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both of whom had recurrent episodes of epistaxis&#46; Later&#44; in 1896&#44; Rendu<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">5</span></a> was the first to describe the syndrome when he identified a man with clinical manifestations of facial telangiectases on the nose&#44; tongue&#44; and lips&#46; This man also had a history of anemia and episodes of recurrent epistaxis from childhood onwards&#46; His father reported episodes of melena&#46; Subsequently&#44; Sir William Osler<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">6</span></a> was the first to report a family association in the syndrome when he described 3 families with telangiectases and hereditary bleeding&#46; In 1907&#44; Weber<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">7</span></a> described the hereditary relationship between telangiectases and bleeding&#46; In 1909&#44; Hanes<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">8</span></a> proposed the term HHT&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Epidemiology</span><p id="par0015" class="elsevierStylePara elsevierViewall">HHT has a broad geographic distribution&#44; 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The main lesions are telangiectases&#44; which arise from arteriovenous shunting between dilated arterioles and venules and which present clinically as punctiform or linear arborizing erythematous macules of 1-2<span class="elsevierStyleHsp" style=""></span>cm that disappear on applying light pressure&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">11</span></a> The pathophysiological mechanism by which telangiectases occur has not been fully elucidated&#46; The Braveman theory proposes as an initial mechanism a focal dilatation of postcapillary venules&#44; which continue to enlarge and eventually connect with dilated arterioles through capillaries that subsequently disappear to form a direct arteriovenous shunt&#46; During this process&#44; a predominantly mononuclear perivascular infiltrate of is present&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">12</span></a> By definition&#44; telangiectases present in mucocutaneous tissues&#44; such as the skin or gastrointestinal mucosa&#46; When these abnormal vascular shunts occur in internal organs&#44; such as the liver&#44; lung&#44; or brain&#44; they are known as arteriovenous malformations &#40;AVMs&#41;&#46; The AVMs are responsible for the systemic manifestations of the disease&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">13</span></a> The fragility of the vascular walls and turbulent blood flow predispose these vessels to the characteristic bleeding that forms part of the syndrome&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">14</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">It has been observed that vascular endothelial growth factor &#40;VEGF&#41;&#44; which is implicated in vasculogenesis and angiogenesis&#44; is elevated in patients with HHT&#44; and so treatments such as bevacizumab that target this factor have been developed and shown to be effective&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">15</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">On the molecular level&#44; more than 600 mutations causative of HHT have been identified&#46; Of these&#44; the most studied to date are mutations in the endoglin &#40;<span class="elsevierStyleItalic">ENG</span>&#41; gene&#44; located on chromosome 9&#44; characteristic of HHT subtype 1&#44; and in the activin-like kinase &#40;<span class="elsevierStyleItalic">ALK1</span>&#41; gene&#44; on chromosome 12&#44; characteristic of subtype 2&#46;<a class="elsevierStyleCrossRefs" href="#bib0215"><span class="elsevierStyleSup">11&#44;16</span></a> Both the corresponding proteins &#40;ENG and ALK1&#41; are transmembrane proteins expressed in endothelial cells with the ability to bind to transforming growth factor &#40;TGF&#41;&#46; These molecules therefore play an important role in angiogenesis and vascular maturation&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">17</span></a> There have also been reports of mutations in the <span class="elsevierStyleItalic">MADH4</span> and <span class="elsevierStyleItalic">SMAD4</span> genes&#44; which predispose the individual to HHT accompanied by juvenile polyposis &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">11</span></a> Another type of mutation is one that affects bone morphogenic protein receptor<span class="elsevierStyleSmallCaps">II</span>&#44; leading to the HHT phenotype accompanied by primary pulmonary hypertension&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">18</span></a></p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Clinical Manifestations</span><p id="par0040" class="elsevierStylePara elsevierViewall">The clinical manifestations of HHT are varied&#44; and present mainly on the nose&#44; skin&#44; and lungs&#44; with possible involvement of the central nervous system and gastrointestinal system&#46; They are characterized by the classic triad of epistaxis&#44; telangiectases&#44; and a family history of HHT&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">19</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">Most patients only experience manifestations of epistaxis&#44; mucocutaneous telangiectases&#44; and anemia due to iron deficiency&#46; Symptoms are not normally present at birth but develop as the individual gets older&#46; It is estimated that 70&#37; of affected individuals present manifestations by 16 years and 90&#37; by 40 years&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">9</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Nose</span><p id="par0050" class="elsevierStylePara elsevierViewall">Epistaxis is usually the primary clinical manifestation&#44; and in many cases&#44; the first&#46; Spontaneous bleeding occurs due to telangiectases that are present in the nasal mucosa&#46; These events can be triggered my many factors&#44; such as changes in temperature&#44; humidity&#44; or posture&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">The frequency of nose bleeds can be very high&#44; leading to iron-deficiency anemia&#46; However&#44; on other occasions&#44; episodes may occur only sporadically or never&#44; and so diagnostic suspicion is less likely&#46; Furthermore&#44; epistaxis is considered a very common symptom in the general population&#44; and so it is not a very sensitive indicator&#46; Episodes of night bleeding are more specific for diagnosis of HHT&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">20</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">Generally&#44; episodes of epistaxis start in childhood&#44; at around 10 years of age&#44; and usually become more severe as the individual gets older&#46; On average&#44; patients with HHT present around 18 episodes of epistaxis a month&#46; Rebeiz et al&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">21</span></a> developed a classification for severity of epistaxis that is still in use today &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0065" class="elsevierStylePara elsevierViewall">Management and prevention of epistaxis can vary from simple interventions&#44; such as nasal saline spray&#44; to more aggressive measures&#44; such as cauterization&#44; laser ablation&#44; surgery&#44; estrogen supplementation&#44; and embolectomy&#44; depending on the severity of the episodes&#46;<a