. Rarely, the angiofibromas in TSC have a segmental distribution. It has been suggested that the segmental expression of tuberous sclerosis may result from a postzygotic mutation. The aim of this concise communication was to describe a patient with unilateral angiofibromas associated with a hypopigmented patch. No other features of TSC were present. We think this could have been a rare presentation of TSC. Key words: Angiofibroma, Hypopigmented patch, Loss of heterozygosity (LOH), Tuberous sclerosis complex (TSC)

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

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. The authors performed a systematic review of the efficacy and safety of laser treatment for TS-related facial angiofibroma. 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. 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%). 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.

Tuberous Sclerosis Complex in a 20-year-old Female: Delayed Recognition and Life-threatening Outcomes

Tuberous sclerosis complex (TSC) is a rare, autosomal dominant multisystem disorder affecting the brain, heart, kidneys, lungs, and skin leading to significant morbidity and mortality. We report a case of TSC and highlight the need for prompt diagnosis and proper surveillance to minimize life-threatening complications. A 20-year-old female presented with facial and ungual papulonodular lesions 4 years after being diagnosed with epilepsy at the age of eight. No family history of genetic diseases was reported. Eight years later, the patient developed recurrent cough, shortness of breath, and blurring of vision. Biopsy of facial and digital nodule showed angiofibroma and ungual fibroma (Koenen tumor), respectively. Chest computed tomography scan revealed extensive cystic lesions diffusely scattered throughout the entire lung parenchyma suggestive of lymphangioleiomyomatosis. Cranial MRI revealed cortical and subependymal tubers, compatible with TSC. The patient had multidisciplinary management. However, her symptoms progressed, and she eventually succumbed to death. Cutaneous lesions such as facial angiofibromas and ungual fibromas along with multisystemic manifestations should alarm the clinician to TSC. Given its highly variable expressivity, awareness of different TSC-associated signs and symptoms is essential for prompt diagnosis, proper treatment, disease monitoring, and early recognition of TSC complications.

Therapeutic effect of Topical Sirolimus on Facial Angiofibromas in Patients of Tuberous Sclerosis Complex

Abstract Introduction: Tuberous sclerosis complex (TSC) is a rare autosomal dominant disorder. Facial angiofibromas are the most common cutaneous findings of TSC. Treatment modalities such as laser, surgery, and/or cryotherapy are employed. Topical therapy with Sirolimus, an mTOR inhibitor, showed beneficial effects. Objective: To study the effects of topical sirolimus (0.1%) on Facial Angiofibromas in patients of TSC. Methodology : Four patients with facial angiofibromas were included. They applied Sirolimus preparation twice daily, for 3 months. The Facial Angiofibroma Severity Index (FASI) was recorded pre-intervention, at 3 months and after 6 months. Results: All the patients showed a reduction in the FASI score at the end of three months of therapy. In three patients, on discontinuing therapy, there was no change in the FASI score at the end of six months, i.e., FASI 3 and FASI 6 were the same. Conclusion: Topical sirolimus is an effective treatment for facial angiofibroma in patients with TSC.

The tuberous sclerosis complex: a review of the literature

Tuberous sclerosis complex (TSC) is a neurocutaneous autosomal dominant genetic disorder characterized by mutations in the TSC1 and TSC2 genes, this leads to dysregulation of the mechanistic target of rapamycin (mTOR) pathway resulting in cellular hyperplasia and the formation of benign tumors in various organs, including the brain and skin. Clinical manifestations encompass a wide range of mainly neurological and dermatological symptoms, often presenting during early childhood and posing diagnostic challenges due to phenotypic variability. Recent advancements in diagnostic criteria, genetic testing, and imaging techniques have facilitated earlier diagnosis and increased disease incidence awareness. Neurologically, TSC commonly presents with cortical tubers, subependymal nodules (SENs), and epilepsy, with seizure control being paramount in preventing long-term neurodevelopmental sequelae. Dermatologically, hypomelanotic macules, facial angiofibromas, and ungual fibromas are hallmark features, often causing significant psychological distress due to disfigurement. Management of TSC requires a multidisciplinary approach, with emerging therapies such as mTOR inhibitors showing promise in addressing both neurological and dermatological manifestations. Early intervention, including epilepsy surgery and targeted treatments for skin lesions, is essential for optimizing outcomes and improving the quality of life for patients with TSC. Continued research into novel therapeutic modalities holds potential for further enhancing the management and prognosis of this complex disorder.

