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Parte II. Actualización sobre otras manifestaciones cutáneas características de la enfermedad. NF1 y cáncer" "tienePdf" => "es" "tieneTextoCompleto" => "es" "tieneResumen" => array:2 [ 0 => "es" 1 => "en" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "465" "paginaFinal" => "473" ] ] "titulosAlternativos" => array:1 [ "en" => array:1 [ "titulo" => "An Update on Neurofibromatosis Type 1: Not Just Café-au-Lait Spots and Freckling. Part II. Other Skin Manifestations Characteristic of NF1. NF1 and Cancer" ] ] "contieneResumen" => array:2 [ "es" => true "en" => true ] "contieneTextoCompleto" => array:1 [ "es" => true ] "contienePdf" => array:1 [ "es" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0015" "etiqueta" => "Figura 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 675 "Ancho" => 900 "Tamanyo" => 77370 ] ] "descripcion" => array:1 [ "es" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Lesiones hipopigmentadas en una paciente con NF1.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "A. Hernández-Martín, A. Duat-Rodríguez" "autores" => array:2 [ 0 => array:2 [ "nombre" => "A." "apellidos" => "Hernández-Martín" ] 1 => array:2 [ "nombre" => "A." "apellidos" => "Duat-Rodríguez" ] ] ] ] ] "idiomaDefecto" => "es" "Traduccion" => array:1 [ "en" => array:9 [ "pii" => "S1578219016300890" "doi" => "10.1016/j.adengl.2016.05.019" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1578219016300890?idApp=UINPBA000044" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0001731016000740?idApp=UINPBA000044" "url" => "/00017310/0000010700000006/v1_201606280028/S0001731016000740/v1_201606280028/es/main.assets" ] ] "itemSiguiente" => array:19 [ "pii" => "S1578219016300865" "issn" => "15782190" "doi" => "10.1016/j.adengl.2016.05.016" "estado" => "S300" "fechaPublicacion" => "2016-07-01" "aid" => "1391" "copyright" => "Elsevier España, S.L.U. and AEDV" "documento" => "article" "crossmark" => 1 "subdocumento" => "fla" "cita" => "Actas Dermosifiliogr. 2016;107:474-81" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 802 "formatos" => array:3 [ "EPUB" => 42 "HTML" => 560 "PDF" => 200 ] ] "en" => array:13 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Special article</span>" "titulo" => "Adaptation and Validation of the Spanish Version of the Actinic Keratosis Quality of Life Questionnaire" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "en" 1 => "es" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "474" "paginaFinal" => "481" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Adaptación y validación de la versión española del cuestionario <span class="elsevierStyleItalic">Actinic Keratosis Quality of Life</span> (AKQoL)" ] ] "contieneResumen" => array:2 [ "en" => true "es" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "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" => 3813 "Ancho" => 2420 "Tamanyo" => 369557 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Flowchart showing process used to translate, culturally adapt, and validate the Actinic Quality of Life Questionnaire (AKQoL) in Spanish.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Isabel Longo Imedio, Carlos Serra-Guillén" "autores" => array:2 [ 0 => array:2 [ "nombre" => "Isabel" "apellidos" => "Longo Imedio" ] 1 => array:2 [ "nombre" => "Carlos" "apellidos" => "Serra-Guillén" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S0001731016300266" "doi" => "10.1016/j.ad.2016.03.003" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0001731016300266?idApp=UINPBA000044" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1578219016300865?idApp=UINPBA000044" "url" => "/15782190/0000010700000006/v2_201704050141/S1578219016300865/v2_201704050141/en/main.assets" ] "itemAnterior" => array:19 [ "pii" => "S1578219016300853" "issn" => "15782190" "doi" => "10.1016/j.adengl.2016.05.015" "estado" => "S300" "fechaPublicacion" => "2016-07-01" "aid" => "1350" "copyright" => "Elsevier España, S.L.U. and AEDV" "documento" => "article" "crossmark" => 1 "subdocumento" => "ssu" "cita" => "Actas Dermosifiliogr. 2016;107:454-64" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 2896 "formatos" => array:3 [ "EPUB" => 66 "HTML" => 2499 "PDF" => 331 ] ] "en" => array:13 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Review</span>" "titulo" => "An Update on Neurofibromatosis Type 1: Not Just Café-au-Lait Spots, Freckling, and Neurofibromas. An Update. Part I. Dermatological Clinical Criteria Diagnostic of the Disease" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "en" 1 => "es" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "454" "paginaFinal" => "464" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Neurofibromatosis tipo 1: más que manchas café con leche, efélides y neurofibromas. Parte I. Actualización sobre los criterios dermatológicos diagnósticos de la enfermedad" ] ] "contieneResumen" => array:2 [ "en" => true "es" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1280 "Ancho" => 850 "Tamanyo" => 160796 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Hyperchromic nevus on the posterior face of the leg of a healthy patient. Note the irregular edge of the lesion, completely different to the smooth border of typical CaLS.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "A. Hernández-Martín, A. Duat-Rodríguez" "autores" => array:2 [ 0 => array:2 [ "nombre" => "A." "apellidos" => "Hernández-Martín" ] 1 => array:2 [ "nombre" => "A." "apellidos" => "Duat-Rodríguez" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S0001731016000636" "doi" => "10.1016/j.ad.2016.01.004" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0001731016000636?idApp=UINPBA000044" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1578219016300853?idApp=UINPBA000044" "url" => "/15782190/0000010700000006/v2_201704050141/S1578219016300853/v2_201704050141/en/main.assets" ] "en" => array:20 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Review</span>" "titulo" => "An Update on Neurofibromatosis Type 1: Not Just Café-au-Lait Spots and Freckling. Part II. 