Congenital Melanocytic Nevus Syndrome: A Case Series

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MED indicates minimal erythema dose." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "M.T. Rodríguez-Granados, A. Estany-Gestal, M. Pousa-Martínez, J. Labandeira, R. Gato Otero, V. Fernández-Redondo" "autores" => array:6 [ 0 => array:2 [ "nombre" => "M.T." "apellidos" => "Rodríguez-Granados" ] 1 => array:2 [ "nombre" => "A." "apellidos" => "Estany-Gestal" ] 2 => array:2 [ "nombre" => "M." "apellidos" => "Pousa-Martínez" ] 3 => array:2 [ "nombre" => "J." "apellidos" => "Labandeira" ] 4 => array:2 [ "nombre" => "R." "apellidos" => "Gato Otero" ] 5 => array:2 [ "nombre" => "V." 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Recio Linares, A.I. Sánchez Moya, V. Félix, Y. Campos" "autores" => array:4 [ 0 => array:4 [ "nombre" => "A." "apellidos" => "Recio Linares" "email" => array:1 [ 0 => "aran.recio.linares@gmail.com" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "A.I." "apellidos" => "Sánchez Moya" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] ] ] 2 => array:3 [ "nombre" => "V." "apellidos" => "Félix" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "c" "identificador" => "aff0015" ] ] ] 3 => array:3 [ "nombre" => "Y." "apellidos" => "Campos" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "d" "identificador" => "aff0020" ] ] ] ] "afiliaciones" => array:4 [ 0 => array:3 [ "entidad" => "Unidad de Neonatología, Servicio de Pediatría, Complejo Hospitalario de Toledo, Toledo, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Servicio de Dermatología, Complejo Hospitalario de Toledo, Toledo, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Miembro investigador del Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER U724), Madrid, Spain" "etiqueta" => "c" "identificador" => "aff0015" ] 3 => array:3 [ "entidad" => "Servicio de Anatomía Patológica, Complejo Hospitalario de Toledo, Toledo, Spain" "etiqueta" => "d" "identificador" => "aff0020" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Síndrome del nevus melanocítico congénito. Serie de casos" ] ] "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" => 524 "Ancho" => 1681 "Tamanyo" => 94916 ] ] "descripcion" => array:1 [ "en" => "Definition of neurocutaneous melanosis." ] ] ] "textoCompleto" => "IntroductionCongenital melanocytic nevi are thought to be hamartomas derived from the neural crest. They are the result of postzygotic mutations that lead to defective migration and/or differentiation of melanocytes. These nevi are present at birth or manifest at a very early age.<a class="elsevierStyleCrossRef" href="#bib0080">1</a>In contrast with acquired melanocytic nevus, congenital nevus is usually larger and has a dual cell population. In the first, junctional melanocytes mature and involute in the dermis. In the second, the neuromesenchymal component comprises lymphocyte-like melanocytes that infiltrate more deeply, extending into the lower two-thirds of the dermis and the subcutaneous cellular tissue and potentially infiltrating the cutaneous adnexa and neurovascular structures.<a class="elsevierStyleCrossRef" href="#bib0085">2</a>In 1979, Kopf classified nevi according to size as small (<1.5cm), medium (1.5-20cm), and large (>20cm). When the nevus is greater than 40cm and located on the trunk, it is known as giant (or “garment”) congenital melanocytic nevus.<a class="elsevierStyleCrossRef" href="#bib0090">3</a>Excessive presence of melanocytic cells on the skin and central nervous system (CNS) was first described by Virchow in 1859 and later referred to as neurocutaneous melanosis by Van Bogaert in 1948. In 1972, Fox proposed the criteria that define this condition, which were revised in 1991 by Kadonga and Friedman.<a class="elsevierStyleCrossRefs" href="#bib0095">4,5</a> Today, the condition is known as congenital melanocytic nevus syndrome (CMNS) and is defined as the presence at birth of a melanocytic nevus measuring >5cm or more than 1 nevus of any size associated with neurological damage (clinical or radiological) and/or ≥3 typical facial characteristics<a class="elsevierStyleCrossRef" href="#bib0105">6</a> (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>).<elsevierMultimedia ident="fig0005"></elsevierMultimedia>The risk of developing CNMS in the presence of a giant congenital melanocytic nevus (GCMN) varies according to the series from 2.5% to 45%.<a class="elsevierStyleCrossRefs" href="#bib0110">7,8</a> The risk is greater in the presence of multiple congenital melanocytic nevi (previously known as satellite metastases) and, albeit to a lesser extent, with larger nevi.<a class="elsevierStyleCrossRef" href="#bib0120">9</a>Case SeriesWe present 5 cases of GCMN in patients born in a tertiary hospital between 2003 and 2014 from a total of 47 164 consecutive births, ie, an incidence of 1 case per 9450 liveborn children, which is much higher than that estimated in the literature (1 case per 20 000 liveborn children).<a class="elsevierStyleCrossRefs" href="#bib0090">3,4</a> Patients 2, 3, and 5 developed CMNS (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>Patient 2The patient was a newborn girl with GCMN (garment-type) and multiple satellite nevi. At 2 months of age, the patient presented partial seizures, and magnetic resonance imaging (MRI) of the brain revealed hyperintense lesions in T1-weighted images of the temporal lobes. The skin lesions were treated with laser and surgery. The molecular biology study of the skin lesion revealed the presence of the p.Q61K mutation in NRAS. The patient is now 9 years and 7 months old and is progressing favorably (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>).