class="elsevierStyleCrossRefs" href="#bib0270"><span class="elsevierStyleSup">22&#44;23</span></a></p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Skin</span><p id="par0070" class="elsevierStylePara elsevierViewall">The main skin manifestations are telangiectases&#44; which occur in up to 75&#37; of patients&#44; with onset typically in childhood and becoming more numerous with increasing age&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">Skin lesions usually appear after the first episode of epistaxis&#46; These lesions usually become apparent when patients are in their 30s and 40s&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">11</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">They present most frequently on the face&#44; lips&#44; nose&#44; tongue&#44; outer ears&#44; hands &#40;especially the fingertips&#41;&#44; trunk&#44; and feet &#40;<a class="elsevierStyleCrossRefs" href="#fig0005">Figs&#46; 1-3</a>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">19</span></a></p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0085" class="elsevierStylePara elsevierViewall">In the early stages&#44; the lesions are small&#44; pulsatile red-violaceous macules 1-3 in diameter&#44; which in the chronic phase may coalesce and increase in diameter to form arborizing lesions&#46;<a class="elsevierStyleCrossRefs" href="#bib0255"><span class="elsevierStyleSup">19&#44;24</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">In most cases&#44; cutaneous telangiectases are asymptomatic and treatment is a question of esthetics&#46; However&#44; in some cases&#44; they can be painful&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">The HHT Foundation International drew up a consensus in which they arrived at the conclusion that the presence of at least 3 typical telangiectases are required for diagnosis of HHT&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">17</span></a></p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Lung</span><p id="par0100" class="elsevierStylePara elsevierViewall">The most frequent pulmonary lesions are AVMs&#44; which are present in up to 15&#37; to 30&#37; of patients with HHT&#46; These AVMs directly connect pulmonary and systemic circulation&#44; causing a right-to-left shunt that is manifest clinically as cyanosis&#44; intolerance of cold&#44; migraine&#44; and polycythemia&#46; The most serious complications include cerebrovascular accidents&#44; massive hemoptysis&#44; and spontaneous hemothorax&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">10</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">In general&#44; these lesions occur in the lung bases&#44; and bleed more readily during pregnancy&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">25</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">Given that pulmonary AVMs do not lead to symptoms in early stages and that complications may be very serious&#44; all patients over 16 years of age with diagnosis of HHT should undergo transthoracic ultrasound&#46; Lesions can be treated by transcatheter embolization or&#44; in the most severe cases&#44; lobectomy&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">10</span></a></p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Gastrointestinal Effects</span><p id="par0115" class="elsevierStylePara elsevierViewall">Gastrointestinal effects arise in a third of patients with HHT&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">The most frequent lesions are telangiectases in the stomach and duodenum&#44; followed by AVMs&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">In the most usual clinical presentation&#44; the patient will have iron-deficiency anemia or episodes of acute gastrointestinal bleeding&#59; these manifestations are more common in individuals aged over 40 years&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">10</span></a> Gastrointestinal monitoring usually starts at the age of 35 years and involves only annual hemoglobin measurement&#59; endoscopy is reserved for episodes of bleeding&#46; Endoscopic ultrasound-guided ablation&#44; embolization&#44; or surgery are the treatments for gastrointestinal manifestations&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Brain</span><p id="par0130" class="elsevierStylePara elsevierViewall">Brain lesions present in 23&#37; of patients&#46; These lesions can be multiple AVMs&#44; telangiectases&#44; and arteriovenous fistulas&#46; When present&#44; they can manifest as episodes of migraine&#44; convulsions&#44; ischemia&#44; or bleeding&#46; The annual rate of AVM rupture is 2&#37; to 4&#37; on average&#46; It is a matter of debate whether screening for early detection is appropriate&#44; but if performed&#44; magnetic resonance imaging is the technique of choice&#44; with a sensitivity of 80&#37; to 95&#37;&#46; Treatment can be by embolization or surgical resection&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Liver</span><p id="par0135" class="elsevierStylePara elsevierViewall">Hepatic involvement in HHT is present in 32&#37; to 78&#37; of patients and symptoms are present in 8&#37; of them&#46; Clinical presentation can include angina and heart failure due to shunting between the hepatic artery and vein&#44; which increases the cardiac overload&#46; Portal hypertension and hepatic encephalopathy may also arise&#46; These lesions can be monitored by Doppler ultrasound&#44; magnetic resonance imagining&#44; and computed tomography&#46; Supportive therapy is administered&#44; with the aim of reducing the complications of portal hypertension and heart failure&#46; Sometimes&#44; transplantation may be performed&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">14</span></a></p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Diagnosis</span><p id="par0140" class="elsevierStylePara elsevierViewall">Timely diagnosis of HHT is of utmost importance to prevent the complications of the disease and to provide genetic counseling for family members&#46; In cases in which the classic 3 criteria of epistaxis&#44; telangiectases&#44; and a family history are present&#44; diagnosis is relatively simple&#59; however&#44; not all patients present with this triad&#46; In 2000&#44; the Cura&#231;ao Diagnostic Criteria for HHT were published&#59; 3 or more criteria are required for definitive diagnosis&#44; 2 positive criteria correspond to a probable diagnosis&#44; and no positive criteria are equivalent to unlikely diagnosis &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0210"><span class="elsevierStyleSup">10&#44;20</span></a></p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0145" class="elsevierStylePara elsevierViewall">There are also genetic tests for diagnosis of HHT&#46; The main use for these is for study of family members of affected patients&#44; particularly children and young adults&#44; who do not meet the clinical diagnostic criteria&#46; Among these tests are those for DNA sequencing to detect mutations in the <span class="elsevierStyleItalic">ENG</span> and <span class="elsevierStyleItalic">ACVRL1</span> genes&#44; which account for the majority of mutations associated with HHT&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">26</span></a> There are also tests to detect mutations in the <span class="elsevierStyleItalic">SMAD4</span> gene&#44; but these are less common&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">27</span></a></p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Capillary