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Madrid, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Servicio de Neurología, Hospital Infantil del Niño Jesús, Madrid, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Neurofibromatosis tipo 1: más que manchas café con leche, efélides y neurofibromas. Parte II. Actualización sobre otras manifestaciones cutáneas características de la enfermedad. NF1 y cáncer" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0015" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 675 "Ancho" => 900 "Tamanyo" => 83313 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Hypopigmented lesions in a female patient with NF1.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">In addition to the classic skin manifestations of NF1 (café-au-lait spots [CaLS], freckling, and neurofibromas), the presence of other common manifestations (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>) may be of high predictive value in patients with typical CaLS but without definitive diagnosis. In addition, the involvement of neurofibromin in the RAS-MAPK pathway may interfere with cell proliferation and differentiation and, therefore, increase the predisposition to development of malignant tumors in these patients.</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Other Common Skin Manifestations in Neurofibromatosis Type 1</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Nevus Anemicus</span><p id="par0010" class="elsevierStylePara elsevierViewall">The association between NF1 and nevus anemicus (NA) was suggested by Naegeli in 1915,<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">1</span></a> but there are hardly any literature reports on the topic until 2013.<a class="elsevierStyleCrossRefs" href="#bib0325"><span class="elsevierStyleSup">2–5</span></a> NAs are pale irregularly shaped macules whose size varies between a few millimeters and several centimeters; clinically they are not readily detected, and become apparent after mild rubbing of the area (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). Lesions can be single or multiple and are located on any area of the body, although they are more frequent on the presternal region.<a class="elsevierStyleCrossRefs" href="#bib0330"><span class="elsevierStyleSup">3,5</span></a> Although the published series reflect a high prevalence in children, the exact time of onset of the lesions is not known, as parents often have not noticed the presence of NAs until they are detected by a dermatologist in the clinic. In our series, patients with NAs were present in at least 50% of patients with confirmed NF1.<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">5</span></a> Possibly, the difference in prevalence in the different studies, which ranges from 8.8% to 51%,<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">3</span></a> is a result of the retrospective or prospective study design as these lesions are difficult to diagnose unless sought systematically. To detect such lesions, we routinely ask the parents if they have seen any transient whitish lesions during bathing, fever, crying, or exercise. We then rub the entire presternal area in babies and young children to highlight the lesions. NAs appear to be due to the absence of focal response to the action of catecholamines, and histologically they are indistinguishable from normal skin.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0015" class="elsevierStylePara elsevierViewall">Although NAs can appear in healthy individuals, in particular, in proximity to capillary malformations, an association of these lesions and CaLS with other genodermatoses or segmental neurofibromatosis has not been reported. In line with other authors,<a class="elsevierStyleCrossRefs" href="#bib0325"><span class="elsevierStyleSup">2–4</span></a> we believe that NAs are a distinctive finding in NF1 and that the presence of these lesions is of important predictive value in NF1.<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">5</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Juvenile Xanthogranulomas</span><p id="par0020" class="elsevierStylePara elsevierViewall">Juvenile xanthogranulomas (JXGs) are the most common form of Langerhans cell histiocytosis, and a relatively frequent finding in NF1 (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>).<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">6</span></a> The lesions disappear spontaneously after a few years, and it is rare to find them in late childhood and early adulthood.<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">7</span></a> Their estimated prevalence in patients with NF1 ranges from 0.7% in adults<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">8</span></a> to 37.5% in children,<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">7</span></a> and these lesions are particularly common in children aged less than 9 years.<a class="elsevierStyleCrossRefs" href="#bib0335"><span class="elsevierStyleSup">4,7</span></a> In our series, the prevalence of JXGs in pediatric patients with definite diagnosis of NF1 was 6.2%,<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">5</span></a> a figure that approximates the 8.5% reported by other authors.<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">3</span></a> In any case, it cannot be denied that JXG is a significant finding in patients with NF1, and it can be of particular importance in cases with no definitive diagnosis. A study found that 8 out of 10 patients with NF1 who only had CaLS at the first visit and who on physical examination had JXGs or NA, subsequently developed the disease,<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">4</span></a> and another study found that NF1 was subsequently confirmed in children with JXGs and CaLS.<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">7</span></a> Therefore, considering that JXG is the most frequent tumor in NF1, it is probable that the coexistence of CaLS and JXGs in small children should not be considered a casual finding but rather one highly indicative of the disease. Their presence has also been associated with a greater risk of childhood leukemia in patients with NF1, in particular juvenile myelomonocytic leukemia (JMML).