Case and Research Letter
A case of Birt-Hogg-Dubé syndrome presenting with a single pedunculated fibrofolliculoma and a novel FLCN gene mutation
Un caso de síndrome de Birt-Hogg-Dubé presentando con un único fibrofoliculoma pediculado y una novedosa mutación en el gen FLCN
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Awareness among psoriasis patients" "tienePdf" => "en" "tieneTextoCompleto" => "en" "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "539" "paginaFinal" => "541" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Importancia de las sesiones educativas sobre comorbilidades cardiometabólicas. Conciencia entre los pacientes con psoriasis" ] ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "F. Mota, M. Selores, T. Torres" "autores" => array:3 [ 0 => array:2 [ "nombre" => "F." "apellidos" => "Mota" ] 1 => array:2 [ "nombre" => "M." "apellidos" => "Selores" ] 2 => array:2 [ "nombre" => "T." 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César, T. Baudrier, A. Mota, F. Azevedo" "autores" => array:4 [ 0 => array:4 [ "nombre" => "A." "apellidos" => "César" "email" => array:1 [ 0 => "arturjfc@gmail.com" ] "referencia" => array:3 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] 2 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "T." "apellidos" => "Baudrier" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 2 => array:3 [ "nombre" => "A." "apellidos" => "Mota" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 3 => array:3 [ "nombre" => "F." "apellidos" => "Azevedo" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Department of Dermatology and Venereology, Centro Hospitalar São João EPE, Porto, Portugal" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Faculty of Medicine, University of Porto, Porto, Portugal" "etiqueta" => "b" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Un caso de síndrome de Birt-Hogg-Dubé presentando con un único fibrofoliculoma pediculado y una novedosa mutación en el gen FLCN" ] ] "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" => 2102 "Ancho" => 1562 "Tamanyo" => 687045 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">(A) Histopathology of the papule located on the columella. Hematoxylin and eosin, original magnification 20×. (B) A central hair follicle (green arrow) with anastomosing bands of follicular epithelium extending from the central hair follicle into the adjacent stroma (black arrows), compatible with a fibrofolliculoma. Hematoxylin and eosin, original magnification 100×.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">In 1997, Birt, Hogg, and Dubé described multiple firm papules on the scalp, forehead, face, and neck in 15 persons belonging to a family of 70 individuals spanning 3 generations.<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">1</span></a> The skin lesions were classified as 3 benign variants of hair follicle hamartomas: fibrofolliculomas, trichodiscomas, and acrochordons. This triad was later designated as the Birt-Hogg-Dubé syndrome (BHDS) (Online Mendelian Inheritance in Man catalog number, #135150).</p><p id="par0010" class="elsevierStylePara elsevierViewall">A number of cases of BHDS have been identified since the original description was published, and significant associations have been reported, particularly with multiple lung cysts<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">2,3</span></a> and renal cancer.<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">2–4</span></a> A study in 2002 found that patients with BHDS have a 9.3-fold risk of developing renal tumors and a 32.3-fold risk of spontaneous pneumothorax.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">2</span></a></p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Case description</span><p id="par0015" class="elsevierStylePara elsevierViewall">A 28-year-old man presented to our department with a 1-year history of skin lesions on the nose. The patient's past medical history was unremarkable, except for 2 spontaneous pneumothoraces at the age of 19 and 23 years. The patient also mentioned that his mother underwent right nephrectomy for a renal tumor at the age of 38 years.</p><p id="par0020" class="elsevierStylePara elsevierViewall">Physical examination revealed 2 wine-colored, pedunculated papules, 1 measuring 3<span class="elsevierStyleHsp" style=""></span>mm on the right side of the columella, the other measuring 2<span class="elsevierStyleHsp" style=""></span>mm on the left alar rim (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>A and B). No other significant alterations were observed on examination.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0025" class="elsevierStylePara elsevierViewall">Both lesions were excised. Histological examination of the papule from the left alar rim was compatible with a vascular hamartoma. The lesion from the columella showed features compatible with a fibrofolliculoma (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>A and B).