Microscopy</span><p id="par0150" class="elsevierStylePara elsevierViewall">Dermoscopy has become a useful tool for the diagnosis of HHT through capillary microscopy&#46; Capillary microscopy findings described to date in HHT suggest that the technique is useful because it can detect microscopic telangiectases&#46; In a study conducted by Mager and Westermann&#44;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">17</span></a> using capillary microscopy of the nail fold&#44; the authors found that 87&#37; of patients with HHT had vascular abnormalities&#44; with giant loops being the most common finding&#46;</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Treatment</span><p id="par0155" class="elsevierStylePara elsevierViewall">Given that HHT syndrome has a multisystemic impact&#44; multidisciplinary treatment is also required&#46; Most studies of HHT are conducted by ear-nose-throat specialists because epistaxis is the main manifestation in these patients&#59; however&#44; although telangiectases are just as evident&#44; few studies have been conducted of their treatment&#46;</p><p id="par0160" class="elsevierStylePara elsevierViewall">Although cutaneous telangiectases are only a cosmetic problem&#44; their presence can have a negative impact on the quality of life of the patients&#44; and so several treatment options have been implemented within dermatology&#44; with varying results&#46; Most articles on the subject are merely case reports&#46;</p><p id="par0165" class="elsevierStylePara elsevierViewall">In recent years&#44; laser treatments have been the most widely used for treatment of cutaneous telangiectases&#46; The most extensively used systems are pulsed dye lasers &#40;595<span class="elsevierStyleHsp" style=""></span>nm&#41;&#44; which are useful for macular telangiectases&#44; and Nd&#58;YAG lasers&#44; which are preferred for lesions with a papular appearance and because of their greater penetration and coagulation power &#40;<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">28</span></a></p><elsevierMultimedia ident="tbl0020"></elsevierMultimedia><p id="par0170" class="elsevierStylePara elsevierViewall">Argon lasers have been used for the treatment of cutaneous telangiectases&#59; however&#44; they have the disadvantage of causing scarring&#46;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">32</span></a></p><p id="par0175" class="elsevierStylePara elsevierViewall">Other studies have reported the use of intense pulsed light&#44; followed by Nd&#58;YAG laser pulses&#44; with acceptable cosmetic outcomes&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">30</span></a></p></span></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Conclusions</span><p id="par0180" class="elsevierStylePara elsevierViewall">Osler-Weber-Rendu syndrome&#44; or HHT&#44; is a rare multisystemic disease with a broad clinical presentation and a substantial risk of complications&#44; and so timely diagnosis and genetic counseling is required&#46; Clinicians do not always have a high awareness of this condition and often do not recognize the disease until the onset of severe life-threatening complications&#46;</p><p id="par0185" class="elsevierStylePara elsevierViewall">Prognosis for survival of patients with HHT is favorable if complications are diagnosed and treated in time&#46;</p><p id="par0190" class="elsevierStylePara elsevierViewall">Laser treatment of cutaneous lesions has shown promise&#44; although more long-term studies are required to more precisely determine their efficacy and to standardize the parameters according to the target site&#46;</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Conflicts of Interest</span><p id="par0195" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflicts of interest&#46;</p></span></span>"
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              "titulo" => "Nose"
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    "fechaRecibido" => "2018-10-05"
    "fechaAceptado" => "2018-11-04"
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        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Osler-Weber-Rendu syndrome&#44; also known as hereditary hemorrhagic telangiectasia&#44; is a rare autosomal dominant disorder with an estimated worldwide prevalence of 1 case per 10&#44;000 population&#46; Its clinical manifestations are the result of arteriovenous malformations characterized by telangiectases that can affect the skin&#44; mucous membranes&#44; and solid organs and cause life-threatening conditions&#44; such as liver disease&#44; systemic emboli&#44; and heart failure&#46; Timely diagnosis is thus essential in order to prevent disease-related complications and offer genetic counseling to families&#46; We review the clinical features of Osler-Weber-Rendu syndrome with a focus on mucocutaneous manifestations and their treatment&#46;</p></span>"
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        "resumen" => "<span id="abst0015" class="elsevierStyleSection elsevierViewall"><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">El s&#237;ndrome de Osler-Weber-Rendu&#44; o s&#237;ndrome hereditario hemorr&#225;gico telangiectasia&#44; es un trastorno raro de herencia autos&#243;mica dominante con una prevalencia estimada de 1&#58;10&#46;000 personas a nivel mundial&#46; Las manifestaciones cl&#237;nicas de este s&#237;ndrome son resultado de malformaciones arteriovenosas y var&#237;an desde telangiectasias en piel y mucosas hasta afecci&#243;n de &#243;rganos s&#243;lidos que ponen en peligro la vida&#44; como alteraciones hep&#225;ticas&#44; &#233;mbolos sist&#233;micos y fallo card&#237;aco&#44; por lo cual el diagn&#243;stico oportuno es de suma importancia para prevenir las complicaciones de la enfermedad y proporcionar apoyo gen&#233;tico a los familiares&#46; En esta revisi&#243;n se analiza el cuadro cl&#237;nico con enfoque principal en las manifestaciones mucocut&#225;neas de la enfermedad y su abordaje terap&#233;utico&#46;</p></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Orizaga-y-Quiroga TL&#44; Villarreal-Mart&#237;nez A&#44; Jaramillo-Moreno G&#44; Ocampo-Candiani J&#46; S&#237;ndrome de Osler-Weber-Rendu y su relaci&#243;n con la dermatolog&#237;a&#46; Actas Dermosifiliogr&#46; 2019&#59;110&#58;527&#8211;532&#46;</p>"
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            "detalle" => "Table "
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            0 => array:2 [
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                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="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">ENG</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Associated with mutations in the endoglin geneMore frequently observed in pulmonary and cerebral AVMs&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">ACVRL1</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Associated with mutations in the <span class="elsevierStyleItalic">ALK-1</span> gene &#40;activin-like kinase receptor&#41;More frequently observed in hepatic AVMs&#44; pulmonary and arterial hypertension&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">SMAD4</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Causes HHT-associated juvenile polyposis&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">Main HHT Mutations&#46;</p>"
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        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