<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">9</span></a> However, this association is not supported by the findings of other studies, and has been questioned by some authors,<a class="elsevierStyleCrossRefs" href="#bib0365"><span class="elsevierStyleSup">10–12</span></a> in particular in the dermatology literature. Although there are several case reports of such an association,<a class="elsevierStyleCrossRefs" href="#bib0380"><span class="elsevierStyleSup">13–16</span></a> a greater incidence of JMML has not been observed in larger series of patients with NF1 who presented with JXGs, including our series.<a class="elsevierStyleCrossRefs" href="#bib0335"><span class="elsevierStyleSup">4,5,7</span></a> Therefore, the suspicion of JMML in a patient with NF1 who develops JXGs should be directed by clinical symptoms and physical exploration, and not by the mere finding itself.<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">11</span></a></p><elsevierMultimedia ident="fig0010"></elsevierMultimedia></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Glomus Tumors</span><p id="par0025" class="elsevierStylePara elsevierViewall">The association of NF1 with glomus tumors was suspected since 1938,<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">17</span></a> but it was not until 2009 when this association was definitively confirmed when <span class="elsevierStyleItalic">NF1</span> mutations on both alleles was demonstrated in glomus cells.<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">18</span></a> Glomus tumors are benign vascular lesions that originate in the glomus body, a neuro-myo-arterial structure specialized in the regulation of vascular flow. The lesions are usually located in acral regions, particularly below the nails, and they are characterized by paroxysmal pain on applying pressure and with temperature changes. In patients with NF1, these lesions are usually multiple and recurring.<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">19</span></a> They are rare in children, with an estimated prevalence of 5% in adult patients with NF1.<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">20</span></a> Although they can appear in healthy individuals, around 30% of patients with glomus tumors have NF1.<a class="elsevierStyleCrossRefs" href="#bib0410"><span class="elsevierStyleSup">19,20</span></a> From the histological point of view, they are characterized by the presence of fine-walled vessels surrounded by uniform cells with rounded and dark nuclei. Unlike in sporadic cases, these cells do not express neurofibromin in individuals with NF1.<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">19</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Other Common Skin Findings in Neurofibromatosis Type 1</span><p id="par0030" class="elsevierStylePara elsevierViewall">Pruritus, generalized hyperpigmentation, presence of hypochromic macules, and soft skin are findings that can be readily detected in patients with NF1.</p><p id="par0035" class="elsevierStylePara elsevierViewall">Pruritus affects 20% of patients with NF1 and considerably impacts their quality of life.<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">21</span></a> The itching has been attributed to increased mastocytes in the skin, but there do not appear to be any differences in plasma levels of histamine in patients with itching compared to the general population.<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">22</span></a> Many patients do, however, have pruritus localized in the neurofibromas, where elevated mastocytes have been detected; administration of ketotifen can suppress the itching.<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">23</span></a> We should bear in mind that localized itching can be a warning for the development of medullary tumors or tumors of the central nervous system,<a class="elsevierStyleCrossRefs" href="#bib0435"><span class="elsevierStyleSup">24,25</span></a> and so it is a relevant symptom in patients with NF1.</p><p id="par0040" class="elsevierStylePara elsevierViewall">Patients with NF1 have diffuse generalized hyperpigmentation that becomes evident on comparing the tone of their skin with that of unaffected family members, and this explains the underlying hyperpigmentation often seen in segmental forms of NF1. Recently, in vitro studies have shown that melanocytes with a mutation in the <span class="elsevierStyleItalic">NF1</span> gene reproduce this hyperpigmentation, which is attributed to overexpression of microphthalmia-associated transcription factor, tyrosinase, and dopachrome tautomerase, all agents involved in melanogenesis.<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">26</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">Just as CaLS are observed in tuberous sclerosis, in children with NF1, hypopigmented macules can be found relatively frequently (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>),<a class="elsevierStyleCrossRef" href="#bib0450"><span class="elsevierStyleSup">27</span></a> but to date, there are no studies that have characterized their prevalence, number, and morphology. Finally, skin softness in patients with NF1 is a subjective perception that is also highlighted by some experts in the disease.<a class="elsevierStyleCrossRef" href="#bib0450"><span class="elsevierStyleSup">27</span></a></p><elsevierMultimedia ident="fig0015"></elsevierMultimedia></span></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Segmental or Mosaic Localized Neurofibromatosis</span><p id="par0050" class="elsevierStylePara elsevierViewall">Currently, segmental neurofibromatosis tends to be denoted mosaic localized neurofibromatosis (MLNF). Characteristically, typical lesions of NF1 are limited to one or several body segments. Four different types can be distinguished according to the clinical findings: 1) MLNF with exclusively pigmentary cutaneous changes (CaLS and freckling); 2) MLNF with neurofibromas alone; 3) MLNF with cutaneous pigmentary changes and neurofibromas; and 4) MLNF with exclusively plexiform neurofibromas.