Topical trametinib for epidermal and sebaceous nevi in a child with Schimmelpenning-Feuerstein-Mims syndrome.

We present the case of a 20-month-old girl with Schimmelpenning-Feuerstein-Mims (SFM) syndrome with extensive head, neck, and torso skin involvement successfully managed with topical trametinib. Trametinib interferes downstream of KRAS and HRAS in the MAPK signaling pathway, of which KRAS was implicated in our child's pathogenic variant. Although other dermatologic conditions have shown benefit from oral trametinib, its topical use has not been well reported. Our patient showed benefit from the use of twice-daily topical trametinib, applied to the epidermal and sebaceous nevi over a 16-month period, leading to decreased pruritus and thinning of the plaques.

Superficial shaving combined with photodynamic therapy for treating verrucous epidermal nevi: A case report.

Verrucous epidermal nevi is a refractory skin disease. Photodynamic therapy is considered a third-line treatment for verrucous epidermal nevi due to its unstable efficacy and high recurrence rate, mainly because of its limited depth of penetration. In this case, we conducted a successful treatment using superficial shaving combined with photodynamic therapy to treat verrucous epidermal nevi and gained a satisfactory efficacy. Before photodynamic therapy treatment, the epidermis in situ of each lesion in the tissue is removed with superficial shaving. Removal of the epidermal layer by intentional in situ injury improves the diffusion and absorption of topically applied photosensitizers and enhances the efficacy of photodynamic therapy. Our results show that photodynamic therapy combined with superficial shaving maybe is a safe and effective treatment for verrucous epidermal nevi.

Improvement of Unilateral Breast Hypoplasia With Oral Spironolactone in a Patient With Becker Nevus Syndrome.

Becker nevus (BN) is a benign cutaneous smooth muscle hamartoma that presents with a hyperpigmented patch or plaque with or without hypertrichosis.1 BN may be associated with ipsilateral breast hypoplasia or other musculoskeletal abnormalities, an association which has been termed Becker nevus syndrome (BNS).

Regression of nevi, vitiligo-like depigmentation and halo phenomenon may indicate response to immunotherapy and targeted therapy in melanoma.

We present two patients with stage IV melanoma, the first with BRAF wild-type melanoma with multiple visceral metastases treated with immunotherapy (pembrolizumab) and the second with BRAFV600E melanoma with subcutaneous and lymph nodes metastasis treated with BRAF and MEK-inhibitors (dabrafenib/trametinib). Already after the second cycle of immunotherapy, the first patient developed a diffuse regression of nevi, perceptible only with the use of dermoscopy and 3 months later a clinically evident poliosis of the eyebrows. The second patient, treated with dabrafenib/trametinib, developed small areas of leukoderma on his chest and white halos around nevi with a dermoscopic globular or structureless pattern. Both observations are suggestive for an immune reaction against melanocytic cells, which is further supported by the complete response to systemic therapy in both patients. It has been demonstrated that the development of vitiligo-like depigmentation during immunotherapy is associated with a better prognosis; in our patient, the phenomenon of poliosis appeared much later than the dermoscopic presence of regression among his nevi, suggesting that the latter may be an early sign (along with vitiligo-like phenomena) of good response to immunotherapy. On the other hand, the development of halo nevi and leukoderma during treatment with BRAF/MEK-inhibitors, suggests that not only immunotherapy but also targeted therapy may induce an immunologic response against melanoma and nevi, again indicative of a favorable prognosis. More data are needed to confirm these findings; however, they indicate that dermatologists should be involved in the follow-up of patients with melanoma, both in studies and clinical practice.

Infantile hemangioma. Part 2: Management.

The majority of infantile hemangiomas (IH) can be managed conservatively, but for those requiring active treatment, management has been revolutionized in the last decade by the discovery of propranolol. Patients that may require active intervention should receive specialist review, ideally before 5 weeks of age to mitigate the risk of sequelae. Propranolol can commence for most infants in the outpatient setting and the most frequently employed dosing regimen is 1 mg/kg twice daily. In the future, ß-blockers with a more-selective mechanism of action, such as atenolol, show some promise. In recalcitrant lesions, systemic corticosteroids or sirolimus may be considered. For small, superficial IHs, topical timolol maleate or pulsed dye laser may be considered. Where the IH involutes with cutaneous sequelae, a range of interventions have been reported, including surgery, laser, and embolization. IHs have a well-described clinical trajectory and are readily diagnosed and managed via telemedicine. Algorithms have been constructed to stratify those patients who can be managed remotely from those who warrant in-person review during the COVID-19 pandemic.