</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0030" class="elsevierStylePara elsevierViewall">Sequencing of the coding exons (exons 4–14) and the intron-exon boundaries of the <span class="elsevierStyleItalic">FLCN</span> gene revealed a heterozygous <span class="elsevierStyleItalic">FLCN</span>:c.50G>C missense variant (p.Arg17Pro) in exon 4, both in the patient and in his mother. Numerous small cysts were observed in the basal regions of both lungs on computed tomography (CT) of the chest (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>C).</p><p id="par0035" class="elsevierStylePara elsevierViewall">Applying the diagnostic criteria of the European BHD Consortium (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>),<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">5</span></a> we made a diagnosis of BHDS based on 1 major criterion (an <span class="elsevierStyleItalic">FLCN</span> germline mutation) and 2 minor criteria (multiple lung cysts and a first-degree relative with BHDS).</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0040" class="elsevierStylePara elsevierViewall">Currently, the patient remains under regular follow-up because of the increased risk of developing renal cancer. Additionally, the patient's first-degree relatives have been referred for gene analysis.</p><p id="par0045" class="elsevierStylePara elsevierViewall">BHDS is an inherited autosomal dominant disorder caused by germline mutations of the folliculin (<span class="elsevierStyleItalic">FLCN</span>) gene located on chromosome 17(17p11.2).<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">5</span></a> BHDS-associated renal tumors display inactivation of the wild-type <span class="elsevierStyleItalic">FLCN</span> allele (for example, loss of heterozygosity, mutation, methylation), confirming that <span class="elsevierStyleItalic">FLCN</span> is a tumor suppressor gene that fits the classic 2-hit model.<a class="elsevierStyleCrossRefs" href="#bib0080"><span class="elsevierStyleSup">6,7</span></a> This gene encodes folliculin, a 579 amino acid protein expressed in a variety of tissues including stromal cells, the distal nephron, and type I pneumocytes, as well in the skin and skin appendages.<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">8</span></a> This widespread expression of folliculin may explain the multisystem involvement of BHDS. Despite some recent research implicating possible interference with the energy-sensing mammalian target of rapamycin (mTOR) pathway in BHDS, the precise role of folliculin remains unknown. Most of the reported pathogenic <span class="elsevierStyleItalic">FLCN</span> mutations are of frameshift or nonsense types, which result in protein truncation.<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">9</span></a> In contrast, the mutation identified in our patient, the heterozygous <span class="elsevierStyleItalic">FLCN</span>:c.50G>C, is a missense variant in exon 4 and has not previously been described in any patient or control.</p><p id="par0050" class="elsevierStylePara elsevierViewall">In addition to identification of this novel mutation, our case is of particular interest because of the pedunculated clinical appearance of the fibrofolliculoma. Most cases of fibrofolliculoma and trichodiscoma present as multiple, dome-shaped, skin-colored or whitish papules on the face and neck. As observed in the majority of patients with BHDS, the skin lesions in our patient arose after the age of 20 years; however, it is estimated that 25% of all <span class="elsevierStyleItalic">FLCN</span>-mutation carriers older than 20 years will never develop skin lesions.<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">10</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">As with the skin lesions, the involvement of internal organs in BHDS tends to develop after the second decade of life. The reported age range of renal cancer is of 25–75 years,<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">5</span></a> and that of spontaneous pneumothoraces is of 22–71 years.<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">3</span></a> Accordingly, the recommended screening of asymptomatic <span class="elsevierStyleItalic">FLCN</span>-mutation carriers should start at 20 years of age. There is no clear indication for routine CT-scanning of the lungs, and preventive measures are aimed largely at the early recognition and treatment of renal cancer. Annual renal MRI scans appear to be the best available screening method, with a high sensitivity and an absence of ionizing radiation. Whenever a pathogenic mutation is detected, gene analysis aimed at identifying and counseling asymptomatic family members should be offered.<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">5</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">Our case underlines the importance of considering BHDS in the differential diagnosis of facial papules, even if inconspicuous or of atypical morphology. This is especially important if a positive personal or family history of pneumothorax or renal tumors is discovered. Finally, an early diagnosis of BHDS should be followed up with appropriate screening for renal cancer, not only for affected patients but also for their relatives who carry the <span class="elsevierStyleItalic">FLCN</span> mutation, improving their outcomes.