<a class="elsevierStyleCrossRef" href="#bib0455"><span class="elsevierStyleSup">28</span></a> A minimal number of CaLS is not required and the freckling does not have to be localized to skin folds to enable diagnosis of LMNF. Likewise, there is no minimum number of 2 cutaneous neurofibromas in the region of skin with typical pigmentary changes. The prevalence is estimated to be between 1:30 000 and 1:40 0000 healthy individuals,<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">8</span></a> but it is probably more common, as it often goes unnoticed by physicians and parents, who consider it a birthmark. The development of lesions follows the same time course as that of the systemic form of the disease. Therefore, most patients will only have pigmentary lesions during childhood and develop neurofibromas from puberty onwards.<a class="elsevierStyleCrossRefs" href="#bib0455"><span class="elsevierStyleSup">28,29</span></a> In the forms with exclusively pigmentary changes, tenuous underlying hyperpigmentation is observed that delimits the affected segment which, although well defined, can slightly exceed the medial line (<a class="elsevierStyleCrossRef" href="#fig0020">Fig. 4</a>). Some patients present with CaLS outside the apparently affected segment, particularly when the segment involves the scapular or pelvic region. In these patients, CaLS may be present along the involved limb. Other cutaneous findings, such as NAs or JXGs have not been described, and systemic complications that are often associated with NF1 appear to be less frequent in MLNF.<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">30</span></a> MLNF is usually asymptomatic but it can cause itching,<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">31</span></a> or pain resulting from nerve root compression or malignant transformation.<a class="elsevierStyleCrossRefs" href="#bib0475"><span class="elsevierStyleSup">32,33</span></a></p><elsevierMultimedia ident="fig0020"></elsevierMultimedia><p id="par0055" class="elsevierStylePara elsevierViewall">It is not uncommon for MLNF to be confused with other lesions such as nevus spilus, pigmentary mosaicism, or, very occasionally, segmental lentiginous pigmentation.<a class="elsevierStyleCrossRef" href="#bib0485"><span class="elsevierStyleSup">34</span></a> These pigmentation disorders are very difficult to distinguish clinically from MLNF, and differentiation can only be achieved by molecular analysis of the tissue. Patients with mosaic forms of NF1 should not be diagnosed with generalized NF1, even when they meet the diagnostic criteria for number and size of CaLS in the affected area. Nevertheless, patients should be aware of a small risk of transmitting generalized disease to their descendents.<a class="elsevierStyleCrossRefs" href="#bib0455"><span class="elsevierStyleSup">28,30</span></a> It is important to highlight that gonadal mosaicism is independent of the site of the affected cutaneous area, which is not necessarily localized on or near the gonadal region. Furthermore, there are no conclusive data on the risk of germline mosaicism. A recent systematic review did find that 4 of 157 cases published (2.5%) transmitted a generalized form of the disease,<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">30</span></a> but the authors themselves pointed out the possibility of publication bias. In addition, we do not have any data on the total number of descendants of patients with MLNF reported or the percentage of offspring affected. This information is essential for reliably calculating the risk of transmission of the disease.</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Neurofibromatosis Type 1 and Cancer</span><p id="par0060" class="elsevierStylePara elsevierViewall">Malignant tumors are, probably, the most feared complication of NF1. The signaling pathway mediated by the MAP-kinases ERK1 and ERK2 plays an essential role in the control of cell proliferation, differentiation, and survival in physiological conditions, and so failures associated with regulation of this pathway significantly contribute to cell transformation, and these are undoubtedly involved in tumor progression (<a class="elsevierStyleCrossRef" href="#fig0025">Fig. 5</a>). In decreasing order, the most frequent neoplasms in NF1 are optic nerve glioma (ONG) (15%-20%), malignant peripheral nerve sheath tumor (MPNST) (8%-13%), gastrointestinal stromal tumors (4%-25%), and pheochromocytomas (0.1%-5%).<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">35</span></a> In addition, patients with NF1 are at 7 to 5 times greater risk than the general population of developing leukemia, brain tumors, and breast cancer. Finally, although the relationship between NF1 and melanoma is not clear, recent findings have implicated neurofibromin in the genesis of this tumor. For reasons of space, we will only discuss tumors of neural origin and the relationship between neurofibromin and melanoma.</p><elsevierMultimedia ident="fig0025"></elsevierMultimedia><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Optic Nerve Gliomas and Other Gliomas</span><p id="par0065" class="elsevierStylePara elsevierViewall">ONGs account for 85% of low-grade gliomas (pilocytic astrocytomas) in patients with NF1, and affect between 15% and 30% of children aged between 3 and 5 years.<a class="elsevierStyleCrossRefs" href="#bib0495"><span class="elsevierStyleSup">36,37</span></a> They are a diagnostic criterion for the disease. Most cases are asymptomatic, but they can cause loss of vision in up to 12% of patients<a class="elsevierStyleCrossRef" href="#bib0500"><span class="elsevierStyleSup">37</span></a> or provoke early onset of puberty.<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">35</span></a> In view of the high incidence of ONGs, close ophthalmological follow-up is advisable in children with NF1, whether this is clinical or radiological, as clinical detection by physical examination can be difficult and some neuropediatricians prefer conducting complementary tests (<a class="elsevierStyleCrossRef" href="#fig0030">Fig. 6</a>).