CLOVES Syndrome Diagnosis and Treatment in an Adult Patient.

CLOVES syndrome is a rare, nonheritable sporadic overgrowth disorder. In the world 130-200 cases have been reported. This is the first case of CLOVES described in Portugal, which had been not been diagnosed for the last 36 years. With this paper, the authors look to highlight the clinical features of this syndrome so that it does not go unrecognized in daily practice. The authors also underline the efficacy and safety of sirolimus, and that this treatment should not be denied, even in adult patients.

Neutralization of HSF1 in cells from PIK3CA-related overgrowth spectrum patients blocks abnormal proliferation.

PIK3CA-related overgrowth spectrum is caused by mosaicism mutations in the PIK3CA gene. These mutations, which are also observed in various types of cancer, lead to a constitutive activation of the PI3K/AKT/mTOR pathway, increasing cell proliferation. Heat shock transcription factor 1 (HSF1) is the major stress-responsive transcription factor. Recent findings indicate that AKT phosphorylates and activates HSF1 independently of heat-shock in breast cancer cells. Here, we aimed to investigate the role of HSF1 in PIK3CA-related overgrowth spectrum. We observed a higher rate of proliferation and increased phosphorylation of AKT and p70S6K in mutant fibroblasts than in control cells. We also found elevated phosphorylation and activation of HSF1, which is directly correlated to AKT activation. Specific AKT inhibitors inhibit HSF1 phosphorylation as well as HSF1-dependent gene transcription. Finally, we demonstrated that targeting HSF1 with specific inhibitors reduced the proliferation of mutant cells. As there is currently no curative treatment for PIK3CA-related overgrowth spectrum, our results identify HSF1 as a new potential therapeutic target.

Síndrome de CLOVES: tratamiento con rapamicina oral: reporte de dos casos / CLOVES syndrome: treatment with oral rapamycin: report of two cases

INTRODUCCIÓN: El síndrome de CLOVES se caracteriza por sobrecrecimiento lipomatoso asociado a malformaciones vasculares, representando un desafío diagnóstico y terapéutico. La rapamicina, un inhibidor de la vía mTOR, ha demostrado ser una buena alternativa terapéutica en un grupo de anomalías vasculares. Reportamos dos casos de síndrome de CLOVES con buena respuesta al tratamiento con rapamicina oral. OBJETIVO: Reportar la experiencia del uso de rapamicina oral en el tratamiento de dos pacientes con síndrome de CLOVES. CASOS CLÍNICOS: Caso 1: preescolar femenino de tres años de edad con sín drome de CLOVES e historia de hospitalizaciones reiteradas por infección severa de malformaciones linfáticas macroquísticas y episodios trombóticos. Evoluciona con mala calidad de vida, múltiples hospitalizaciones, riesgo quirúrgico y progresión de las lesiones, por lo que se indicó rapamicina oral. A los 6 meses de tratamiento se evidenció reducción clínica y radiológica del tamaño de las masas lipomatosas y linfáticas, ausencia de linforrea cutánea y mejoría significativa de la calidad de vida, sin requerir nuevas hospitalizaciones. Caso 2: escolar femenino de diez años de edad, portadora de síndrome de CLOVES, que desarrolló escoliosis y deterioro de su capacidad motora, haciéndose dependiente del uso de silla de ruedas. Se indicó rapamicina oral, evidenciándose a los cuatro meses de tratamiento mejoría en su capacidad física, independencia y autovalencia, con desaparición de la linforrea. CONCLUSIÓN: Proponemos la rapamicina oral para el tratamiento de pacientes con sín drome de CLOVES que presenten complicaciones y deterioro de la calidad de vida producto de su enfermedad.