Validation of the Index for Facial Angiofibromas: Data analysis from a randomized controlled trial of sirolimus gel treatment in patients with tuberous sclerosis complex.

The Index for Facial Angiofibromas (IFA), a novel scoring system for angiofibromas, has been validated in patients with tuberous sclerosis complex (TSC). The objective of this analysis was to further validate the IFA using data from a clinical trial of topical sirolimus in patients with TSC. This was an analysis of photographs from a Phase III trial conducted in Japan (NCT02635789). Patients (n = 62) were randomized 1:1 to receive sirolimus or placebo gel for 12 weeks. Changes in angiofibromas were independently assessed using the primary composite endpoint, the Facial Angiofibroma Severity Index (FASI), and the IFA. Thresholds for a clinically meaningful change in IFA score were evaluated using receiver operating characteristic (ROC) analysis. The IFA scores had good-to-excellent inter-assessor reliability, very high intra-assessor reliability, and could be used to evaluate the distribution of disease severity at baseline. High correlations were observed between the categorized change from baseline in IFA scores and the primary composite endpoint (Kendall's coefficient of concordance, W = 0.8655, p < 0.0001), and between the change from baseline in IFA and FASI scores (Kendall's coefficient of concordance, W = 0.745, p < 0.0001). By ROC analysis, an optimal IFA cut-off point of 1.667 was determined to distinguish patients with markedly improved or improved angiofibromas from those with slightly improved or unchanged angiofibromas (area under the curve 0.937) as determined by the primary composite endpoint. The IFA score is potentially clinically useful because of its high validity and reliability. A decrease in score from baseline of ≥1.667 may be considered clinically meaningful.

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.

Topical Sirolimus for Facial Angiofibroma in Tuberous Sclerosis Complex: A Case Series

Facial angiofibromas (FAs) are a distressing manifestation of Tuberous Sclerosis Complex (TSC), often leading to significant physical and psychological burdens. Traditional treatment modalities have limitations, prompting the exploration of alternative therapies. In the present case series, topical sirolimus, a Mammalian Target of Rapamycin (mTOR) inhibitor, was used to manage FAs associated with TSC. Four cases (1 male and 3 female) of FAs in patients with TSC were treated with 0.1% sirolimus ointment applied once daily. The Facial Angiofibroma Severity Index (FASI) was utilised to assess FA severity at baseline and during follow-up visits, which spanned 3 to 12 months. Patient satisfaction and tolerability were also evaluated. Results demonstrated a consistent reduction in FASI scores across all patients, indicating improved FA severity. Patient satisfaction varied, with higher contentment observed in cases where treatment was initiated at a younger age. Importantly, no significant adverse effects were noted, affirming the safety profile of topical sirolimus. These findings underscore the potential of topical sirolimus as a promising therapeutic avenue for FAs in TSC, offering a cost-effective and well-tolerated alternative to conventional treatments. Further research is warranted to elucidate optimal dosing strategies and long-term outcomes, but current evidence supports its consideration as a viable option in the management of FAs associated with TSC.