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Ethical disclosures</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Protection of human and animal subjects</span><p id="par0065" class="elsevierStylePara elsevierViewall">The authors declare that the procedures followed were in accordance with the regulations of the relevant clinical research ethics committee and with those of the Code of Ethics of the World Medical Association (Declaration of Helsinki).</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Confidentiality of data</span><p id="par0070" class="elsevierStylePara elsevierViewall">The authors declare that no patient data appear in this article.</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Right to privacy and informed consent</span><p id="par0075" class="elsevierStylePara elsevierViewall">The authors declare that no patient data appears in this article.</p></span></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Conflict of interest</span><p id="par0080" class="elsevierStylePara elsevierViewall">The authors declare no conflict of interest.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:5 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Case description" ] 1 => array:3 [ "identificador" => "sec0010" "titulo" => "Ethical disclosures" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Protection of human and animal subjects" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Confidentiality of data" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Right to privacy and informed consent" ] ] ] 2 => array:2 [ "identificador" => "sec0030" "titulo" => "Conflict of interest" ] 3 => array:2 [ "identificador" => "xack276615" "titulo" => "Acknowledgment" ] 4 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "multimedia" => array:3 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2296 "Ancho" => 1632 "Tamanyo" => 394537 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">(A and B) Pedunculated papules on the columella and left alar rim. (C) Axial CT image demonstrating lung cysts in the basal regions (arrow).</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" => 2102 "Ancho" => 1562 "Tamanyo" => 687045 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">(A) Histopathology of the papule located on the columella. Hematoxylin and eosin, original magnification 20×. (B) A central hair follicle (green arrow) with anastomosing bands of follicular epithelium extending from the central hair follicle into the adjacent stroma (black arrows), compatible with a fibrofolliculoma. Hematoxylin and eosin, original magnification 100×.</p>" ] ] 2 => 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 [ "leyenda" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Diagnosis of Birt-Hogg-Dubé syndrome requires the presence of 1 major or 2 minor criteria.</p>" "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" title="table-entry " rowspan="2" align="left" valign="middle">Major</td><td class="td" title="table-entry " align="left" valign="top">At least 5 fibrofolliculomas or trichodiscomas with onset in adult life and with at least 1 confirmed histopathologically \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">A pathogenic FLCN germline mutation \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="middle"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="3" align="left" valign="middle">Minor</td><td class="td" title="table-entry " align="left" valign="top">Multiple lung cysts: bilateral basal cysts with no other apparent cause, with or without spontaneous pneumothorax \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">Multifocal or bilateral renal cancer of early onset (>50 years), or renal cancer of mixed chromophobe and oncoytic histology \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">A first-degree relative with Birt-Hogg-Dubé syndrome \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1386733.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Diagnostic criteria of the European BHD Consortium.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:10 [ 0 => array:3 [ "identificador" => "bib0055" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Hereditary multiple fibrofolliculomas with trichodiscomas and acrochordons" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "A.R. Birt" 1 => "G.R. Hogg" 2 => "W.J. Dube" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Arch Dermatol" "fecha" => "1977" "volumen" => "113" "paginaInicial" => "1674" "paginaFinal" => "1677" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/596896" "web" => "Medline" ] ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0060" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Risk of renal and colonic neoplasms and spontaneous pneumothorax in the Birt-Hogg-Dubé syndrome" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "B. Zbar" 1 => "W.G. Alvord" 2 => "G. Glenn" 3 => "M. Turner" 4 => "C.P. Pavlovich" 5 => "L. 