<elsevierMultimedia ident="fig0010"></elsevierMultimedia>Patient 3The patient was a girl with GCMN (garment-type) and satellite nevi in whom a prenatal ultrasound scan (week 34) revealed an anechoic image in the posterior fossa (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>). A neonatal ultrasound scan of the head taken at birth revealed ventriculomegaly and cysts associated with the Dandy-Walker variant. A lumbar puncture performed at 15 days after birth revealed the presence of melanocytes, and MRI of the brain revealed the presence of melanosis in the amygdala, thalamus, internal capsule, and brain stem. At 2 months of life, the patient developed intracranial hypertension, and a ventriculoperitoneal shunt was inserted. The patient's condition improved until age 2 years, when she began to experience repeated episodes of pleural effusion and massive ascites secondary to peritoneal melanosis. Therefore, antitumor treatment was started with sorafenib and temozolomide. However, the patient died at 26 months of age. Analysis of the lesion revealed a p.Q61R mutation in NRAS.<elsevierMultimedia ident="fig0015"></elsevierMultimedia>Patient 5The patient was a girl with GCMN (garment-type) and satellite nevi. At birth, she presented paralysis affecting the right side and center of her face, sixth nerve palsy, and marked hypertonia. An ultrasound scan of the brain revealed bilateral ventriculomegaly, and MRI of the brain revealed melanosis lesions in the thalami and brain stem (<a class="elsevierStyleCrossRef" href="#fig0020">Fig. 4</a>). Analysis of the lesion also revealed the p.Q61R mutation in NRAS. The patient is currently 20 months old and lives in Morocco.<elsevierMultimedia ident="fig0020"></elsevierMultimedia>No malignant cutaneous lesions were detected during follow-up.DiscussionIt has been postulated that CMNS results from sporadic, postzygotic mutations that affect the proliferation and migration of melanocytes between weeks 5 and 21 of gestation.One of the factors involved is hepatic growth factor, which can bind to the transmembrane c-Met receptor (tyrosine kinase) and activate the RAS-RAF-MEK-pERK-MAPK cascade to stimulate the growth of melanocytes during morphogenesis.The application of new therapies in patients with the syndrome could be affected by the recently described mutation in codon 61 of the NRAS gene. The mutation appears in the cells of the skin and nerve tissue of patients with CMNS, although it has not been detected in healthy tissue.<a class="elsevierStyleCrossRefs" href="#bib0110">7,10,11</a>About 10% of patients with CMNS experience neurological symptoms at some time during their life, generally before the age of 2 years. We can distinguish 2 subgroups, those with intraparenchymal melanosis, who have a better prognosis, and those who develop abnormalities that require surgery, such as hydrocephalus, syringomyelia, or CNS melanomas, all of which have a poorer prognosis.<a class="elsevierStyleCrossRef" href="#bib0120">9</a>Melanin deposits are normal in the leptomeninges, base of the brain, ventral surface of the medulla oblongata at the level of the neck, and the dark matter.<a class="elsevierStyleCrossRef" href="#bib0135">12</a>MRI of the brain is the imaging test of choice for detection of CNS lesions. It is recommended during the first 6 months of life, especially, in the presence of ≥2 congenital melanocytes. The most frequent sites are the amygdala, the cerebellum, the pons, and the spinal cord.<a class="elsevierStyleCrossRef" href="#bib0100">5</a>Recent studies suggest that urine dopamine levels could act as a prognostic marker of disease, since some series report higher values in cases of CMNS than in patients without CNS involvement.<a class="elsevierStyleCrossRef" href="#bib0140">13</a>The finding of a giant nevus at birth requires multidisciplinary management. The risk of developing a melanoma for these patients is not as high as previously thought (2% for GCMN), and it is not known whether surgery reduces this risk, since 30% of malignant lesions do not develop on the base of the nevus.<a class="elsevierStyleCrossRef" href="#bib0145">14</a>To date, symptomatic treatment of congenital melanocytic nevus has been palliative. During the last few years, BRAF inhibitors and MEK inhibitors have been authorized for the treatment of metastatic melanoma. These are efficacious in cases with mutations in NRAS. Mutations in BRAF are common in small congenital melanocytic nevi and in acquired nevi, in which exposure to sunlight plays an important role in malignant transformation. Furthermore, mutations in NRAS have been found in 70%-75% of cases of GCMN and in the nerve tissue of patients who present with CNS involvement. This gene participates in the intracellular NRAS-BRAF-MEK-pERK-MAPK cascade, which, when activated, stimulates the growth of melanocytes.<a class="elsevierStyleCrossRef" href="#bib0150">15</a>A recent article made reference to the compassionate use of a MEK inhibitor in a 13-year-old child with CMNS who died as a result of disease progression. The autopsy revealed diminished expression of pERK in melanocytes.