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                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="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Mild&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Few episodes a week without need for transfusion&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Moderate&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1-2 episodes a day&#44; fewer than 10 transfusions&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Severe&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Daily episodes lasting more than 30<span class="elsevierStyleHsp" style=""></span>minutes&#44; more than 10 transfusions&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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                0 => "xTab2114491.png"
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        "descripcion" => array:1 [
          "en" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Rebeiz Classification for Epistaxis Severity&#46;</p>"
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      5 => array:8 [
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        "etiqueta" => "Table 3"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at3"
            "detalle" => "Table "
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        "tabla" => array:1 [
          "tablatextoimagen" => array:1 [
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              "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="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Recurrent and spontaneous epistaxis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Multiple mucocutaneous telangiectases&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Lesions in internal organs &#40;gastrointestinal&#44; pulmonary&#44; cerebral&#44; or hepatic&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">First-degree relative with HHT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Cura&#231;ao Diagnostic Criteria&#46;</p>"
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            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="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Study&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Number of Patients&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Treatment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Treated Areas&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Outcome&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cheung et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">28</span></a> 2015&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Pulsed dye laser at 595<span class="elsevierStyleHsp" style=""></span>nmSpot&#44; 5<span class="elsevierStyleHsp" style=""></span>mmPulse duration&#44; 1&#46;5 msFluence&#44; 8<span class="elsevierStyleHsp" style=""></span>J&#47;cm<span class="elsevierStyleSup">2</span> on cheeks and 9<span class="elsevierStyleHsp" style=""></span>J&#47;cm<span class="elsevierStyleSup">2</span> on the nose&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Face and mucosa&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Resolution of lesions in 5 days&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Halachmi et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">29</span></a> 2013&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Pulsed dye laser &#40;Vbeam Perfecta&#44; Candela&#44; Wayland&#41;Spot&#44; 5-7<span class="elsevierStyleHsp" style=""></span>mmPulse duration&#44; 1&#46;5 msFluence&#44; 9&#46;5 to 11<span class="elsevierStyleHsp" style=""></span>J&#47;cm<span class="elsevierStyleSup">2</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cheek&#44; nose&#44; and lips&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Excellent improvement in all patients &#40;75&#37;-100&#37;&#41;Mean number of sessions to obtain response&#58; 2&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Werner et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">30</span></a> 2008&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Nd&#58;YAGPulse duration&#44; 0&#46;5-90<span class="elsevierStyleHsp" style=""></span>msMaximum fluence&#44; 450<span class="elsevierStyleHsp" style=""></span>J&#47;cm<span class="elsevierStyleSup">2</span>Spot&#44; 3-10<span class="elsevierStyleHsp" style=""></span>mm&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Case 1&#58; cheeks&#44; chin&#44; and foreheadCase 2&#58; fingertipsCase 3&#58; fingers&#44; ears&#44; cheeks&#44; chinCase 4&#58; cheeks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Case 1&#58; 50&#37;-75&#37; response at 8 weeksCase 2&#58; 75&#37;-95&#37; response at 8<span class="elsevierStyleHsp" style=""></span>weeks&#59; adverse effects&#58; white-greyish pigmentationCase 3&#58; 75&#37;-95&#37; improvement in fingers after 2 sessions&#59; 50&#37; improvement in ears&#44; chin&#44; and cheeks with mild atrophy and hypopigmentationCase 4&#58; 90&#37; response after 8 weeks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Fern&#225;ndez-Jorge et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">31</span></a> 2007&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Photoderm-Vasculight system&#44; which combined intense pulsed light &#43; Nd&#58;YAG 1064<span class="elsevierStyleHsp" style=""></span>nm&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cheek&#44; lips&#44; nose&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Complete response in all cases without any relapse during follow-up at 2 years in 2 of the 3 cases&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
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                0 => "xTab2114494.png"
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        "descripcion" => array:1 [
          "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Review of Case Reports of Telangiectases in HHT Treated With Laser Light&#46;</p>"
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    "bibliografia" => array:2 [
      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0015"
          "bibliografiaReferencia" => array:32 [
            0 => array:3 [
              "identificador" => "bib0165"
              "etiqueta" => "1"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "A rare and misdiagnosed bleeding disorder&#58; Hereditary hemorrhagic telangiectasia"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "C&#46; Sabb&#224;"
                          ]
                        ]
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                    ]
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/j.1538-7836.2005.01345.x"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Thromb Haemost"
                        "fecha" => "2005"
                        "volumen" => "3"
                        "paginaInicial" => "2201"
                        "paginaFinal" => "2210"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15892861"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
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            1 => array:3 [
              "identificador" => "bib0170"
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Review
Osler-Weber-Rendu Syndrome in Relation to Dermatology
Síndrome de Osler-Weber-Rendu y su relación con la dermatología
T.L. Orizaga-y-Quiroga, A. Villarreal-Martínez, G. Jaramillo-Moreno, J. Ocampo-Candiani
Autor para correspondencia
jocampo2000@yahoo.com.mx

Corresponding author.