<a class="elsevierStyleCrossRef" href="#bib0500"><span class="elsevierStyleSup">37</span></a> The remaining 15% of low-grade gliomas also occur more frequently in the first 10 years of life, and can appear in any part of the brain. They are manifest clinically as headaches, unstable gait, or lethargy.<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">35</span></a> By contrast, high-grade gliomas (glioblastoma multiforme) are more often seen in young adults. The risk of such tumors is 5-fold greater in patients with NF1 than in the general population and prognosis is poor.<a class="elsevierStyleCrossRefs" href="#bib0490"><span class="elsevierStyleSup">35,38</span></a> Treatment for ONG in patients with NF1 is usually conservative, unless a decrease in visual acuity or progression in the size of the tumor in imaging tests is observed. If necessary, first-line treatment is chemotherapy with vincristine and carboplatin. Radiotherapy is not recommended given the high risk of secondary tumors. Surgery is reserved for large orbital tumors in which the patient has no useful vision, when the cornea is exposed, or if there is proptosis.<a class="elsevierStyleCrossRef" href="#bib0510"><span class="elsevierStyleSup">39</span></a></p><elsevierMultimedia ident="fig0030"></elsevierMultimedia></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Malignant Peripheral Nerve Sheaf Tumor</span><p id="par0070" class="elsevierStylePara elsevierViewall">MPNST (or neurofibrosarcoma) is a type of sarcoma that is thought to be derived from Schwann cells. It accounts for 3% to 10% of all sarcomas and is almost always associated with NF1. The approximate prevalence in patients with NF1 is 0.1% and the cumulative life-long risk is 8% to 13%.<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">35</span></a> In NF1, these tumors present in less than 5% of adult patients<a class="elsevierStyleCrossRefs" href="#bib0515"><span class="elsevierStyleSup">40,41</span></a> and in less than 2% of children.<a class="elsevierStyleCrossRef" href="#bib0495"><span class="elsevierStyleSup">36</span></a> The sites at greatest risk are areas with preexisting plexiform neurofibroma, when there is complete deletion of the gene or a history of prior radiotherapy. Factors predictive of the presence of internal (or deep) plexiform neurofibromas have been discussed in another section, but although the majority of MPNST result from malignant transformation of plexiform neurofibromas, they can also appear on subcutaneous neurofibromas and even where there are no prior lesions.<a class="elsevierStyleCrossRefs" href="#bib0495"><span class="elsevierStyleSup">36,40,42</span></a> The molecular mechanisms of malignant transformation of neurofibromas are not well known, but mutation of the <span class="elsevierStyleItalic">NF1</span> gene on both alleles in tumors, along with other epigenetic mechanisms, may lead to mutation of other important genes such as <span class="elsevierStyleItalic">p53</span> and <span class="elsevierStyleItalic">InK4A.</span><a class="elsevierStyleCrossRef" href="#bib0520"><span class="elsevierStyleSup">41</span></a> Warning symptoms include sudden increase in size, change in texture (increased consistency), intense or unremitting pain, and neurological symptoms other than those usually present.<a class="elsevierStyleCrossRef" href="#bib0515"><span class="elsevierStyleSup">40</span></a> In these cases, a radiological assessment and biopsy (with surgical resection if appropriate) should be performed immediately as a delay in diagnosis (in direct relation to the tumor size) is directly correlated to prognosis.<a class="elsevierStyleCrossRef" href="#bib0530"><span class="elsevierStyleSup">43</span></a> It should be remembered that magnetic resonance imaging offers data on the extent and site, but not on the biological behavior of the tumor. For such information, positron emission tomography with 18-fluorodesoxyglucose is necessary. This imaging technique will also provide information on potential metastases. Fine needle aspiration biopsy is not necessary as the histological sample should provide enough tissue sample for analysis. Radical surgery is the only curative therapeutic procedure, but it is often impossible or too disfiguring. Use of coadjuvant chemotherapy is controversial and not standard practice, except the use of anthralin in patients with metastatic tumors.<a class="elsevierStyleCrossRefs" href="#bib0535"><span class="elsevierStyleSup">44,45</span></a> Currently, MPNST has poor prognosis for survival.<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">35</span></a></p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Melanomas</span><p id="par0075" class="elsevierStylePara elsevierViewall">It is not clear whether there is a true association between NF1 and melanoma or whether the published cases, which are usually sporadic, are merely anecdotic. In the largest series, which included 11 patients with NF1 and cutaneous melanoma, melanoma was found to occur more frequently in women (in a proportion of 1:10), and young people (median age, 33 years). The mean Breslow depth was 3.2<span class="elsevierStyleHsp" style=""></span>mm, that is, considerably greater than in other series of patients with melanoma without NF1,<a class="elsevierStyleCrossRef" href="#bib0545"><span class="elsevierStyleSup">46</span></a> perhaps because other pigmented lesions make detection more difficult. Despite the uncertainty of the association, the relationship between melanoma and the RAS pathways is irrefutable, as not only do 50% of melanomas have <span class="elsevierStyleItalic">BRAF</span> mutations (particularly <span class="elsevierStyleItalic">V600E</span>) and 15% to 20% of these have <span class="elsevierStyleItalic">NRAS</span> mutations (particularly in codon 61) but also many melanomas have <span class="elsevierStyleItalic">NF1</span> mutations, whether associated or not with the aforementioned mutations.