<a class="elsevierStyleCrossRef" href="#bib0130">11</a>MEK inhibitors could potentially be used in selected pediatric patients with GCMN and a mutation in codon 61 in NRAS with the objective of curbing abnormal proliferation of melanocytes. High-quality studies are necessary to demonstrate the safety and efficacy of these drugs for the use referred to above.New research lines and more in-depth knowledge of embryological aspects and the pathophysiology of this disease will pave the way for new therapeutic applications.Ethical DisclosuresProtection of humans and animalsThe authors declare that no tests were carried out in humans or animals for the purposes of this study.Confidentiality of dataThe authors declare that they have followed their institutional protocols on publication of patient data.Right to privacy and informed consentThe authors declare that no private patient data appear in this article.Conflicts of InterestThe authors declare that they have no conflicts of interest." "textoCompletoSecciones" => array:1 [ "secciones" => array:10 [ 0 => array:3 [ "identificador" => "xres934535" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec908599" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres934534" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec908600" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Case Series" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Patient 2" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Patient 3" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Patient 5" ] ] ] 6 => array:2 [ "identificador" => "sec0030" "titulo" => "Discussion" ] 7 => array:3 [ "identificador" => "sec0035" "titulo" => "Ethical Disclosures" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0040" "titulo" => "Protection of humans and animals" ] 1 => array:2 [ "identificador" => "sec0045" "titulo" => "Confidentiality of data" ] 2 => array:2 [ "identificador" => "sec0050" "titulo" => "Right to privacy and informed consent" ] ] ] 8 => array:2 [ "identificador" => "sec0055" "titulo" => "Conflicts of Interest" ] 9 => array:1 [ "titulo" => "Références" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2016-01-24" "fechaAceptado" => "2016-07-31" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec908599" "palabras" => array:4 [ 0 => "Giant congenital melanocytic nevus" 1 => "Neurocutaneous melanosis" 2 => "NRAS mutation" 3 => "Trametinib" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec908600" "palabras" => array:4 [ 0 => "Nevus melanocítico congénito gigante" 1 => "Melanosis neurocutánea" 2 => "mutación NRAS" 3 => "Trametinib" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "Congenital melanocytic nevus syndrome (CMNS) is the result of an abnormal proliferation of melanocytes in the skin and central nervous system caused by progenitor-cell mutations during embryonic development. Mutations in the NRAS gene have been detected in many of these cells. We present 5 cases of giant congenital melanocytic nevus, 3 of them associated with CMNS; NRAS gene mutation was studied in these 3 patients. Until a few years ago, surgery was the treatment of choice, but the results have proved unsatisfactory because aggressive interventions do not improve cosmetic appearance and only minimally reduce the risk of malignant change. In 2013, trametinib was approved for use in advanced melanoma associated with NRAS mutations. This drug, which acts on the intracellular RAS/RAF/MEK/pERK/MAPK cascade, could be useful in pediatric patients with CMNS. A better understanding of this disease will facilitate the development of new strategies." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "El síndrome del nevus melanocítico congénito (SNMC) consiste en la proliferación anormal de melanocitos en la piel y el sistema nervioso central, y se debe a mutaciones de las células progenitoras durante el desarrollo embrionario. En muchas de estas células se han detectado mutaciones en el gen NRAS. Se exponen 5 casos de nevus melanocítico congénito gigante, 3 de ellos asociados al SNMC, en los que se ha estudiado dicha mutación. Hasta hace unos años la cirugía era el tratamiento de elección, sin embargo, sus resultados son insatisfactorios, con cirugías agresivas que no mejoran el aspecto estético y reducen mínimamente el riesgo de malignización. En el año 2013 se aprobó el trametinib en el uso del melanoma avanzado con mutaciones de NRAS. Dicho fármaco, que participa en la cascada intracelular de RAS-RAF-MEK-pERK-MAPK, podría ser útil en pacientes pediátricos con SNMC. El conocimiento más amplio de esta enfermedad permitirá crear nuevas estrategias." ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Recio Linares A, Sánchez Moya AI, Félix V, Campos Y. Síndrome del nevus melanocítico congénito. Serie de casos Síndrome del nevus melanocítico congénito. Serie de casos. Actas Dermosifiliogr. 2017;108:e57–e62." ] ] "multimedia" => array:5 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 524 "Ancho" => 1681 "Tamanyo" => 94916 ] ] "descripcion" => array:1 [ "en" => "Definition of neurocutaneous melanosis." ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 860 "Ancho" => 950 "Tamanyo" => 114428 ] ] "descripcion" => array:1 [ "en" => "Giant (or garment) congenital melanocytic nevus with satellite nevi." ] ] 2 => array:7 [ "identificador" => "fig0015" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1142 "Ancho" => 1500 "Tamanyo" => 259800 ] ] "descripcion" => array:1 [ "en" => "Giant (or garment) congenital melanocytic nevus extending to the trunk, buttocks, and proximal upper legs." ] ] 3 => array:7 [ "identificador" => "fig0020" "etiqueta" => "Figure 4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr4.jpeg" "Alto" => 637 "Ancho" => 1337 "Tamanyo" => 95558 ] ] "descripcion" => array:1 [ "en" => "A. Sagittal magnetic resonance image of the brain: hyperintense T1 image at the junction of the medulla oblongata and the pons. B. Coronal magnetic resonance image of the brain: hyperintense T1 images at the level of the thalamus and temporal lobes." ] ] 4 => 