Facultad de Medicina, Departamento de Dermatología, Universidad Autónoma de Nuevo León, Hospital Universitario «Dr. José E. González», Monterrey, Nuevo León, México
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Osler-Weber-Rendu syndrome&#44; also known as hereditary hemorrhagic telangiectasia &#40;HHT&#41;&#44; is a rare autosomal dominant disorder resulting from abnormal communication between veins and arteries&#46; These arteriovenous malformations are manifest as telangiectases that can affect the skin&#44; mucous membranes&#44; and solid organs&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">1</span></a> The presence of skin telangiectases is a cosmetic problem for patients with HHT&#59; however&#44; systemic manifestations such as recurrent epistaxis&#44; liver disease&#44; systemic emboli&#44; and heart failure can be life-threatening&#46; The estimated worldwide prevalence is between 1&#58;5000 and 1&#58;10&#160;000 population&#44; but it is thought to be underdiagnosed&#46;<a class="elsevierStyleCrossRefs" href="#bib0165"><span class="elsevierStyleSup">1&#44;2</span></a> Patients with HHT require a multidisciplinary approach due to the different systemic complications that may be present&#46; Physicians should therefore be familiar with this condition and contribute to timely diagnosis and treatment of the disease&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">History</span><p id="par0010" class="elsevierStylePara elsevierViewall">The first recorded report of HHT was made by Sutton<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">3</span></a> in 1864&#44; when the author described a male patient with recurrent episodes of bleeding and vascular malformations&#46; In 1865&#44; Babington<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">4</span></a> published a case of hereditary epistaxis in a boy and his mother&#44; both of whom had recurrent episodes of epistaxis&#46; Later&#44; in 1896&#44; Rendu<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">5</span></a> was the first to describe the syndrome when he identified a man with clinical manifestations of facial telangiectases on the nose&#44; tongue&#44; and lips&#46; This man also had a history of anemia and episodes of recurrent epistaxis from childhood onwards&#46; His father reported episodes of melena&#46; Subsequently&#44; Sir William Osler<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">6</span></a> was the first to report a family association in the syndrome when he described 3 families with telangiectases and hereditary bleeding&#46; In 1907&#44; Weber<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">7</span></a> described the hereditary relationship between telangiectases and bleeding&#46; In 1909&#44; Hanes<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">8</span></a> proposed the term HHT&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Epidemiology</span><p id="par0015" class="elsevierStylePara elsevierViewall">HHT has a broad geographic distribution&#44; and in recent years&#44; given greater awareness and knowledge of the disease&#44; the number of case reports has increased&#46; The exact prevalence is therefore unknown&#44; with estimates ranging from 1&#58;2351 inhabitants in France and 1&#58;3500 in Denmark to 1&#58;39 216 in the North of England&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">9</span></a> Worldwide&#44; the disease is estimated to affect 1&#46;4 million people&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">Although most patients have another family member with HHT&#44; 20&#37; of cases are sporadic&#46; It is estimated that the offspring of someone with HHT has a 50&#37; risk of developing the disease&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">10</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Pathophysiology</span><p id="par0025" class="elsevierStylePara elsevierViewall">The clinical manifestations observed in HHT are the result of abnormalities in vascular structure&#46; The main lesions are telangiectases&#44; which arise from arteriovenous shunting between dilated arterioles and venules and which present clinically as punctiform or linear arborizing erythematous macules of 1-2<span class="elsevierStyleHsp" style=""></span>cm that disappear on applying light pressure&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">11</span></a> The pathophysiological mechanism by which telangiectases occur has not been fully elucidated&#46; The Braveman theory proposes as an initial mechanism a focal dilatation of postcapillary venules&#44; which continue to enlarge and eventually connect with dilated arterioles through capillaries that subsequently disappear to form a direct arteriovenous shunt&#46; During this process&#44; a predominantly mononuclear perivascular infiltrate of is present&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">12</span></a> By definition&#44; telangiectases present in mucocutaneous tissues&#44; such as the skin or gastrointestinal mucosa&#46; When these abnormal vascular shunts occur in internal organs&#44; such as the liver&#44; lung&#44; or brain&#44; they are known as arteriovenous malformations &#40;AVMs&#41;&#46; The AVMs are responsible for the systemic manifestations of the disease&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">13</span></a> The fragility of the vascular walls and turbulent blood flow predispose these vessels to the characteristic bleeding that forms part of the syndrome&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">14</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">It has been observed that vascular endothelial growth factor &#40;VEGF&#41;&#44; which is implicated in vasculogenesis and angiogenesis&#44; is elevated in patients with HHT&#44; and so treatments such as bevacizumab that target this factor have been developed and shown to be effective&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">15</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">On the molecular level&#44; more than 600 mutations causative of HHT have been identified&#46; Of these&#44; the most studied to date are mutations in the endoglin &#40;<span class="elsevierStyleItalic">ENG</span>&#41; gene&#44; located on chromosome 9&#44; characteristic of HHT subtype 1&#44; and in the activin-like kinase &#40;<span class="elsevierStyleItalic">ALK1</span>&#41; gene&#44; on chromosome 12&#44; characteristic of subtype 2&#46;<a class="elsevierStyleCrossRefs" href="#bib0215"><span class="elsevierStyleSup">11&#44;16</span></a> Both the corresponding proteins &#40;ENG and ALK1&#41; are transmembrane proteins expressed in endothelial cells with the ability to bind to transforming growth factor &#40;TGF&#41;&#46; These molecules therefore play an important role in angiogenesis and vascular maturation&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">17</span></a> There have also been reports of mutations in the <span class="elsevierStyleItalic">MADH4</span> and <span class="elsevierStyleItalic">SMAD4</span> genes&#44; which predispose the individual to HHT accompanied by juvenile polyposis &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">11</span></a> Another type of mutation is one that affects bone morphogenic protein receptor<span class="elsevierStyleSmallCaps">II</span>&#44; leading to the HHT phenotype accompanied by primary pulmonary hypertension&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">18</span></a></p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Clinical Manifestations</span><p id="par0040" class="elsevierStylePara elsevierViewall">The clinical manifestations of HHT are varied&#44; and