Case and Research Letters
Topical 0.2% Rapamycin to Treat Facial Angiofibromas and Hypomelanotic Macules in Tuberous Sclerosis
Rapamicina tópica al 0,2% para el tratamiento de angiofibromas faciales y máculas hipomelanóticas en la esclerosis tuberosa
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"apellidos" => "Hervás" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Servicio de Dermatología, Hospital Universitario Son Espases, Palma de Mallorca, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Instituto Universitario de Ciencias de la Salud-IUNICS, Universidad de las Islas Baleares, Palma de Mallorca, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Rapamicina tópica al 0,2% para el tratamiento de angiofibromas faciales y máculas hipomelanóticas en la esclerosis tuberosa" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 621 "Ancho" => 1000 "Tamanyo" => 129507 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Facial angiofibromas and hypomelanotic macules. A, Before treatment. B, After 20 weeks of 0.2% topical rapamycin.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Tuberous sclerosis is an autosomal dominant neurocutaneous disorder caused by mutations in tumor suppressor genes <span class="elsevierStyleItalic">TSC1</span> (in chromosome 9q34), which encodes hamartin, and <span class="elsevierStyleItalic">TSC2</span> (in chromosome 16p13.3), which encodes tuberin. Hamartin and tuberin, under normal circumstances, form a complex that inhibits the mammalian target of rapamycin (mTOR), which plays a crucial role in cell-cycle regulation. Mutations in the <span class="elsevierStyleItalic">TSC1</span> and <span class="elsevierStyleItalic">TSC2</span> genes lead to defective functioning of these proteins and result in uncontrolled cell proliferation that is characterized by the formation of hamartomas in multiple organs, including the skin and kidneys, and in the central nervous system.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1,2</span></a> Rapamycin (sirolimus) is an immunosuppressant that inhibits the mTOR pathway. Its only approved indication is prophylaxis of renal transplant rejection. Thanks to its antineoplastic properties, sirolimus inhibits angiogenesis and tumor cell proliferation, and has also been shown to be effective in reducing the number and size of tumors in patients with tuberous sclerosis. Recent publications suggest that topical rapamycin is effective for treating facial angiofibromas<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3–7</span></a> and reducing hypomelanotic macules<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> in patients with tuberous sclerosis.</p><p id="par0010" class="elsevierStylePara elsevierViewall">We report a case of a 13-year-old boy who had been clinically diagnosed with tuberous sclerosis at age 4 months based on the presence of typical manifestations of this condition, namely epilepsy, multiple hypomelanotic macules, and facial angiofibromas. Genetic analysis confirmed sporadic tuberous sclerosis caused by a c5043C>G mutation in exon 38 of the <span class="elsevierStyleItalic">TSC2</span> gene, changing the sequence to the N1681K variant. Magnetic resonance imaging of the brain showed multiple cortical and subcortical tubers, multiple intraventricular and subependymal hamartomas, and bilateral retinal astrocytomas. Abdominal ultrasound revealed the presence in the liver and kidneys of multiple angiomyolipomas, which were asymptomatic at the time of evaluation. Skin manifestations included facial angiofibromas that appeared gradually, multiple hypomelanotic macules, a periungual fibroma, and a shagreen patch on the back.