Subependymal giant cell astrocytoma, report of a rare case

Tuberous sclerosis complex (TSC) is a rare genetic disease that is inherited autosomal dominantly and may be associated with subependymal giant cell astrocytoma (SEGA) in 10-20% of cases. Different phenotypes are related to the form of lesions in different parts of the body, including skin, brain, kidneys, lungs, and heart. The age of the patient, the location of the tumor, and associated skin or neurological lesions may guide the pathologist for a definite diagnosis. Here we report a case of SEGA in an adolescent with TSC. Neurological clues including seizure and mental retardation, facial angiofibroma, renal mass, and histopathology examination of the brain tumor culminated in the diagnosis of TSC and SEGA.

Optimization, Formulation, and Stability of Topical Rapamycin Used for Rare Tuberous Sclerosis Disease: from Ointment to Liposomes

IntroductionTopical rapamycin has been established as an effective and safe therapy for facial angiofibromas in tuberous sclerosis. Different formulations have been tested for this skin disease, most using an ointment as a vehicle.PurposeTo improve the classical formulation of topical rapamycin and to determine the validity period of the proposed options based on chemical, physical, and microbiological stability studies.MethodsFour different 0.4% rapamycin formulations were prepared (ointment, emulsion, gel, and liposomes). The stability studies for each formulation over 56 days were as follows: (1) chemical: extraction with different solvents and high-performance liquid chromatography assay; (2) physical: pH, uniformity, extensibility, absence of crystals, absence of phase separation, and only for liposomal formulation, particle size, zeta potential, and encapsulation efficiency were determined; and (3) microbiological: culture samples in blood-agar media.ResultsOnly liposomes were chemically, physically, and microbiologically stable after 8 weeks. Ointment, emulsion, and gel formulations lost their chemical or physical stability before 56 days.ConclusionsThe authors describe four new formulations to improve the previous treatment for facial angiofibromas in tuberous sclerosis. The liposome-based formulation was the most appropriate according to chemical, physical, and microbiological stability studies. However, it would be necessary to carry out clinical studies to ensure the effectiveness and safety of this formulation and also guarantee an improvement in the quality of life of patients.

Treatment of tuberous sclerosis complex manifestations in children with mTOR inhibitors.

Tuberous sclerosis complex (TSC) is a rare autosomal dominant genetic disorder that affects multiple organ systems. Mutations in the TSC1 and TSC2 genes result in the constitutive hyperactivation of the mammalian target of rapamycin (mTOR) pathway, contributing to the growth of benign tumors or hamartomas in various organs. Due to the implication of mTOR pathway dysregulation in the disease pathology, increasing evidence supports the use of mTOR inhibitors for treating multiple manifestations of TSC. In this study, we conducted a retrospective analysis of clinical findings and treatment data from 38 patients diagnosed with tuberous sclerosis who were followed up in the Pediatric Oncology Clinic between 2010 and 2020. We collected information on patients' ages, genders, affected sites, familial history, imaging findings, presence of tumors, and treatments. Among the patients, nine individuals with TSC manifestations were treated with mTOR inhibitors. Specifically, everolimus was successfully administered to five patients with inborn cardiac rhabdomyoma causing hemodynamic impairment. In addition, two patients with refractory seizures received everolimus in combination with anti-epileptic drugs. A patient with renal angiomyolipomas larger than 3cm was treated with everolimus, while a patient with extensive facial angiofibroma received topical sirolimus. All patients tolerated the mTOR inhibitors well, and the side effects were deemed acceptable. The utilization of mTOR inhibition in TSC is expected to become more prevalent in clinical practice, as current research is anticipated to provide a better understanding of the therapeutic roles of these treatments in TSC.

Hyftor: An Emerging Therapy For Facial Angiofibromas.