present mainly on the nose&#44; skin&#44; and lungs&#44; with possible involvement of the central nervous system and gastrointestinal system&#46; They are characterized by the classic triad of epistaxis&#44; telangiectases&#44; and a family history of HHT&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">19</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">Most patients only experience manifestations of epistaxis&#44; mucocutaneous telangiectases&#44; and anemia due to iron deficiency&#46; Symptoms are not normally present at birth but develop as the individual gets older&#46; It is estimated that 70&#37; of affected individuals present manifestations by 16 years and 90&#37; by 40 years&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">9</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Nose</span><p id="par0050" class="elsevierStylePara elsevierViewall">Epistaxis is usually the primary clinical manifestation&#44; and in many cases&#44; the first&#46; Spontaneous bleeding occurs due to telangiectases that are present in the nasal mucosa&#46; These events can be triggered my many factors&#44; such as changes in temperature&#44; humidity&#44; or posture&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">The frequency of nose bleeds can be very high&#44; leading to iron-deficiency anemia&#46; However&#44; on other occasions&#44; episodes may occur only sporadically or never&#44; and so diagnostic suspicion is less likely&#46; Furthermore&#44; epistaxis is considered a very common symptom in the general population&#44; and so it is not a very sensitive indicator&#46; Episodes of night bleeding are more specific for diagnosis of HHT&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">20</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">Generally&#44; episodes of epistaxis start in childhood&#44; at around 10 years of age&#44; and usually become more severe as the individual gets older&#46; On average&#44; patients with HHT present around 18 episodes of epistaxis a month&#46; Rebeiz et al&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">21</span></a> developed a classification for severity of epistaxis that is still in use today &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0065" class="elsevierStylePara elsevierViewall">Management and prevention of epistaxis can vary from simple interventions&#44; such as nasal saline spray&#44; to more aggressive measures&#44; such as cauterization&#44; laser ablation&#44; surgery&#44; estrogen supplementation&#44; and embolectomy&#44; depending on the severity of the episodes&#46;<a class="elsevierStyleCrossRefs" href="#bib0270"><span class="elsevierStyleSup">22&#44;23</span></a></p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Skin</span><p id="par0070" class="elsevierStylePara elsevierViewall">The main skin manifestations are telangiectases&#44; which occur in up to 75&#37; of patients&#44; with onset typically in childhood and becoming more numerous with increasing age&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">Skin lesions usually appear after the first episode of epistaxis&#46; These lesions usually become apparent when patients are in their 30s and 40s&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">11</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">They present most frequently on the face&#44; lips&#44; nose&#44; tongue&#44; outer ears&#44; hands &#40;especially the fingertips&#41;&#44; trunk&#44; and feet &#40;<a class="elsevierStyleCrossRefs" href="#fig0005">Figs&#46; 1-3</a>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">19</span></a></p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0085" class="elsevierStylePara elsevierViewall">In the early stages&#44; the lesions are small&#44; pulsatile red-violaceous macules 1-3 in diameter&#44; which in the chronic phase may coalesce and increase in diameter to form arborizing lesions&#46;<a class="elsevierStyleCrossRefs" href="#bib0255"><span class="elsevierStyleSup">19&#44;24</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">In most cases&#44; cutaneous telangiectases are asymptomatic and treatment is a question of esthetics&#46; However&#44; in some cases&#44; they can be painful&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">The HHT Foundation International drew up a consensus in which they arrived at the conclusion that the presence of at least 3 typical telangiectases are required for diagnosis of HHT&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">17</span></a></p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Lung</span><p id="par0100" class="elsevierStylePara elsevierViewall">The most frequent pulmonary lesions are AVMs&#44; which are present in up to 15&#37; to 30&#37; of patients with HHT&#46; These AVMs directly connect pulmonary and systemic circulation&#44; causing a right-to-left shunt that is manifest clinically as cyanosis&#44; intolerance of cold&#44; migraine&#44; and polycythemia&#46; The most serious complications include cerebrovascular accidents&#44; massive hemoptysis&#44; and spontaneous hemothorax&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">10</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">In general&#44; these lesions occur in the lung bases&#44; and bleed more readily during pregnancy&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">25</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">Given that pulmonary AVMs do not lead to symptoms in early stages and that complications may be very serious&#44; all patients over 16 years of age with diagnosis of HHT should undergo transthoracic ultrasound&#46; Lesions can be treated by transcatheter embolization or&#44; in the most severe cases&#44; lobectomy&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">10</span></a></p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Gastrointestinal Effects</span><p id="par0115" class="elsevierStylePara elsevierViewall">Gastrointestinal effects arise in a third of patients with HHT&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">The most frequent lesions are telangiectases in the stomach and duodenum&#44; followed by AVMs&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">In the most usual clinical presentation&#44; the patient will have iron-deficiency anemia or episodes of acute gastrointestinal bleeding&#59; these manifestations are more common in individuals aged over 40 years&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">10</span></a> Gastrointestinal monitoring usually starts at the age of 35 years and involves only annual hemoglobin measurement&#59; endoscopy is reserved for episodes of bleeding&#46; Endoscopic ultrasound-guided ablation&#44; embolization&#44; or surgery are the treatments for gastrointestinal manifestations&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Brain</span><p id="par0130" class="elsevierStylePara elsevierViewall">Brain lesions present in 23&#37; of patients&#46; These lesions can be multiple AVMs&#44; telangiectases&#44; and arteriovenous fistulas&#46; When present&#44; they can manifest as episodes of migraine&#44; convulsions&#44; ischemia&#44; or bleeding&#46; The annual rate of AVM rupture is 2&#37; to 4&#37; on average&#46; It is a matter of debate whether screening for early detection is appropriate&#44; but if performed&#44; magnetic resonance imaging is the technique of choice&#44; with a sensitivity of 80&#37; to 95&#37;&#46; Treatment can be by embolization or surgical resection&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Liver</span><p id="par0135" class="elsevierStylePara elsevierViewall">Hepatic involvement in HHT is present in 32&#37; to 