INTRODUCTION: CLOVES syndrome is characterized by lipomatous overgrowth associated with vascular malforma tions, representing a diagnostic and a therapeutic challenge. Rapamycin, an mTOR inhibitor, has proved to be a good therapeutic option in some vascular anomalies. In this article, we report two ca ses of CLOVES syndrome with good response to oral rapamycin treatment. OBJECTIVE: To report the outcome of two patients with CLOVES syndrome treated with oral rapamycin. CLINICAL CASES: Case 1: A three-year-old female preschooler with CLOVES syndrome and history of repeated hospita lizations due to severe infections resulting from macrocystic lymphatic malformations and due to thrombotic episodes. The patient evolved with poor quality of life, multiple hospitalizations, surgical risk and progression of the lesions, therefore, oral rapamycin was indicated. After six months of treatment, clinical and radiological reduction in the size of the lipomatous and lymphatic masses, cutaneous lymphorrhea absence and a significant improvement of her quality of life were observed, without requiring new hospitalizations. Case 2: a ten-year-old female schooler with CLOVES syndro me, who developed scoliosis and deterioration of her motor skills, becoming wheelchair-dependent. Oral rapamycin was indicated, showing improvement in her physical capacity, independence and au tonomy, and absence of lymphorrhea after four months of treatment. CONCLUSION: We propose oral rapamycin for the treatment of patients with CLOVES syndrome who present with complications and deterioration in the quality of life as a result of the disease.

Alpelisib Treatment for Genital Vascular Malformation in a Patient with Congenital Lipomatous Overgrowth, Vascular Malformations, Epidermal Nevi, and Spinal/Skeletal Anomalies and/or Scoliosis (CLOVES) Syndrome.

BACKGROUND: Most patients with phosphoinositide-3-kinase, catalytic, alpha polypeptide (PIK3CA)-related overgrowth spectrum become symptomatic early in life and need treatment before puberty. Recently, the specific inhibition of PIK3CA pathways has been proposed as a therapeutic option for these patients improving their surgical options and quality of life. Alpelisib, a specific alpha fraction inhibitor, has shown promising results. CASE: A 17-year-old girl presented with severe involvement of her external genitalia with a combined vascular malformation in the context of congenital, lipomatous, overgrowth, vascular malformations, epidermal nevi and spinal/skeletal anomalies and/or scoliosis syndrome, needing frequent blood transfusions for anemia due to vaginal bleeding and use of a crutch for walking. After failure of treatment with rapamycin, compassionate treatment with alpelisib was started with excellent response. SUMMARY AND CONCLUSION: PIK3CA inhibitors might become a new option of treatment for PIK3CA-related overgrowth spectrum patients.

Topical sirolimus therapy for epidermal nevus with features of acanthosis nigricans.

We present a 4-year-old developmentally appropriate boy with short stature and widespread expanding epidermal nevus with features of acanthosis nigricans. He was found to have a mosaic mutation in FGFR3, the R248C variant. Despite several therapies, he continued to have growth, fissuring, and bleeding of the affected skin. Ultimately, topical sirolimus was attempted and found to improve thickness and overall symptoms.

CLOVES syndrome: Treatment with oral Rapamycin. Report of two cases. / Síndrome de CLOVES: Tratamiento con Rapamicina oral. Reporte de dos casos.

INTRODUCTION: CLOVES syndrome is characterized by lipomatous overgrowth associated with vascular malforma tions, representing a diagnostic and a therapeutic challenge. Rapamycin, an mTOR inhibitor, has proved to be a good therapeutic option in some vascular anomalies. In this article, we report two ca ses of CLOVES syndrome with good response to oral rapamycin treatment. OBJECTIVE: To report the outcome of two patients with CLOVES syndrome treated with oral rapamycin. CLINICAL CASES: Case 1: A three-year-old female preschooler with CLOVES syndrome and history of repeated hospita lizations due to severe infections resulting from macrocystic lymphatic malformations and due to thrombotic episodes. The patient evolved with poor quality of life, multiple hospitalizations, surgical risk and progression of the lesions, therefore, oral rapamycin was indicated. After six months of treatment, clinical and radiological reduction in the size of the lipomatous and lymphatic masses, cutaneous lymphorrhea absence and a significant improvement of her quality of life were observed, without requiring new hospitalizations. Case 2: a ten-year-old female schooler with CLOVES syndro me, who developed scoliosis and deterioration of her motor skills, becoming wheelchair-dependent. Oral rapamycin was indicated, showing improvement in her physical capacity, independence and au tonomy, and absence of lymphorrhea after four months of treatment. CONCLUSION: We propose oral rapamycin for the treatment of patients with CLOVES syndrome who present with complications and deterioration in the quality of life as a result of the disease.