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Schmidt" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1097/01.ju.0000154629.45832.30" "Revista" => array:6 [ "tituloSerie" => "J Urol" "fecha" => "2005" "volumen" => "173" "paginaInicial" => "1482" "paginaFinal" => "1486" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15821464" "web" => "Medline" ] ] ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib0075" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Birt-Hogg-Dubé syndrome: diagnosis and management" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "F.H. Menko" 1 => "M.A. van Steensel" 2 => "S. Giraud" 3 => "L. Friis-Hansen" 4 => "S. Richard" 5 => "S. Ungari" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/S1470-2045(09)70188-3" "Revista" => array:6 [ "tituloSerie" => "Lancet Oncol" "fecha" => "2009" "volumen" => "10" "paginaInicial" => "1199" "paginaFinal" => "1206" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19959076" "web" => "Medline" ] ] ] ] ] ] ] ] 5 => array:3 [ "identificador" => "bib0080" "etiqueta" => "6" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The Birt-Hogg-Dubé cancer predisposition syndrome: current challenges" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "P.R. Benusiglio" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.5582/irdr.2015.01017" "Revista" => array:6 [ "tituloSerie" => "Intractable Rare Dis Res" "fecha" => "2015" "volumen" => "4" "paginaInicial" => "162" "paginaFinal" => "163" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26361570" "web" => "Medline" ] ] ] ] ] ] ] ] 6 => array:3 [ "identificador" => "bib0085" "etiqueta" => "7" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Molecular genetics and clinical features of Birt-Hogg-Dubé syndrome" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "L.S. Schmidt" 1 => "W.M. Linehan" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/nrurol.2015.206" "Revista" => array:6 [ "tituloSerie" => "Nat Rev Urol" "fecha" => "2015" "volumen" => "12" "paginaInicial" => "558" "paginaFinal" => "569" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26334087" "web" => "Medline" ] ] ] ] ] ] ] ] 7 => array:3 [ "identificador" => "bib0090" "etiqueta" => "8" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Mutations in a novel gene lead to kidney tumors, lung wall defects, and benign tumors of the hair follicle in patients with the Birt-Hogg-Dubé syndrome" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "M.L. Nickerson" 1 => "M.B. Warren" 2 => "J.R. Toro" 3 => "V. Matrosova" 4 => "G. Glenn" 5 => "M.L. Turner" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Cancer Cell" "fecha" => "2002" "volumen" => "2" "paginaInicial" => "157" "paginaFinal" => "164" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12204536" "web" => "Medline" ] ] ] ] ] ] ] ] 8 => array:3 [ "identificador" => "bib0095" "etiqueta" => "9" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Kidney-targeted Birt-Hogg-Dube gene inactivation in a mouse model: Erk1/2 and Akt-mTOR activation, cell hyperproliferation, and polycystic kidneys" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "M. Baba" 1 => "M. Furihata" 2 => "S.B. Hong" 3 => "L. Tessarollo" 4 => "D.C. Haines" 5 => "E. Southon" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1093/jnci/djm288" "Revista" => array:6 [ "tituloSerie" => "J Natl Cancer Inst" "fecha" => "2008" "volumen" => "100" "paginaInicial" => "140" "paginaFinal" => "154" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18182616" "web" => "Medline" ] ] ] ] ] ] ] ] 9 => array:3 [ "identificador" => "bib0100" "etiqueta" => "10" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The folliculin mutation database: an online database of mutations associated with Birt-Hogg-Dubé syndrome" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "M.H. Wei" 1 => "P.W. Blake" 2 => "J. Shevchenko" 3 => "J.R. Toro" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/humu.21075" "Revista" => array:6 [ "tituloSerie" => "Hum Mutat" "fecha" => "2009" "volumen" => "30" "paginaInicial" => "E880" "paginaFinal" => "E890" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19562744" "web" => "Medline" ] ] ] ] ] ] ] ] ] ] ] ] "agradecimientos" => array:1 [ 0 => array:4 [ "identificador" => "xack276615" "titulo" => "Acknowledgment" "texto" => "<p id="par0085" class="elsevierStylePara elsevierViewall">We would like to thank Dr. J. Pardal, MD from the Department of Pathological Anatomy, Centro Hospitalar São João EPE in Oporto, Portugal, for providing the histologic images.</p>" "vista" => "all" ] ] ] "idiomaDefecto" => "en" "url" => "/15782190/0000010700000006/v2_201704050141/S1578219016301299/v2_201704050141/en/main.assets" "Apartado" => array:4 [ "identificador" => "6157" "tipo" => "SECCION" "en" => array:2 [ "titulo" => "Case and Research Letters" "idiomaDefecto" => true ] "idiomaDefecto" => "en" ] "PDF" => "https://static.elsevier.es/multimedia/15782190/0000010700000006/v2_201704050141/S1578219016301299/v2_201704050141/en/main.pdf?idApp=UINPBA000044&text.app=https://actasdermo.org/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1578219016301299?idApp=UINPBA000044" ]
| año/Mes | Html | Total | |
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| 2017 Junio | 19 | 14 | 33 |
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