78&#37; of patients and symptoms are present in 8&#37; of them&#46; Clinical presentation can include angina and heart failure due to shunting between the hepatic artery and vein&#44; which increases the cardiac overload&#46; Portal hypertension and hepatic encephalopathy may also arise&#46; These lesions can be monitored by Doppler ultrasound&#44; magnetic resonance imagining&#44; and computed tomography&#46; Supportive therapy is administered&#44; with the aim of reducing the complications of portal hypertension and heart failure&#46; Sometimes&#44; transplantation may be performed&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">14</span></a></p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Diagnosis</span><p id="par0140" class="elsevierStylePara elsevierViewall">Timely diagnosis of HHT is of utmost importance to prevent the complications of the disease and to provide genetic counseling for family members&#46; In cases in which the classic 3 criteria of epistaxis&#44; telangiectases&#44; and a family history are present&#44; diagnosis is relatively simple&#59; however&#44; not all patients present with this triad&#46; In 2000&#44; the Cura&#231;ao Diagnostic Criteria for HHT were published&#59; 3 or more criteria are required for definitive diagnosis&#44; 2 positive criteria correspond to a probable diagnosis&#44; and no positive criteria are equivalent to unlikely diagnosis &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0210"><span class="elsevierStyleSup">10&#44;20</span></a></p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0145" class="elsevierStylePara elsevierViewall">There are also genetic tests for diagnosis of HHT&#46; The main use for these is for study of family members of affected patients&#44; particularly children and young adults&#44; who do not meet the clinical diagnostic criteria&#46; Among these tests are those for DNA sequencing to detect mutations in the <span class="elsevierStyleItalic">ENG</span> and <span class="elsevierStyleItalic">ACVRL1</span> genes&#44; which account for the majority of mutations associated with HHT&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">26</span></a> There are also tests to detect mutations in the <span class="elsevierStyleItalic">SMAD4</span> gene&#44; but these are less common&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">27</span></a></p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Capillary Microscopy</span><p id="par0150" class="elsevierStylePara elsevierViewall">Dermoscopy has become a useful tool for the diagnosis of HHT through capillary microscopy&#46; Capillary microscopy findings described to date in HHT suggest that the technique is useful because it can detect microscopic telangiectases&#46; In a study conducted by Mager and Westermann&#44;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">17</span></a> using capillary microscopy of the nail fold&#44; the authors found that 87&#37; of patients with HHT had vascular abnormalities&#44; with giant loops being the most common finding&#46;</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Treatment</span><p id="par0155" class="elsevierStylePara elsevierViewall">Given that HHT syndrome has a multisystemic impact&#44; multidisciplinary treatment is also required&#46; Most studies of HHT are conducted by ear-nose-throat specialists because epistaxis is the main manifestation in these patients&#59; however&#44; although telangiectases are just as evident&#44; few studies have been conducted of their treatment&#46;</p><p id="par0160" class="elsevierStylePara elsevierViewall">Although cutaneous telangiectases are only a cosmetic problem&#44; their presence can have a negative impact on the quality of life of the patients&#44; and so several treatment options have been implemented within dermatology&#44; with varying results&#46; Most articles on the subject are merely case reports&#46;</p><p id="par0165" class="elsevierStylePara elsevierViewall">In recent years&#44; laser treatments have been the most widely used for treatment of cutaneous telangiectases&#46; The most extensively used systems are pulsed dye lasers &#40;595<span class="elsevierStyleHsp" style=""></span>nm&#41;&#44; which are useful for macular telangiectases&#44; and Nd&#58;YAG lasers&#44; which are preferred for lesions with a papular appearance and because of their greater penetration and coagulation power &#40;<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">28</span></a></p><elsevierMultimedia ident="tbl0020"></elsevierMultimedia><p id="par0170" class="elsevierStylePara elsevierViewall">Argon lasers have been used for the treatment of cutaneous telangiectases&#59; however&#44; they have the disadvantage of causing scarring&#46;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">32</span></a></p><p id="par0175" class="elsevierStylePara elsevierViewall">Other studies have reported the use of intense pulsed light&#44; followed by Nd&#58;YAG laser pulses&#44; with acceptable cosmetic outcomes&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">30</span></a></p></span></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Conclusions</span><p id="par0180" class="elsevierStylePara elsevierViewall">Osler-Weber-Rendu syndrome&#44; or HHT&#44; is a rare multisystemic disease with a broad clinical presentation and a substantial risk of complications&#44; and so timely diagnosis and genetic counseling is required&#46; Clinicians do not always have a high awareness of this condition and often do not recognize the disease until the onset of severe life-threatening complications&#46;</p><p id="par0185" class="elsevierStylePara elsevierViewall">Prognosis for survival of patients with HHT is favorable if complications are diagnosed and treated in time&#46;</p><p id="par0190" class="elsevierStylePara elsevierViewall">Laser treatment of cutaneous lesions has shown promise&#44; although more long-term studies are required to more precisely determine their efficacy and to standardize the parameters according to the target site&#46;</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Conflicts of Interest</span><p id="par0195" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflicts of interest&#46;</p></span></span>"
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          "titulo" => "Palabras clave"
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          "titulo" => "Introduction"
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            1 => array:2 [
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              "titulo" => "Nose"
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              "identificador" => "sec0040"
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              "identificador" => "sec0045"
              "titulo" => "Gastrointestinal Effects"
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              "titulo" => "Brain"
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          "titulo" => "Conclusions"
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    "fechaRecibido" => "2018-10-05"
    "fechaAceptado" => "2018-11-04"
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        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Osler-Weber-Rendu syndrome&#44; also known as hereditary hemorrhagic telangiectasia&#44; is a rare autosomal dominant disorder with an estimated worldwide prevalence of 1 case per 10&#44;000 population&#46; Its clinical manifestations are the result of arteriovenous malformations characterized by telangiectases that can affect the skin&#44; mucous membranes&#44; and solid organs and cause life-threatening conditions&#44; such as liver disease&#44; systemic emboli&#44; and heart failure&#46; Timely diagnosis is thus essential in order to prevent disease-related complications and offer genetic counseling to families&#46; We review the clinical features of Osler-Weber-Rendu syndrome with a focus on mucocutaneous manifestations and their treatment&#46;</p></span>"