Tuberous Sclerosis Complex (TSC) is a rare autosomal dominant genetic disease caused by a deactivating mutation in one of the two tumour suppressor genes, TSC1 or TSC2.1,2 These mutations can lead to hyperactivation of the mammalian Target of Rapamycin (mTOR) signalling pathway, which in turn mediates cellular growth and proliferation. As the mTOR pathway is usually responsible for stimulating the synthesis of protein, cells' survival, and cell cycle progression.1,3 This causes the formation of multiple benign non-invasive tumours, called hamartoma, in different body tissues and organs.1,3 Facial Angiofibroma (FA) is the most prevalent skin manifestation of TSC.4 These are multiple, erythematous, small hamartomatous papules of around 1 to 3 mm in size formed by the excessive production of skin cells coupled with angiogenesis.3,4 The most classical sites of occurrence include the center of the face, alar grooves, cheeks, nose, and chin.3 FA has increased chances of bleeding; it can damage the eyesight and can cause psychological distress due to aesthetic disfiguration.4 Physical removal of FA is associated with pain, hyperpigmentation, scarring, bleeding, and recurrence of the lesions.4 Therefore, recently, on March 22, 2022, the FDA approved the topical use of Hyftor (Sirolimus, also known as Rapamycin mTOR inhibitor) for the treatment of FA.5 Hyftor has earned its position as the most appropriate treatment for FA in TSC due to its anti-tumour, anti-angiogenic and immunosuppressive properties, which highly favours this drug’s effectiveness and safety profile.1 It binds to the FK-binding protein-12 (FKBP-12), which in turn impedes the hyperactivity of mTOR, eventually causing the down-regulation of cellular growth. It also reduces levels of vascular endothelial growth factor levels depriving the tumour cells of their blood supply. Furthermore, it also halts the progression and proliferation of the cell cycle by blocking the response of T and B cell activation by cytokines.3 Long-term serious systematic side effects of mTOR inhibitors were overcome by the topical formulation of sirolimus.3,4 All concentrations of this drug are very well-tolerated with minor adverse effects, which include dry skin, application site irritation, burning sensation, and pruritis.3 Hyftor has proven to be a practical therapeutic innovation in the medical field due to its high specificity for mTOR and meager adverse effects profile. However, this drug requires additional large population-based studies and trials to substantiate further its efficacy and safety in patients with FA.

FRI213 Multiple Endocrine Neoplasia Syndromes: A Rare Case With Variable Presentation

Abstract Disclosure: D.J. Gomez D' Aza: None. M. Kasap: None. T. Zahedi: None. F. Zhang: None. Introduction: Multiple endocrine neoplasia (MEN) syndromes are rare autosomal dominant inherited groups of disorders characterized by the presence of two or more primary endocrine glands tumors. MEN type 1 is usually associated with neoplastic lesions of the pituitary gland, the parathyroid gland, and the pancreas. MEN type 2 typically presents with overgrowth of parathyroid, adrenal glands (pheochromocytoma), and parathyroid hyperplasia (MEN 2A), Marfanoid body habitus, or mucosal neuromas (MEN 2B). It can also manifest with non-endocrine tumors including carcinoid tumors, adrenocortical tumors, meningiomas, facial angiofibromas, collagenomas, lipomas, and germline mutations (MEN type 4). It is extremely rare for MEN type 1 syndrome to have concomitant pheochromocytoma. Case Report: We present a case of a 69 yo female with multiple comorbidities who was hospitalized for heart failure exacerbation. CT scan showed incidental findings of a 4.1 cm right adrenal nodule, a 2.1 cm left anterior mediastinum nodule, and a 1.1 cm oval pituitary mass. She had multiple episodes of hypertension urgency during the last two years. After patient recovered to her base line, workup labs revealed elevated serum Catecholamine with Metanephrine 431.1 pg/mL, Normetanephrine 466.5 pg/mL, Norepinephrine 137 pg/mL, and high PTH 258 pg/mL. Further study was normal for pituitary function tests, aldosterone, renin, cortisol, thyroid, and renal function. PET scan showed mild hypermetabolic activity in bilateral adrenal glands without any abnormal hypermetabolic activity in the chest. Thyroid Ultrasound identified a 1 cm thyroid nodule. Phenoxybenzamine was started due to concern for pheochromocytoma. Patient was monitored closely since she declined surgical intervention. Discussion: MEN syndromes have variable clinical presentation with multiple hormone excess. This patient has imaging and laboratory findings highly suggestive of MEN syndrome with pituitary adenoma, pheochromocytoma, and hyperparathyroidism. Further work up and genetic testing would be helpful to identify the mutation of MEN type 1 or type 2. Clinicians should be aware of the variable presentation of MEN syndrome, and prompt treatment is warranted to prevent life-threatening conditions. Presentation: Friday, June 16, 2023