Targeted therapy in patients with PIK3CA-related overgrowth syndrome.

CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis/skeletal and spinal syndrome) is a genetic disorder that results from somatic, mosaic gain-of-function mutations of the PIK3CA gene, and belongs to the spectrum of PIK3CA-related overgrowth syndromes (PROS). This rare condition has no specific treatment and a poor survival rate. Here, we describe a postnatal mouse model of PROS/CLOVES that partially recapitulates the human disease, and demonstrate the efficacy of BYL719, an inhibitor of PIK3CA, in preventing and improving organ dysfunction. On the basis of these results, we used BYL719 to treat nineteen patients with PROS. The drug improved the disease symptoms in all patients. Previously intractable vascular tumours became smaller, congestive heart failure was improved, hemihypertrophy was reduced, and scoliosis was attenuated. The treatment was not associated with any substantial side effects. In conclusion, this study provides the first direct evidence supporting PIK3CA inhibition as a promising therapeutic strategy in patients with PROS.

Burosumab: First Global Approval.

Burosumab (Crysvita®; Kyowa Hakko Kirin Co., Ltd. and Ultragenyx Pharmaceutical Inc.) is a fully human monoclonal antibody directed at fibroblast growth factor 23 (FGF23). Excessive FGF23 production has been implicated in various hypophosphataemic diseases. Inhibition of FGF23 by burosumab results in increased renal phosphate reabsorption and increased serum levels of phosphorus and active vitamin D. In February 2018, the EMA granted subcutaneous burosumab conditional marketing authorization for the treatment of X-linked hypophosphataemia (XLH) with radiographic evidence of bone disease in children one year of age and older and adolescents with growing skeletons. In April 2018, the US FDA approved burosumab for the treatment of XLH in adults and children one year of age and older. Multinational phase III trials of burosumab are currently underway in adult and paediatric patients with XLH. Burosumab is also being evaluated in the phase II setting in adults with tumour-induced osteomalacia and epidermal nevus syndrome in the USA, as well as in Japan and Korea. This article summarizes the milestones in the development of burosumab leading to its first global approval in the EU for XLH in paediatric patients.

Evaluation of Biodistribution of Sulforaphane after Administration of Oral Broccoli Sprout Extract in Melanoma Patients with Multiple Atypical Nevi.

Broccoli sprout extract containing sulforaphane (BSE-SFN) has been shown to inhibit ultraviolet radiation-induced damage and tumor progression in skin. This study evaluated the toxicity and potential effects of oral BSE-SFN at three dosages. Seventeen patients who each had at least 2 atypical nevi and a prior history of melanoma were randomly allocated to 50, 100, or 200 µmol oral BSE-SFN daily for 28 days. Atypical nevi were photographed on days 1 and 28, and plasma and nevus samples were taken on days 1, 2, and 28. Endpoints assessed were safety, plasma and skin sulforaphane levels, gross and histologic changes, IHC for phospho-STAT3(Y705), Ki-67, Bcl-2, HMOX1, and TUNEL, plasma cytokine levels, and tissue proteomics. All 17 patients completed 28 days with no dose-limiting toxicities. Plasma sulforaphane levels pooled for days 1, 2, and 28 showed median postadministration increases of 120 ng/mL for 50 µmol, 206 ng/mL for 100 µmol, and 655 ng/mL for 200 µmol. Median skin sulforaphane levels on day 28 were 0.0, 3.1, and 34.1 ng/g for 50, 100, and 200 µmol, respectively. Plasma levels of proinflammatory cytokines decreased from day 1 to 28. The tumor suppressor decorin was increased from day 1 to 28. Oral BSE-SFN is well tolerated at daily doses up to 200 µmol and achieves dose-dependent levels in plasma and skin. A larger efficacy evaluation of 200 µmol daily for longer intervals is now reasonable to better characterize clinical and biological effects of BSE-SFN as chemoprevention for melanoma. Cancer Prev Res; 11(7); 429-38. ©2018 AACR.