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:3 [ "leyenda" => "Abbreviations: CSF, cerebrospinal fluid; MRI, magnetic resonance imaging." "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=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Case \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Sex \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Location \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Satellitosis \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Neurologic Symptoms \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Additional Tests \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">NRAS Mutation \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Treatment \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Progress and Follow-up \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">M \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Right leg and head \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">MRI normal \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Not performed \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">None \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Alive at 12y and 7mo \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="9" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">M \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Trunk and proximal upper legs \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">> 20 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Yes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">MRI of the brain at 2mo: melanosis in temporal lobes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Q61K<a class="elsevierStyleCrossRef" href="#tblfn0010">b</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Surgery for resection starting at 8mo. Laser treatment. Antiseizure treatment starting at 2mo \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Alive at 9y and 9mo \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="9" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="4" align="left" valign="top">3</td><td class="td" title="table-entry " rowspan="4" align="left" valign="top">M</td><td class="td" title="table-entry " rowspan="4" align="left" valign="top">Trunk and proximal upper legs</td><td class="td" title="table-entry " rowspan="4" align="left" valign="top">> 20</td><td class="td" title="table-entry " rowspan="4" align="left" valign="top">Yes</td><td class="td" title="table-entry " align="left" valign="top">Brain ultrasound at birth: Dandy-Walker variant suspected. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " rowspan="4" align="left" valign="top">Q61R<a class="elsevierStyleCrossRef" href="#tblfn0010">b</a></td><td class="td" title="table-entry " align="left" valign="top">Insertion of shunt \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " rowspan="4" align="left" valign="top">Dead at 26mo of life</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Brain MRI and CSF at 15 days of life: data indicating melanosis. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Antiseizure treatment \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Ultrasound of chest and abdomenat 2y: ascites and pleural effusion \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Paracentesis and thoracocentesis at 2y because of abdominal melanosis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Antitumor treatment with sorafenib and temozolomide. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="9" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">M \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Trunk and face \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><10 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">MRI normal \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Not performed \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Surgery starting at 8mo \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Alive at 3y and 4mo \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="9" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="2" align="left" valign="top">5</td><td class="td" title="table-entry " rowspan="2" align="left" valign="top">M</td><td class="td" title="table-entry " rowspan="2" align="left" valign="top">Trunk</td><td class="td" title="table-entry " rowspan="2" align="left" valign="top">> 20</td><td class="td" title="table-entry " rowspan="2" align="left" valign="top">Yes</td><td class="td" title="table-entry " align="left" valign="top">Ultrasound of brain at 1 mo of life: bilateral ventriculomegaly \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " rowspan="2" align="left" valign="top">Q61R<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a></td><td class="td" title="table-entry " rowspan="2" align="left" valign="top">Evaluation pending</td><td class="td" title="table-entry " rowspan="2" align="left" valign="top">Alive at 22mo</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Brain MRI at 2mo: melanosis in brain stem and thalamus \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1579658.png" ] ] ] "notaPie" => array:2 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "Children born in a tertiary hospital over a 15-year period." ] 1 => array:3 [ "identificador" => "tblfn0010" "etiqueta" => "b" "nota" => "Molecular study performed to detect mutations in RAS using therascreen KRAS, NRAS, RAS extension Pyro kit (Quiagen)." ] ] ] "descripcion" => array:1 [ "en" => "Five Cases of Giant Congenital Melanocytic Nevus, 3 of Which Occurred With 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e- Case Report