<a class="elsevierStyleCrossRef" href="#bib0550"><span class="elsevierStyleSup">47</span></a> The <span class="elsevierStyleItalic">NF1</span> gene is therefore the third most affected gene in melanoma. <span class="elsevierStyleItalic">NF1</span> mutations are particularly common in desmoplastic melanomas, where they are detected in 93% of cases, compared with 20% in nondesmoplastic melanomas.<a class="elsevierStyleCrossRef" href="#bib0555"><span class="elsevierStyleSup">48</span></a> However, the predictive value for response to treatment with MEK inhibitors of the presence of these mutations is subject to debate.<a class="elsevierStyleCrossRefs" href="#bib0560"><span class="elsevierStyleSup">49,50</span></a> In addition to melanoma, mutations in the neurofibromin gene have been detected sporadically in other cancers, such as brain tumors, breast cancer, ovarian cancer, and leukemias, and this is a promising line of research.<a class="elsevierStyleCrossRef" href="#bib0570"><span class="elsevierStyleSup">51</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">Finally, it is important to note that the rate of mortality due to cancer in individuals with NF1 is somewhat higher in individuals under 50 years of age, with this increased rate driven mainly by breast cancer and JMML, but the rates of cancer compared with the general population even out above this age.<a class="elsevierStyleCrossRef" href="#bib0575"><span class="elsevierStyleSup">52</span></a> Likewise, although the mean life expectancy is somewhat lower in patients with NF1 than in healthy individuals, the majority of NF1 patients live past 70 years of age.</p></span></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Diagnosis of Neurofibromatosis Type 1</span><p id="par0085" class="elsevierStylePara elsevierViewall">Currently, diagnosis of NF1 is still mainly based on clinical observations.<a class="elsevierStyleCrossRef" href="#bib0580"><span class="elsevierStyleSup">53</span></a> However, the timing of development of diagnostic criteria hinders diagnosis in small children and, in fact, only 46% of patients with no family history of the disease are diagnosed before the age of 2 years.<a class="elsevierStyleCrossRef" href="#bib0585"><span class="elsevierStyleSup">54</span></a> In recent years, several authors have proposed the inclusion of other cutaneous findings such as NAs and xanthogranulomas in the diagnostic criteria to facilitate diagnosis in this age group,<a class="elsevierStyleCrossRefs" href="#bib0325"><span class="elsevierStyleSup">2–5,7,27</span></a> and some authors go as far as to propose a revision and update of the classical clinical criteria.<a class="elsevierStyleCrossRefs" href="#bib0450"><span class="elsevierStyleSup">27,55</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">Genetic diagnosis of NF1 is not generally available. The large size of the <span class="elsevierStyleItalic">NF1</span> gene, the presence of homologous pseudogenes in pericentric regions of other chromosomes, the limited genotype-phenotype correlation, and the absence of hotspots make study of mutations laborious and costly. The combination of molecular techniques increases the sensitivity of detection of genetic mutations. Specifically, the combination of RNA analysis (denaturing high performance liquid chromatography) and multiplex ligation-dependent probe amplification, validated by Spanish researchers, has a sensitivity of 95% for detection of mutations in the <span class="elsevierStyleItalic">NF1</span> gene and provides very reliable results.<a class="elsevierStyleCrossRef" href="#bib0595"><span class="elsevierStyleSup">56</span></a> To date, more than 1000 mutations have been reported throughout the entire <span class="elsevierStyleItalic">NF1</span> gene; the majority of <span class="elsevierStyleItalic">NF1</span> mutations occur due to point changes in the gene coding sequence, while gene deletion occurs only in a minority of cases. Although the penetration of the disease is almost 100% in adults, there is good genotype-phenotype correlation in only a very few cases, and such correlation is not usually seen even in the same family or identical twins.<a class="elsevierStyleCrossRefs" href="#bib0600"><span class="elsevierStyleSup">57–60</span></a> The exceptions are cases of complete microdeletion of the <span class="elsevierStyleItalic">NF1</span> gene of 1.4 Mb (patients with such mutations have a severe form of the disease, with numerous and early-onset neurofibromas, cognitive impairment, dysmorphic features, and a tendency to develop malignancies),<a class="elsevierStyleCrossRefs" href="#bib0605"><span class="elsevierStyleSup">58,61</span></a> deletions of 3 base pairs in exon 17 affecting a single amino acid, p.Met992del (cases present CaLS and freckling without neurofibromas),<a class="elsevierStyleCrossRef" href="#bib0615"><span class="elsevierStyleSup">60</span></a> and mutations in codon 1809 of exon 29, which presents with pulmonary stenosis and short stature (phenotypic characteristics of Noonan syndrome).<a class="elsevierStyleCrossRef" href="#bib0610"><span class="elsevierStyleSup">59</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">Problems with the genetic study have led some authors to consider routine genetic studies unnecessary in small children who still do not meet the criteria for the disease, as: 1) 95% of children will meet the clinical criteria at the age of 8 years; 2) a negative result in the genetic test, in absence of a known familial mutation, does not rule out diagnosis; and 3) the absence of correlation between genotype and phenotype does not allow a prognosis to be made or change the approach to follow-up.<a class="elsevierStyleCrossRefs" href="#bib0625"><span class="elsevierStyleSup">62,63</span></a> Set against this opinion is the day-to-day reality of physicians who attend children with NF1: worried parents (who are perfectly informed about the risks and worst aspects of the disease) who want to know for sure whether their child has the disease. It is likely that advances in molecular diagnostic techniques will decreases costs and genetic studies will become widespread.