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      "es" => array:2 [
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        "resumen" => "<span id="abst0015" class="elsevierStyleSection elsevierViewall"><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">El s&#237;ndrome de Osler-Weber-Rendu&#44; o s&#237;ndrome hereditario hemorr&#225;gico telangiectasia&#44; es un trastorno raro de herencia autos&#243;mica dominante con una prevalencia estimada de 1&#58;10&#46;000 personas a nivel mundial&#46; Las manifestaciones cl&#237;nicas de este s&#237;ndrome son resultado de malformaciones arteriovenosas y var&#237;an desde telangiectasias en piel y mucosas hasta afecci&#243;n de &#243;rganos s&#243;lidos que ponen en peligro la vida&#44; como alteraciones hep&#225;ticas&#44; &#233;mbolos sist&#233;micos y fallo card&#237;aco&#44; por lo cual el diagn&#243;stico oportuno es de suma importancia para prevenir las complicaciones de la enfermedad y proporcionar apoyo gen&#233;tico a los familiares&#46; En esta revisi&#243;n se analiza el cuadro cl&#237;nico con enfoque principal en las manifestaciones mucocut&#225;neas de la enfermedad y su abordaje terap&#233;utico&#46;</p></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Orizaga-y-Quiroga TL&#44; Villarreal-Mart&#237;nez A&#44; Jaramillo-Moreno G&#44; Ocampo-Candiani J&#46; S&#237;ndrome de Osler-Weber-Rendu y su relaci&#243;n con la dermatolog&#237;a&#46; Actas Dermosifiliogr&#46; 2019&#59;110&#58;527&#8211;532&#46;</p>"
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          "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Multiple facial telangiectases on a patient with HHT&#46;</p>"
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          "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Multiple arborizing telangiectases on the cheek and ear&#46;</p>"
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                  <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="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">ENG</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">Associated with mutations in the endoglin geneMore frequently observed in pulmonary and cerebral AVMs&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">ACVRL1</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">Associated with mutations in the <span class="elsevierStyleItalic">ALK-1</span> gene &#40;activin-like kinase receptor&#41;More frequently observed in hepatic AVMs&#44; pulmonary and arterial hypertension&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">SMAD4</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Causes HHT-associated juvenile polyposis&nbsp;\t\t\t\t\t\t\n
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
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                  \t\t\t\t">Mild&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Few episodes a week without need for transfusion&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Moderate&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">1-2 episodes a day&#44; fewer than 10 transfusions&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Severe&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Daily episodes lasting more than 30<span class="elsevierStyleHsp" style=""></span>minutes&#44; more than 10 transfusions&nbsp;\t\t\t\t\t\t\n
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                  <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="\n
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                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Recurrent and spontaneous epistaxis&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Multiple mucocutaneous telangiectases&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Lesions in internal organs &#40;gastrointestinal&#44; pulmonary&#44; cerebral&#44; or hepatic&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">First-degree relative with HHT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Study&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">Cheung et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">28</span></a> 2015&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Pulsed dye laser at 595<span class="elsevierStyleHsp" style=""></span>nmSpot&#44; 5<span class="elsevierStyleHsp" style=""></span>mmPulse duration&#44; 1&#46;5 msFluence&#44; 8<span class="elsevierStyleHsp" style=""></span>J&#47;cm<span class="elsevierStyleSup">2</span> on cheeks and 9<span class="elsevierStyleHsp" style=""></span>J&#47;cm<span class="elsevierStyleSup">2</span> on the nose&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Face and mucosa&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Resolution of lesions in 5 days&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">Halachmi et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">29</span></a> 2013&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">8&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">Pulsed dye laser &#40;Vbeam Perfecta&#44; Candela&#44; Wayland&#41;Spot&#44; 5-7<span class="elsevierStyleHsp" style=""></span>mmPulse duration&#44; 1&#46;5 msFluence&#44; 9&#46;5 to 11<span class="elsevierStyleHsp" style=""></span>J&#47;cm<span class="elsevierStyleSup">2</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Cheek&#44; nose&#44; and lips&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Excellent improvement in all patients &#40;75&#37;-100&#37;&#41;Mean number of sessions to obtain response&#58; 2&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">Werner et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">30</span></a> 2008&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">Nd&#58;YAGPulse duration&#44; 0&#46;5-90<span class="elsevierStyleHsp" style=""></span>msMaximum fluence&#44; 450<span class="elsevierStyleHsp" style=""></span>J&#47;cm<span class="elsevierStyleSup">2</span>Spot&#44; 3-10<span class="elsevierStyleHsp" style=""></span>mm&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Case 1&#58; cheeks&#44; chin&#44; and foreheadCase 2&#58; fingertipsCase 3&#58; fingers&#44; ears&#44; cheeks&#44; chinCase 4&#58; cheeks&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Case 1&#58; 50&#37;-75&#37; response at 8 weeksCase 2&#58; 75&#37;-95&#37; response at 8<span class="elsevierStyleHsp" style=""></span>weeks&#59; adverse effects&#58; white-greyish pigmentationCase 3&#58; 75&#37;-95&#37; improvement in fingers after 2 sessions&#59; 50&#37; improvement in ears&#44; chin&#44; and cheeks with mild atrophy and hypopigmentationCase 4&#58; 90&#37; response after 8 weeks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">Fern&#225;ndez-Jorge et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">31</span></a> 2007&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Photoderm-Vasculight system&#44; which combined intense pulsed light &#43; Nd&#58;YAG 1064<span class="elsevierStyleHsp" style=""></span>nm&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Cheek&#44; lips&#44; nose&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Complete response in all cases without any relapse during follow-up at 2 years in 2 of the 3 cases&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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