Congenital Melanocytic Nevus Syndrome: A Case Series

Síndrome del nevus melanocítico congénito. Serie de casos

A. Recio Linaresa,

Corresponding author

aran.recio.linares@gmail.com

Corresponding author.

, A.I. Sánchez Moyab, V. Félixa,c, Y. Camposd

a Unidad de Neonatología, Servicio de Pediatría, Complejo Hospitalario de Toledo, Toledo, Spain

b Servicio de Dermatología, Complejo Hospitalario de Toledo, Toledo, Spain

c Miembro investigador del Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER U724), Madrid, Spain

d Servicio de Anatomía Patológica, Complejo Hospitalario de Toledo, Toledo, Spain

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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Congenital melanocytic nevi are thought to be hamartomas derived from the neural crest&#46; They are the result of postzygotic mutations that lead to defective migration and&#47;or differentiation of melanocytes&#46; These nevi are present at birth or manifest at a very early age&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">1</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">In contrast with acquired melanocytic nevus&#44; congenital nevus is usually larger and has a dual cell population&#46; In the first&#44; junctional melanocytes mature and involute in the dermis&#46; In the second&#44; the neuromesenchymal component comprises lymphocyte-like melanocytes that infiltrate more deeply&#44; extending into the lower two-thirds of the dermis and the subcutaneous cellular tissue and potentially infiltrating the cutaneous adnexa and neurovascular structures&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">2</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">In 1979&#44; Kopf classified nevi according to size as small &#40;&#60;<span class="elsevierStyleHsp" style=""></span>1&#46;5<span class="elsevierStyleHsp" style=""></span>cm&#41;&#44; medium &#40;1&#46;5-20<span class="elsevierStyleHsp" style=""></span>cm&#41;&#44; and large &#40;&#62;<span class="elsevierStyleHsp" style=""></span>20<span class="elsevierStyleHsp" style=""></span>cm&#41;&#46; When the nevus is greater than 40<span class="elsevierStyleHsp" style=""></span>cm and located on the trunk&#44; it is known as giant &#40;or &#8220;garment&#8221;&#41; congenital melanocytic nevus&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">3</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">Excessive presence of melanocytic cells on the skin and central nervous system &#40;CNS&#41; was first described by Virchow in 1859 and later referred to as neurocutaneous melanosis by Van Bogaert in 1948&#46; In 1972&#44; Fox proposed the criteria that define this condition&#44; which were revised in 1991 by Kadonga and Friedman&#46;<a class="elsevierStyleCrossRefs" href="#bib0095"><span class="elsevierStyleSup">4&#44;5</span></a> Today&#44; the condition is known as congenital melanocytic nevus syndrome &#40;CMNS&#41; and is defined as the presence at birth of a melanocytic nevus measuring &#62;<span class="elsevierStyleHsp" style=""></span>5<span class="elsevierStyleHsp" style=""></span>cm or more than 1 nevus of any size associated with neurological damage &#40;clinical or radiological&#41; and&#47;or &#8805;<span class="elsevierStyleHsp" style=""></span>3 typical facial characteristics<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">6</span></a> &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0025" class="elsevierStylePara elsevierViewall">The risk of developing CNMS in the presence of a giant congenital melanocytic nevus &#40;GCMN&#41; varies according to the series from 2&#46;5&#37; to 45&#37;&#46;<a class="elsevierStyleCrossRefs" href="#bib0110"><span class="elsevierStyleSup">7&#44;8</span></a> The risk is greater in the presence of multiple congenital melanocytic nevi &#40;previously known as satellite metastases&#41; and&#44; albeit to a lesser extent&#44; with larger nevi&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">9</span></a></p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Case Series</span><p id="par0030" class="elsevierStylePara elsevierViewall">We present 5 cases of GCMN in patients born in a tertiary hospital between 2003 and 2014 from a total of 47&#160;164 consecutive births&#44; ie&#44; an incidence of 1 case per 9450 liveborn children&#44; which is much higher than that estimated in the literature &#40;1 case per 20&#160;000 liveborn children&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0090"><span class="elsevierStyleSup">3&#44;4</span></a> Patients 2&#44; 3&#44; and 5 developed CMNS &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Patient 2</span><p id="par0035" class="elsevierStylePara elsevierViewall">The patient was a newborn girl with GCMN &#40;garment-type&#41; and multiple satellite nevi&#46; At 2 months of age&#44; the patient presented partial seizures&#44; and magnetic resonance imaging &#40;MRI&#41; of the brain revealed hyperintense lesions in T1-weighted images of the temporal lobes&#46; The skin lesions were treated with laser and surgery&#46; The molecular biology study of the skin lesion revealed the presence of the p&#46;Q61K mutation in <span class="elsevierStyleItalic">NRAS</span>&#46; The patient is now 9 years and 7 months old and is progressing favorably &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Patient 3</span><p id="par0040" class="elsevierStylePara elsevierViewall">The patient was a girl with GCMN &#40;garment-type&#41; and satellite nevi in whom a prenatal ultrasound scan &#40;week 34&#41; revealed an anechoic image in the posterior fossa &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#41;&#46; A neonatal ultrasound scan of the head taken at birth revealed ventriculomegaly and cysts associated with the Dandy-Walker variant&#46; A lumbar puncture performed at 15 days after birth revealed the presence of melanocytes&#44; and MRI of the brain revealed the presence of melanosis in the amygdala&#44; thalamus&#44; internal capsule&#44; and brain stem&#46; At 2 months of life&#44; the patient developed intracranial hypertension&#44; and a ventriculoperitoneal shunt was inserted&#46; The patient&#39;s condition improved until age 2 years&#44; when she began to experience repeated episodes of pleural effusion and massive ascites secondary to peritoneal melanosis&#46; Therefore&#44; antitumor treatment was started with sorafenib and temozolomide&#46; However&#44; the patient died at 26 months of age&#46; Analysis of the lesion revealed a p&#46;Q61R mutation in <span class="elsevierStyleItalic">NRAS</span>&#46;</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Patient 5</span><p id="par0045" class="elsevierStylePara elsevierViewall">The patient was a girl with GCMN &#40;garment-type&#41; and satellite nevi&#46; At birth&#44; she presented paralysis affecting the right side and center of her face&#44; sixth nerve palsy&#44; and marked hypertonia&#46; An ultrasound scan of the brain revealed bilateral ventriculomegaly&#44; and MRI of the brain revealed melanosis lesions in the thalami and brain stem &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>&#41;&#46; Analysis of the lesion also revealed the p&#46;Q61R mutation in <span class="elsevierStyleItalic">NRAS</span>&#46; The patient is currently 20 months old and lives in Morocco&#46;</p><elsevierMultimedia ident="fig0020"></elsevierMultimedia><p id="par0050" class="elsevierStylePara elsevierViewall">No malignant cutaneous lesions were detected during follow-up&#46;</p></span></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Discussion</span><p id="par0055" class="elsevierStylePara elsevierViewall">It has been postulated that CMNS results from sporadic&#44; postzygotic mutations that affect the proliferation and migration of melanocytes between weeks 5 and 21 of gestation&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">One of the factors involved is hepatic growth factor&#44; which can bind to the transmembrane c-Met receptor &#40;tyrosine kinase&#41; and activate the RAS-RAF-MEK-pERK-MAPK cascade to stimulate the growth of melanocytes during morphogenesis&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">The application of new therapies in patients with the syndrome could be affected by the recently described mutation in codon 61 of the <span class="elsevierStyleItalic">NRAS</span> gene&#46; The mutation appears in the cells of the skin and nerve tissue of patients with CMNS&#44; although it has not been detected in healthy tissue&#46;<a class="elsevierStyleCrossRefs" href="#bib0110"><span class="elsevierStyleSup">7&#44;10&#44;11</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">About 10&#37; of patients with CMNS experience neurological symptoms at some time during their life&#44; generally before the age of 2 years&#46; We can distinguish 2 subgroups&#44; those with intraparenchymal melanosis&#44; who have a better prognosis&#44; and those who develop abnormalities that require surgery&#44; such as hydrocephalus&#44; syringomyelia&#44; or CNS melanomas&#44; all of which have a poorer prognosis&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">9</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">Melanin deposits are normal in the leptomeninges&#44; base of the brain&#44; ventral surface of the medulla oblongata at the level of the neck&#44; and the dark matter&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">12</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">MRI of the brain is the imaging test of choice for detection of CNS lesions&#46; It is recommended during the first 6 months of life&#44; especially&#44; in the presence of &#8805;<span class="elsevierStyleHsp" style=""></span>2 congenital melanocytes&#46; The most frequent sites are the amygdala&#44; the cerebellum&#44; the pons&#44; and the spinal cord&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">5</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">Recent studies suggest that urine dopamine levels could act as a prognostic marker of disease&#44; since some series report higher values in cases of CMNS than in patients without CNS involvement&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">13</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">The finding of a giant nevus at birth requires multidisciplinary management&#46; The risk of developing a melanoma for these patients is not as high as previously thought &#40;2&#37; for GCMN&#41;&#44; and it is not known whether surgery reduces this risk&#44; since 30&#37; of malignant lesions do not develop on the base of the nevus&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">14</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">To date&#44; symptomatic treatment of congenital melanocytic nevus has been palliative&#46; During the last few years&#44; BRAF inhibitors and MEK inhibitors have been authorized for the treatment of metastatic melanoma&#46; These are efficacious in cases with mutations in <span class="elsevierStyleItalic">NRAS</span>&#46; Mutations in <span class="elsevierStyleItalic">BRAF</span> are common in small congenital melanocytic nevi and in acquired nevi&#44; in which exposure to sunlight plays an important role in malignant transformation&#46; Furthermore&#44; mutations in <span class="elsevierStyleItalic">NRAS</span> have been found in 70&#37;-75&#37; of cases of GCMN and in the nerve tissue of patients who present with CNS involvement&#46; This gene participates in the intracellular NRAS-BRAF-MEK-pERK-MAPK cascade&#44; which&#44; when activated&#44; stimulates the growth of melanocytes&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">15</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">A recent article made reference to the compassionate use of a MEK inhibitor in a 13-year-old child with CMNS who died as a result of disease progression&#46; The autopsy revealed diminished expression of pERK in melanocytes&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">11</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">MEK inhibitors could potentially be used in selected pediatric patients with GCMN and a mutation in codon 61 in <span class="elsevierStyleItalic">NRAS</span> with the objective of curbing abnormal proliferation of melanocytes&#46; High-quality studies are necessary to demonstrate the safety and efficacy of these drugs for the use referred to above&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">New research lines and more in-depth knowledge of embryological aspects and the pathophysiology of this disease will pave the way for new therapeutic applications&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Ethical Disclosures</span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Protection of humans and animals</span><p id="par0115" class="elsevierStylePara elsevierViewall">The authors declare that no tests were carried out in humans or animals for the purposes of this study&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Confidentiality of data</span><p id="par0120" class="elsevierStylePara elsevierViewall">The authors declare that they have followed their institutional protocols on publication of patient data&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Right to privacy and informed consent</span><p id="par0125" class="elsevierStylePara elsevierViewall">The authors declare that no private patient data appear in this article&#46;</p></span></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Conflicts of Interest</span><p id="par0130" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflicts of interest&#46;</p></span></span>"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Congenital melanocytic nevus syndrome &#40;CMNS&#41; is the result of an abnormal proliferation of melanocytes in the skin and central nervous system caused by progenitor-cell mutations during embryonic development&#46; Mutations in the <span class="elsevierStyleItalic">NRAS</span> gene have been detected in many of these cells&#46; We present 5 cases of giant congenital melanocytic nevus&#44; 3 of them associated with CMNS&#59; <span class="elsevierStyleItalic">NRAS</span> gene mutation was studied in these 3 patients&#46; Until a few years ago&#44; surgery was the treatment of choice&#44; but the results have proved unsatisfactory because aggressive interventions do not improve cosmetic appearance and only minimally reduce the risk of malignant change&#46; In 2013&#44; trametinib was approved for use in advanced melanoma associated with <span class="elsevierStyleItalic">NRAS</span> mutations&#46; This drug&#44; which acts on the intracellular RAS&#47;RAF&#47;MEK&#47;pERK&#47;MAPK cascade&#44; could be useful in pediatric patients with CMNS&#46; A better understanding of this disease will facilitate the development of new strategies&#46;</p></span>"