</p><p id="par0100" class="elsevierStylePara elsevierViewall">In conclusion, the presence of cutaneous findings such as NAs and JXGs seem to be of high predictive value in patients with CaLS but with no definite diagnosis of NF1. Patients with NF1 have a predisposition to cancer, and early diagnosis of malignant tumors is the determining factor in prognosis. NF1 is a multisystemic disease that requires multidisciplinary follow-up with dermatologists playing an important role.</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Conflicts of Interest</span><p id="par0105" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflicts of interest.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:11 [ 0 => array:3 [ "identificador" => "xres824800" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec821276" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres824799" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec821275" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Other Common Skin Manifestations in Neurofibromatosis Type 1" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Nevus Anemicus" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Juvenile Xanthogranulomas" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Glomus Tumors" ] 3 => array:2 [ "identificador" => "sec0030" "titulo" => "Other Common Skin Findings in Neurofibromatosis Type 1" ] ] ] 6 => array:2 [ "identificador" => "sec0035" "titulo" => "Segmental or Mosaic Localized Neurofibromatosis" ] 7 => array:3 [ "identificador" => "sec0040" "titulo" => "Neurofibromatosis Type 1 and Cancer" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0045" "titulo" => "Optic Nerve Gliomas and Other Gliomas" ] 1 => array:2 [ "identificador" => "sec0050" "titulo" => "Malignant Peripheral Nerve Sheaf Tumor" ] 2 => array:2 [ "identificador" => "sec0055" "titulo" => "Melanomas" ] ] ] 8 => array:2 [ "identificador" => "sec0060" "titulo" => "Diagnosis of Neurofibromatosis Type 1" ] 9 => array:2 [ "identificador" => "sec0065" "titulo" => "Conflicts of Interest" ] 10 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2015-11-16" "fechaAceptado" => "2016-01-17" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec821276" "palabras" => array:8 [ 0 => "Neurofibromatosis type 1" 1 => "Juvenile xanthogranuloma" 2 => "Nevus anemicus" 3 => "Glomus tumor" 4 => "Malignant peripheral nerve sheath tumor" 5 => "Glioma" 6 => "Melanoma" 7 => "Genetic counseling" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec821275" "palabras" => array:8 [ 0 => "Neurofibromatosis tipo 1" 1 => "Xantogranuloma juvenil" 2 => "Nevus anemicus" 3 => "Tumor glómico" 4 => "Tumor maligno de vaina nerviosa de nervio periférico" 5 => "Glioma" 6 => "Melanoma" 7 => "Consejo genético" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">In addition to the classic skin manifestations of NF1 (café-au-lait spots, freckling, and neurofibromas), the presence of other manifestations such as nevus anemicus and juvenile xanthogranuloma may be of high predictive value in patients with an uncertain diagnosis. Localized or mosaic NF1, also known as segmental neurofibromatosis, is caused by a postzygotic mutation responsible for the presence of the typical disease manifestations limited to a body segment. Although no follow-up protocols are available for these patients with mosaic NF1, the risk of complications is much lower than in the generalized forms of the disease. Malignant tumors are, probably, the most feared complication of NF1. In decreasing order, the most frequent neoplasms are optic nerve glioma, malignant peripheral nerve sheath tumor, gastrointestinal stromal tumors, and pheochromocytomas. Most malignant peripheral nerve sheath tumors are the result of malignant transformation of plexiform neurofibromas and early diagnosis is a decisive factor in the prognosis. In conclusion, NF1 is a multisystemic disease that requires multidisciplinary follow-up with dermatologists playing an important role.</p></span>" ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Además de las manifestaciones dermatológicas diagnósticas de la NF1 (MCCL, efélides y neurofibromas), existen otras alteraciones cutáneas como los nevus anémicos y los xantogranulomas juveniles, cuya presencia parece ser de gran valor predictivo en los pacientes sin diagnóstico de certeza. La NF1 mosaica localizada, clásicamente denominada neurofibromatosis segmentaria, se produce a causa de una mutación poszigótica que determina que la presencia de las manifestaciones típicas de la enfermedad se limite a un segmento corporal. Aunque no existen protocolos de seguimiento de estos pacientes, el riesgo de complicaciones es mucho menor que en las formas generalizadas de la enfermedad. Los tumores malignos son, probablemente, la complicación más temida de la NF1. En orden decreciente, las neoplasias más frecuentes son los gliomas del nervio óptico, el tumor maligno de vaina nerviosa periférica (TMVNP), los tumores estromales gastrointestinales y los feocromocitomas. La mayoría de los TMVNP son el resultado de la transformación maligna de los neurofibromas plexiformes y su diagnóstico precoz es determinante para el pronóstico. En conclusión, la NF1 es una enfermedad multisistémica que requiere seguimiento multidisciplinar, pero en cuyo diagnóstico y seguimiento los dermatólogos tenemos un papel destacado.</p></span>" ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0010">Please cite this article as: Hernández-Martín A, Duat-Rodríguez A. Neurofibromatosis tipo 1: más que manchas café con leche, efélides y neurofibromas. Parte II. Actualización sobre otras manifestaciones cutáneas características de la enfermedad. NF1 y cáncer. Actas Dermosifiliogr. 2016;107:465–473.</p>" ] ] "multimedia" => array:7 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 713 "Ancho" => 1500 "Tamanyo" => 155575 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Presternal nevus anemicus on an 8-year-old patient. The lesion can hardly be discerned before rubbing the area (A). After rubbing, a pale irregular macule can be seen surrounded by an erythematous halo (B).