</p><p id="par0015" class="elsevierStylePara elsevierViewall">With the aim of improving the patient's facial appearance by reducing the number of angiofibromas, we obtained informed consent to start treatment with a 0.2% rapamycin ointment formulated by the hospital pharmacy and provided at no cost to the patient. We prescribed once-daily application 5 days a week, for 12 months.</p><p id="par0020" class="elsevierStylePara elsevierViewall">The ointment was applied only to the face; because of the high cost of the drug preparation we did not consider treating the macules on the trunk and limbs.</p><p id="par0025" class="elsevierStylePara elsevierViewall">After 2 weeks of treatment we began to observe a reduction in the number of facial angiofibromas, with maximum effect observed at 12 weeks. We also noted considerable improvement in the hypomelanotic macules on the patient's face, with similar responses in the glabella and left cheek (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>).</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0030" class="elsevierStylePara elsevierViewall">Treatment was well tolerated with no local or systemic adverse effects, and plasma rapamycin levels remained below 0.3 ng/mL. We decided to maintain this treatment for a year to prevent the development of new angiofibromas.</p><p id="par0035" class="elsevierStylePara elsevierViewall">Facial angiofibromas are a characteristic feature of tuberous sclerosis. Although benign, they have a considerable psychological impact on patients.</p><p id="par0040" class="elsevierStylePara elsevierViewall">Our case shows that 0.2% topical rapamycin is a safe and effective therapy for both facial angiofibromas and hypomelanotic macules. The high cost of treatment and the lack of an approved indication for topical rapamycin limit the use of this therapeutic agent in daily practice. This is the third case published in the literature describing a marked improvement in hypomelanotic macules, with almost complete remission. The effectiveness of rapamycin against hypomelanotic macules might be explained by the fact that it increases transcription of microphthalmia transcription factor (MITF), which is involved in melanogenic gene expression and in the induction of melanogenesis in melanoma cells.<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">In conclusion, the present case further supports the usefulness of topical rapamycin to treat hypomelanotic macules in patients with tuberous sclerosis. However, more patients treated with topical rapamycin are needed in order to establish its safety and long-term effectiveness and to determine the most appropriate treatment regimen.</p></span>" "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Knöpfel N, Martín-Santiago A, Bauza A, Hervás JA. Rapamicina tópica al 0,2% para el tratamiento de angiofibromas faciales y máculas hipomelanóticas en la esclerosis tuberosa. Actas Dermosifiliogr. 2014;105:802–803.</p>" ] ] "multimedia" => array:1 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 621 "Ancho" => 1000 "Tamanyo" => 129507 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Facial angiofibromas and hypomelanotic macules. A, Before treatment. B, After 20 weeks of 0.2% topical rapamycin.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:9 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The tuberous sclerosis complex" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "K.A. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 12 | 8 | 20 |
| 2024 October | 96 | 45 | 141 |