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          "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">A&#46; Sagittal magnetic resonance image of the brain&#58; hyperintense T1 image at the junction of the medulla oblongata and the pons&#46; B&#46; Coronal magnetic resonance image of the brain&#58; hyperintense T1 images at the level of the thalamus and temporal lobes&#46;</p>"
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          "leyenda" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Abbreviations&#58; CSF&#44; cerebrospinal fluid&#59; MRI&#44; magnetic resonance imaging&#46;</p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Case&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Sex&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Location&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Satellitosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Neurologic Symptoms&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Additional Tests&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">NRAS</span> Mutation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Treatment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Progress and Follow-up&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">M</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Right leg and head&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">MRI normal&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Not performed&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">None&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Alive at 12<span class="elsevierStyleHsp" style=""></span>y and 7<span class="elsevierStyleHsp" style=""></span>mo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="9" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">M&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Trunk and proximal upper legs&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#62; <span class="elsevierStyleHsp" style=""></span>20&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">MRI of the brain at 2<span class="elsevierStyleHsp" style=""></span>mo&#58; melanosis in temporal lobes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Q61K<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Surgery for resection starting at 8<span class="elsevierStyleHsp" style=""></span>mo&#46;<br>Laser treatment&#46;<br>Antiseizure treatment starting at 2<span class="elsevierStyleHsp" style=""></span>mo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Alive at 9<span class="elsevierStyleHsp" style=""></span>y and 9<span class="elsevierStyleHsp" style=""></span>mo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="9" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="4" align="left" valign="top">3</td><td class="td" title="table-entry  " rowspan="4" align="left" valign="top">M</td><td class="td" title="table-entry  " rowspan="4" align="left" valign="top">Trunk and proximal upper legs</td><td class="td" title="table-entry  " rowspan="4" align="left" valign="top">&#62; <span class="elsevierStyleHsp" style=""></span>20</td><td class="td" title="table-entry  " rowspan="4" align="left" valign="top">Yes</td><td class="td" title="table-entry  " align="left" valign="top">Brain ultrasound at birth&#58; Dandy-Walker variant suspected&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " rowspan="4" align="left" valign="top">Q61R<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a></td><td class="td" title="table-entry  " align="left" valign="top">Insertion of shunt&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " rowspan="4" align="left" valign="top">Dead at 26<span class="elsevierStyleHsp" style=""></span>mo of life</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Brain MRI and CSF at 15 days of life&#58; data indicating melanosis&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Antiseizure treatment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Ultrasound of chest and abdomenat 2<span class="elsevierStyleHsp" style=""></span>y&#58; ascites and pleural effusion&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Paracentesis and thoracocentesis at 2<span class="elsevierStyleHsp" style=""></span>y because of abdominal melanosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Antitumor treatment with sorafenib and temozolomide&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="9" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">M&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Trunk and face&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#60;<span class="elsevierStyleHsp" style=""></span>10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">MRI normal&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Not performed&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Surgery starting at 8<span class="elsevierStyleHsp" style=""></span>mo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Alive at 3<span class="elsevierStyleHsp" style=""></span>y and 4<span class="elsevierStyleHsp" style=""></span>mo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="9" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="2" align="left" valign="top">5</td><td class="td" title="table-entry  " rowspan="2" align="left" valign="top">M</td><td class="td" title="table-entry  " rowspan="2" align="left" valign="top">Trunk</td><td class="td" title="table-entry  " rowspan="2" align="left" valign="top">&#62; <span class="elsevierStyleHsp" style=""></span>20</td><td class="td" title="table-entry  " rowspan="2" align="left" valign="top">Yes</td><td class="td" title="table-entry  " align="left" valign="top">Ultrasound of brain at 1 mo of life&#58; bilateral ventriculomegaly&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " rowspan="2" align="left" valign="top">Q61R<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a></td><td class="td" title="table-entry  " rowspan="2" align="left" valign="top">Evaluation pending</td><td class="td" title="table-entry  " rowspan="2" align="left" valign="top">Alive at 22<span class="elsevierStyleHsp" style=""></span>mo</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Brain MRI at 2<span class="elsevierStyleHsp" style=""></span>mo&#58; melanosis in brain stem and thalamus&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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          "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Five Cases of Giant Congenital Melanocytic Nevus&#44; 3 of Which Occurred With Neurocutaneous Melanosis<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a></p>"
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                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
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Article information