A survey of patients with facial angiofibromas associated with tuberous sclerosis complex: Short-, medium- and long-term efficacy and safety of topical rapamycin

AimsTopical rapamycin is used to reduce facial angiofibromas in patients with tuberous sclerosis (TSC). In the absence of a commercially available preparation, numerous formulations have been tested clinically, although only in the short term. MethodsThe pharmacy at Angers University Hospital (France) produced a cream formulation that was administered to people presenting this genetic disease. We conducted a questionnaire-based survey among 79 patients with TSC about their perceptions regarding the short-, medium- and long-term efficacy and safety of a topical rapamycin preparation in relation to facial angiofibromas. ResultsThis formulation was very well tolerated and its efficacy was sustained over the long term with a mean treatment duration of 33 months (extremes 1–60). Efficacy was rated ≥ 8/10 by 67.1% of patients while safety was rated ≥ 8/10 by 84.8% of patients. ConclusionThis survey supports the safety and efficacy of topical rapamycin in the short-, medium- and long-term in the treatment of facial angiofibromas in a cohort of 79 patients with TSC.

Can Radiofrequency Ablation Be Utilized With Equal Effect in Place of Carbon Dioxide Laser in the Treatment of Facial Angiofibromas in Patients of Tuberous Sclerosis?

Can Radiofrequency Ablation Be Utilized With Equal Effect in Place of Carbon Dioxide Laser in the Treatment of Facial Angiofibromas in Patients of Tuberous Sclerosis?

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

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. A review of the literature was conducted using the Medline (PubMed) and EMBASE databases using the keywords topical sirolimus, rapamycin, Hyftor, and tuberous sclerosis. Articles written in English and relevant to the topic were included. 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. 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. Topical sirolimus 0.2% gel is a moderately effective treatment for TSC-associated facial angiofibromas with an adequate safety profile.

EE407 Healthcare Resource Utilization and Cost Burden of Facial Angiofibroma Associated with Tuberous Sclerosis Complex: A Real-World Claims Database Analysis in the United States

Tuberous sclerosis complex (TSC), a rare genetic disorder affects over 50,000 people in the United States (US). The disease burden of facial angiofibroma (FA), the most predominant cutaneous manifestation of TSC, is substantial. We aimed to document healthcare resource utilization (HCRU) and costs related with management of TSC and in a subset of TSC patients with FA.

EE177 Topical Sirolimus 0.2% Gel for Treatment of Facial Angiofibroma Associated with Tuberous Sclerosis Complex in the United States: A Budget Impact Analysis

Facial angiofibroma (FA), one of the predominant dermatological manifestations of tuberous sclerosis complex (TSC) disorder, occurs in 75%-88% of patients. Managing FA with TSC adds a substantial clinical and economic burden on the healthcare system. We assessed the budget impact of including sirolimus 0.2% gel (HYFTOR™), the first and only US FDA approved topical medication for FA associated with TSC from a US third-party payer perspective (Commercial, Medicaid, and Medicare).

CO217 Treatment Options for Management of Facial Angiofibroma Associated with Tuberous Sclerosis Complex: A Systematic Review of Evidence of Clinical Effectiveness and Cost-Effectiveness

We conducted a systematic review to analyze clinical and cost-effectiveness evidence of treatment options for facial angiofibroma (FA) associated with tuberous sclerosis complex (TSC) which lacks established therapeutic opportunities.