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

AIMS: Topical 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. METHODS: The 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. RESULTS: This 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. CONCLUSION: This 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.

Basosquamous carcinoma and melanoma collision tumor in a child with xeroderma pigmentosum.

Xeroderma pigmentosum (XP) is a rare autosomal recessive genodermatosis associated with hypersensitivity to ultraviolet radiation (UVR), being due to defects involving the nucleotide excision repair pathway. Patients with XP are prone to develop multiple cutaneous neoplasms including non-melanoma skin cancers and melanoma. Collision tumors in patients with XP have been reported in the literature including the following lesions, actinic keratosis, basal cell carcinoma, squamous cell carcinoma, and in situ melanoma. Herein, we present a rare collision tumor composed of melanoma and basosquamous carcinoma in a 13-year-old XP patient and describe the dermoscopic features.

Facial segmental haemangioma with PHACE Syndrome successfully treated with oral propranolol.

PHACE syndrome describes the association of large segmental haemangioma with extracutaneous features (posterior fossa anomalies, arterial, cardiac, eye and endocrine anomalies). We report a case of segmental facial infantile haemangioma with PHACE syndrome treated successfully with oral propranolol without neurological sequelae.

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.

Traumatic Facial Myopericytoma: A Differential to Consider.

Myopericytoma is a slow-growing, benign soft tissue neoplasm that arises from perivascular smooth muscle cells. This tumor is a rare entity itself, but it is only scarcely mentioned in the literature occurring secondary to trauma. The authors report a 21-year-old male patient who presented with a pulsatile mass in the medial canthal area where he had experienced previous trauma from a car accident 1-year prior. The mass was excised and histopathology revealed myopericytoma. This clinical report adds to the limited body of evidence supporting trauma as an etiology for this rare tumor.

B-Cell Lymphoma in a Patient With a History of Foreign Body Injection.

Dermal filler injection has been one of the most evolving areas of interest in the field of esthetic plastic surgery. This procedure is sometimes preferred to surgery due to shorter procedure and patient recovery times, and because it is suitable for a wide range of applications. Dermal filler injection is considered to be relatively safe, but various late complications such as infection and foreign body granuloma sometimes occur. Postprocedure development of lymphoma also occurs, but is extremely rare. The authors diagnosed extranodal marginal zone B-cell lymphoma of the mucosa associated lymphoid tissue that developed after a filler injection procedure was performed on a patient's face. This 72-year-old female first presented with a palpable mass on her left cheek that developed after a probable silicone injection. An magnetic resonance imaging (MRI) scan and excisional biopsy confirmed the presence of the lymphoma. Complete remission occurred after radiotherapy. This rare case of lymphoma in a patient with a history of foreign body injection indicated that practitioners must be aware that long-standing chronic inflammation resulting from dermal filler injections can trigger lymphoma development.

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.

Cowden syndrome presenting with trichilemmomas.

Cowden syndrome (CS) is a genetic cancerpredisposition syndrome that is associated withgermline mutations in the phosphate and tensinhomologue deleted on chromosome ten (PTEN)tumor suppressor gene. It is characterizedby the formation of benign and malignanttumors. Characteristic benign tumors includetrichilemmommas, acral keratoses, mucocutaneousneuromas, and oral papillomas. The most commonmalignant condition include breast, thyroid, andendometrial cancers. We present a case of a30-year-old woman with CS, who initially presentedwith trichilemmomas that were misdiagnosed ascomedonal acne. Recognition of the presentingfeatures of CS is important to ensure proper referral,management, and treatment for these patients.

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.

Effect of Field Treatment of Actinic Keratosis With Ingenol Mebutate Gel on the Identification of Lesions for Biopsy.

Actinic keratoses (AKs) are premalignant skin lesions caused by cumulative ultraviolet-light exposure that may progress to invasive squamous cell carcinoma (SCC). As the clinical presentation of AKs varies widely, only a histopathologic analysis of a biopsied sample can eliminate or confirm a diagnosis of invasive SCC. Reducing the burden of AK with a combination of lesion-directed and field-directed treatments may help to identify persistent, suspicious lesions that require further evaluation. We present 10 cases of SCC that were identified and histologically confirmed in 7 patients after complete or substantial clearance of AKs by sequential treatment of sun-damaged skin with cryosurgery and ingenol mebutate.

Basal Cell Carcinoma in a Patient With Brooke-Spiegler Syndrome.

A 46-year-old woman was diagnosed with Brooke-Spiegler syndrome (BSS) with lesions on her head, predominantly on the center of her face, auricles, and scalp. The facial lesions were polymorphic, pale, confluent, skin-colored, and papular, whereas the scalpel lesions appeared as erythematous and violet lumps that varied in size (Figure 1A, B).

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.

[The influence of risk factors for malignant tumors of maxillo-facial area on the expression of matrix metalloproteinases and tissue inhibitors of matrix metalloproteinases in patients of elderly and senile age period].

Morbidity and mortality from malignant neoplasms increases each year, and the average age of patients with first diagnosed decreases. The peak of incidence of malignant tumors of maxillofacial region falls on the elderly life. Not only age-related changes of the organism contribute in the development of this pathology, but also harmful habits. A comprehensive approach to solving the problem requires monitoring of this group of patients to identify risk factors for the development of pathologies in the oral and maxillofacial 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.