| 2024 September | 110 | 33 | 143 |
| 2024 August | 156 | 64 | 220 |
| 2024 July | 111 | 32 | 143 |
| 2024 June | 77 | 25 | 102 |
| 2024 May | 85 | 31 | 116 |
| 2024 April | 90 | 22 | 112 |
| 2024 March | 69 | 18 | 87 |
| 2024 February | 52 | 33 | 85 |
| 2024 January | 60 | 39 | 99 |
| 2023 December | 76 | 32 | 108 |
| 2023 November | 91 | 33 | 124 |
| 2023 October | 60 | 43 | 103 |
| 2023 September | 78 | 39 | 117 |
| 2023 August | 70 | 10 | 80 |
| 2023 July | 87 | 31 | 118 |
| 2023 June | 72 | 27 | 99 |
| 2023 May | 113 | 23 | 136 |
| 2023 April | 91 | 27 | 118 |
| 2023 March | 57 | 24 | 81 |
| 2023 February | 68 | 21 | 89 |
| 2023 January | 62 | 19 | 81 |
| 2022 December | 90 | 31 | 121 |
| 2022 November | 39 | 27 | 66 |
| 2022 October | 48 | 28 | 76 |
| 2022 September | 61 | 28 | 89 |
| 2022 August | 38 | 36 | 74 |
| 2022 July | 25 | 38 | 63 |
| 2022 June | 30 | 27 | 57 |
| 2022 May | 94 | 39 | 133 |
| 2022 April | 98 | 30 | 128 |
| 2022 March | 89 | 36 | 125 |
| 2022 February | 80 | 25 | 105 |
| 2022 January | 60 | 36 | 96 |
| 2021 December | 50 | 27 | 77 |
| 2021 November | 59 | 41 | 100 |
| 2021 October | 78 | 48 | 126 |
| 2021 September | 80 | 34 | 114 |
| 2021 August | 77 | 28 | 105 |
| 2021 July | 67 | 30 | 97 |
| 2021 June | 51 | 33 | 84 |
| 2021 May | 74 | 26 | 100 |
| 2021 April | 210 | 67 | 277 |
| 2021 March | 102 | 28 | 130 |
| 2021 February | 102 | 35 | 137 |
| 2021 January | 71 | 18 | 89 |
| 2020 December | 33 | 19 | 52 |
| 2020 November | 24 | 18 | 42 |
| 2020 October | 32 | 18 | 50 |
| 2020 September | 42 | 15 | 57 |
| 2020 August | 37 | 20 | 57 |
| 2020 July | 37 | 22 | 59 |
| 2020 June | 44 | 27 | 71 |
| 2020 May | 36 | 23 | 59 |
| 2020 April | 24 | 20 | 44 |
| 2020 March | 38 | 17 | 55 |
| 2020 February | 5 | 4 | 9 |
| 2020 January | 4 | 6 | 10 |
| 2019 December | 8 | 3 | 11 |
| 2019 November | 4 | 2 | 6 |
| 2019 October | 3 | 6 | 9 |
| 2019 September | 9 | 8 | 17 |
| 2019 August | 4 | 2 | 6 |
| 2019 July | 2 | 5 | 7 |
| 2019 June | 6 | 7 | 13 |
| 2019 May | 2 | 13 | 15 |
| 2019 April | 0 | 1 | 1 |
| 2019 March | 2 | 5 | 7 |
| 2019 January | 1 | 2 | 3 |
| 2018 December | 0 | 1 | 1 |
| 2018 October | 3 | 0 | 3 |
| 2018 September | 1 | 0 | 1 |
| 2018 June | 0 | 4 | 4 |
| 2018 May | 0 | 5 | 5 |
| 2018 April | 0 | 5 | 5 |
| 2018 March | 1 | 6 | 7 |
| 2018 February | 42 | 10 | 52 |
| 2018 January | 78 | 10 | 88 |
| 2017 December | 40 | 11 | 51 |
| 2017 November | 40 | 8 | 48 |
| 2017 October | 50 | 15 | 65 |
| 2017 September | 34 | 12 | 46 |
| 2017 August | 39 | 16 | 55 |
| 2017 July | 28 | 9 | 37 |
| 2017 June | 38 | 20 | 58 |
| 2017 May | 26 | 22 | 48 |
| 2017 April | 25 | 9 | 34 |
| 2017 March | 23 | 30 | 53 |
| 2017 February | 19 | 11 | 30 |
| 2017 January | 18 | 13 | 31 |
| 2016 December | 35 | 28 | 63 |
| 2016 November | 43 | 18 | 61 |
| 2016 October | 35 | 17 | 52 |
| 2016 September | 1 | 13 | 14 |
| 2016 August | 0 | 2 | 2 |
| 2016 July | 8 | 1 | 9 |
| 2016 June | 5 | 1 | 6 |
| 2016 May | 10 | 3 | 13 |
| 2016 April | 17 | 32 | 49 |
| 2016 March | 12 | 2 | 14 |
| 2016 February | 15 | 16 | 31 |
| 2016 January | 9 | 1 | 10 |
| 2015 December | 21 | 1 | 22 |
| 2015 November | 16 | 2 | 18 |
| 2015 October | 13 | 3 | 16 |
| 2015 September | 8 | 5 | 13 |
| 2015 August | 17 | 1 | 18 |
| 2015 July | 28 | 3 | 31 |
| 2015 June | 21 | 4 | 25 |
| 2015 May | 22 | 11 | 33 |
| 2015 April | 11 | 7 | 18 |
| 2015 March | 13 | 4 | 17 |
| 2015 February | 9 | 7 | 16 |
| 2015 January | 11 | 5 | 16 |
| 2014 December | 9 | 4 | 13 |
| 2014 November | 8 | 4 | 12 |
| 2014 October | 13 | 2 | 15 |
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