ISSN: 15782190
Original language: English

DOI:10.1016/j.adengl.2017.08.018

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Year/Month	Html	Pdf	Total

2024 November	17	8	25
2024 October	144	34	178
2024 September	148	19	167
2024 August	175	78	253
2024 July	157	37	194
2024 June	187	41	228
2024 May	152	39	191
2024 April	132	30	162
2024 March	154	36	190
2024 February	163	36	199
2024 January	135	34	169
2023 December	180	19	199
2023 November	229	37	266
2023 October	259	53	312
2023 September	247	33	280
2023 August	253	13	266
2023 July	293	30	323
2023 June	210	31	241
2023 May	267	23	290
2023 April	197	13	210
2023 March	211	25	236
2023 February	210	28	238
2023 January	221	32	253
2022 December	161	50	211
2022 November	113	33	146
2022 October	99	38	137
2022 September	130	49	179
2022 August	59	51	110
2022 July	87	48	135
2022 June	111	27	138
2022 May	176	51	227
2022 April	196	40	236
2022 March	186	52	238
2022 February	213	28	241
2022 January	250	38	288
2021 December	155	67	222
2021 November	163	57	220
2021 October	162	56	218
2021 September	159	55	214
2021 August	224	53	277
2021 July	161	49	210
2021 June	171	38	209
2021 May	124	69	193
2021 April	332	97	429
2021 March	171	52	223
2021 February	134	38	172
2021 January	93	38	131
2020 December	103	31	134
2020 November	68	27	95
2020 October	68	21	89
2020 September	84	18	102
2020 August	54	29	83
2020 July	59	25	84
2020 June	34	34	68
2020 May	49	24	73
2020 April	57	36	93
2020 March	31	22	53
2020 February	3	0	3
2020 January	4	0	4
2019 December	8	0	8
2019 November	4	0	4
2019 September	4	0	4
2019 August	4	0	4
2019 July	8	0	8
2019 June	4	0	4
2019 May	7	0	7
2019 April	2	0	2
2019 March	2	0	2
2019 February	4	0	4
2018 December	2	0	2
2018 November	3	0	3
2018 October	3	0	3
2018 September	2	0	2
2018 February	86	11	97
2018 January	87	17	104
2017 December	101	19	120
2017 November	113	54	167
2017 October	11	19	30
2017 September	3	10	13

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