</p>" ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 675 "Ancho" => 900 "Tamanyo" => 108719 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Juvenile xanthogranulomas on the eyebrow tail and the medial angle of the right eye, and nevus anemicus in the left clavicular region in a patient aged 15 months.</p>" ] ] 2 => array:7 [ "identificador" => "fig0015" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 675 "Ancho" => 900 "Tamanyo" => 83313 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Hypopigmented lesions in a female patient with NF1.</p>" ] ] 3 => array:7 [ "identificador" => "fig0020" "etiqueta" => "Figure 4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr4.jpeg" "Alto" => 1046 "Ancho" => 800 "Tamanyo" => 89780 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Localized mosaic neurofibromatosis with exclusively pigmentary lesions. Underlying mild pigmentation delimits the lesion, which slightly exceeds the medial line.</p>" ] ] 4 => array:7 [ "identificador" => "fig0025" "etiqueta" => "Figure 5" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr5.jpeg" "Alto" => 2594 "Ancho" => 2500 "Tamanyo" => 190921 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">RAS MAPK metabolic pathway. After stimulation of the cell receptors, intracellular proteins are activated (SHC,GRB2, and SHP2), and these recruit intracytoplasmic SOS1, activating the RAS proteins. Activation of the RAS proteins is accompanied by activation of RAF (BRAF, RAF1), MEK1A1/MEK1A2 and, finally, ERK/ERK2, which are the last effectors of the RAS/MAPK pathway and responsible for maintaining the cell life cycle.</p>" ] ] 5 => array:7 [ "identificador" => "fig0030" "etiqueta" => "Figure 6" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr6.jpeg" "Alto" => 726 "Ancho" => 850 "Tamanyo" => 78943 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Optic nerve glioma. T1-weighted coronal magnetic resonance imaging. Circumferential thickening of the left optic chiasm is observed (arrow), consistent with optic nerve glioma.</p>" ] ] 6 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Pruritus \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Diffuse hyperpigmentation \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Nevus anemicus<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Juvenile Xanthogranulomas<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Glomus Tumors \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Hypopigmented lesions \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Soft skin \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1386695.png" ] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Possible predictive value for NF1 in small children with CaLS and no other criteria for NF1 and no genetic confirmation of the disease.</p>" ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Frequent Cutaneous Disorders in Neurofibromatosis Type 1 (NF1).</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:63 [ 0 => array:3 [ "identificador" => "bib0320" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Naevi anaemici und Reckinghausensche Krankheit" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "O. 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año/Mes | Html | Total | |
---|---|---|---|
2024 Noviembre | 8 | 12 | 20 |
2024 Octubre | 112 | 66 | 178 |
2024 Septiembre | 160 | 58 | 218 |
2024 Agosto | 188 | 89 | 277 |
2024 Julio | 181 | 70 | 251 |
2024 Junio | 206 | 76 | 282 |
2024 Mayo | 187 | 70 | 257 |
2024 Abril | 157 | 62 | 219 |
2024 Marzo | 201 | 48 | 249 |
2024 Febrero | 164 | 50 | 214 |
2024 Enero | 174 | 65 | 239 |
2023 Diciembre | 362 | 37 | 399 |
2023 Noviembre | 310 | 60 | 370 |
2023 Octubre | 435 | 41 | 476 |
2023 Septiembre | 367 | 58 | 425 |
2023 Agosto | 142 | 26 | 168 |
2023 Julio | 203 | 52 | 255 |
2023 Junio | 182 | 44 | 226 |
2023 Mayo | 173 | 50 | 223 |
2023 Abril | 208 | 37 | 245 |
2023 Marzo | 260 | 37 | 297 |
2023 Febrero | 209 | 37 | 246 |
2023 Enero | 198 | 41 | 239 |
2022 Diciembre | 201 | 58 | 259 |
2022 Noviembre | 144 | 41 | 185 |
2022 Octubre | 126 | 39 | 165 |
2022 Septiembre | 140 | 67 | 207 |
2022 Agosto | 145 | 37 | 182 |
2022 Julio | 136 | 48 | 184 |
2022 Junio | 144 | 24 | 168 |
2022 Mayo | 216 | 53 | 269 |
2022 Abril | 270 | 32 | 302 |
2022 Marzo | 276 | 57 | 333 |
2022 Febrero | 325 | 44 | 369 |
2022 Enero | 305 | 59 | 364 |
2021 Diciembre | 162 | 60 | 222 |
2021 Noviembre | 144 | 51 | 195 |
2021 Octubre | 158 | 74 | 232 |
2021 Septiembre | 142 | 46 | 188 |
2021 Agosto | 172 | 36 | 208 |
2021 Julio | 203 | 48 | 251 |
2021 Junio | 206 | 41 | 247 |
2021 Mayo | 216 | 70 | 286 |
2021 Abril | 1144 | 67 | 1211 |
2021 Marzo | 345 | 56 | 401 |
2021 Febrero | 273 | 30 | 303 |
2021 Enero | 260 | 23 | 283 |
2020 Diciembre | 246 | 35 | 281 |
2020 Noviembre | 201 | 36 | 237 |
2020 Octubre | 137 | 17 | 154 |
2020 Septiembre | 184 | 30 | 214 |
2020 Agosto | 183 | 41 | 224 |
2020 Julio | 146 | 24 | 170 |
2020 Junio | 192 | 38 | 230 |
2020 Mayo | 110 | 20 | 130 |
2020 Abril | 70 | 18 | 88 |
2020 Marzo | 166 | 25 | 191 |
2020 Febrero | 10 | 2 | 12 |
2020 Enero | 3 | 0 | 3 |
2019 Diciembre | 9 | 0 | 9 |
2019 Noviembre | 3 | 0 | 3 |
2019 Septiembre | 4 | 0 | 4 |
2019 Agosto | 5 | 2 | 7 |
2019 Julio | 4 | 0 | 4 |
2019 Junio | 14 | 0 | 14 |
2019 Mayo | 6 | 1 | 7 |
2019 Abril | 11 | 3 | 14 |
2019 Marzo | 3 | 5 | 8 |
2019 Febrero | 1 | 0 | 1 |
2019 Enero | 5 | 0 | 5 |
2018 Diciembre | 4 | 0 | 4 |
2018 Noviembre | 2 | 0 | 2 |
2018 Octubre | 2 | 0 | 2 |
2018 Septiembre | 5 | 0 | 5 |
2018 Junio | 1 | 0 | 1 |
2018 Febrero | 27 | 12 | 39 |
2018 Enero | 32 | 19 | 51 |
2017 Diciembre | 41 | 17 | 58 |
2017 Noviembre | 56 | 19 | 75 |
2017 Octubre | 45 | 21 | 66 |
2017 Septiembre | 19 | 14 | 33 |
2017 Agosto | 31 | 16 | 47 |
2017 Julio | 25 | 10 | 35 |
2017 Junio | 46 | 16 | 62 |
2017 Mayo | 43 | 23 | 66 |
2017 Abril | 47 | 12 | 59 |
2017 Marzo | 34 | 17 | 51 |
2017 Febrero | 123 | 15 | 138 |
2017 Enero | 33 | 22 | 55 |
2016 Diciembre | 55 | 30 | 85 |
2016 Noviembre | 43 | 39 | 82 |
2016 Octubre | 36 | 37 | 73 |
2016 Agosto | 1 | 2 | 3 |
2016 Julio | 3 | 16 | 19 |