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          "es" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">N&#250;mero de pacientes que han alcanzado cada nivel de escolarizaci&#243;n&#46; Se diferencian 2 grupos&#44; seg&#250;n la edad&#58; &#60; 18 a&#241;os &#40;25 pacientes&#41; y &#8805; 18 a&#241;os &#40;13 pacientes&#41;&#46; Diez ni&#241;os precisaron refuerzo educativo&#46;</p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Introducci&#243;n</span><p id="par0005" class="elsevierStylePara elsevierViewall">El s&#237;ndrome de hipoventilaci&#243;n central cong&#233;nita &#40;SHCC&#41; o enfermedad de Ondine es una patolog&#237;a gen&#233;tica muy rara del sistema nervioso aut&#243;nomo &#40;SNA&#41;&#44; caracterizada por la p&#233;rdida del control autom&#225;tico de la respiraci&#243;n<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">1&#44;2</span></a>&#59; se manifiesta t&#237;picamente durante el sue&#241;o no REM o&#44; en casos m&#225;s graves&#44; en todo el sue&#241;o&#44; incluso en vigilia&#46; Puede asociar otras disautonom&#237;as &#40;alteraciones del ritmo cardiaco<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">3</span></a>&#44; de la motilidad intestinal y ocular<a class="elsevierStyleCrossRefs" href="#bib0220"><span class="elsevierStyleSup">4&#44;5</span></a>&#44; enfermedad de Hirschsprung<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">6</span></a> y tumores de la cresta neural<a class="elsevierStyleCrossRefs" href="#bib0235"><span class="elsevierStyleSup">7&#44;8</span></a>&#41;&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">Se produce por mutaciones en heterocigosis del gen paired-like Homeobox 2<span class="elsevierStyleHsp" style=""></span>B <span class="elsevierStyleItalic">&#40;PHOX2B&#41;</span>&#44; cuya funci&#243;n es clave en el desarrollo del SNA durante la embriog&#233;nesis<a class="elsevierStyleCrossRefs" href="#bib0245"><span class="elsevierStyleSup">9&#44;10</span></a>&#46; Las mutaciones m&#225;s frecuentes &#40;90&#37; de los casos&#41;&#44; denominadas &#171;poly-ala-repeat mutations&#187; &#40;PARM&#41;&#44; consisten en expansiones del segmento de 20 residuos de alanina presente en el ex&#243;n 3 de <span class="elsevierStyleItalic">PHOX2B</span>&#59; la longitud de dichas expansiones es variable&#44; habi&#233;ndose detectado genotipos desde 20&#47;24 hasta 20&#47;33&#46; El 10&#37; restante de las mutaciones identificadas&#44; denominadas &#171;non-poly-ala-repeat mutations&#187; &#40;NPARM&#41;&#44; son mutaciones puntuales missense&#44; peque&#241;as inserciones&#47;deleciones que alteran la pauta de lectura<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">11</span></a>&#44; o&#44; m&#225;s raramente &#40;&#60; 1&#37;&#41;&#44; deleciones&#47;duplicaciones del ex&#243;n 3 o del gen completo<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">12</span></a>&#46; La mayor&#237;a de las mutaciones se producen de novo&#44; aunque hasta un 25&#37; de los progenitores asintom&#225;ticos pueden tener mosaicismo som&#225;tico<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">13</span></a>&#46; El estudio gen&#233;tico confirma el diagn&#243;stico cl&#237;nico e informa sobre la gravedad&#44; ya que las mutaciones con expansiones m&#225;s cortas &#40;20&#47;24 y 20&#47;25&#41; presentan penetrancia variable&#44; pudiendo manifestarse incluso con fenotipo normal&#59; por el contrario&#44; las PARM con mayores expansiones &#40;20&#47;27 y 20&#47;33&#41; asocian disautonom&#237;as de mayor gravedad y mayor necesidad de ventilaci&#243;n mec&#225;nica &#40;VM&#41; 24 h<a class="elsevierStyleCrossRefs" href="#bib0270"><span class="elsevierStyleSup">14&#44;15</span></a>&#46; Las mutaciones NPARM asocian mayor incidencia de tumores y enfermedad de Hirschsprung<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">16</span></a>&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">Generalmente&#44; la dependencia de VM aparece desde el nacimiento &#40;SHCC de inicio precoz&#41;&#59; no obstante&#44; a veces la hipoventilaci&#243;n pasa desapercibida o se manifiesta m&#225;s tarde&#44; diagnostic&#225;ndose despu&#233;s del mes de vida&#44; incluso en adultos portadores de mutaci&#243;n &#40;SHCC de inicio o diagn&#243;stico tard&#237;o&#41;<a class="elsevierStyleCrossRefs" href="#bib0285"><span class="elsevierStyleSup">17-20</span></a>&#46; Existen otras formas tard&#237;as de hipoventilaci&#243;n central primaria sin mutaci&#243;n conocida&#44; entidades diferentes del SHCC&#44; tales como la entidad &#8220;rapid-onset obesity with hypoventilation&#44; hypothalamic dysfunction and autonomic dysregulation&#8221; &#40;ROHHAD&#41;<a class="elsevierStyleCrossRefs" href="#bib0305"><span class="elsevierStyleSup">21&#44;22</span></a>&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">Los ni&#241;os afectados de SHCC precisan &#243;ptima VM en domicilio para sobrevivir y&#47;o alcanzar un &#243;ptimo neurodesarrollo&#44; por lo que el diagn&#243;stico precoz y la vigilancia continua de su estado respiratorio son claves para evitar complicaciones y secuelas derivadas de la hipoxemia y la hipercapnia cr&#243;nica<a class="elsevierStyleCrossRefs" href="#bib0275"><span class="elsevierStyleSup">15&#44;23</span></a>&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">Es una enfermedad muy rara&#44; con incidencia desconocida&#44; aunque estimada de 1&#47;200&#46;000 reci&#233;n nacidos &#40;RN&#41; vivos<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">24</span></a>&#46; En 2010 se organiz&#243; el Consorcio Europeo del S&#237;ndrome de Hipoventilaci&#243;n Central&#44; para optimizar el cuidado de los pacientes<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">25</span></a> &#40;<a href="http://www.ichsnetwork.eu/">www&#46;ichsnetwork&#46;eu&#47;</a>&#41;&#59; en este marco fue dise&#241;ado un Registro europeo online de pacientes&#44; siguiendo las normas de seguridad&#44; anonimicidad y confidencialidad vigentes&#46; Catorce pa&#237;ses europeos participan actualmente&#44; incluida Espa&#241;a&#46; Los objetivos del presente trabajo son&#58; <span class="elsevierStyleItalic">a&#41;</span> conocer las caracter&#237;sticas fenot&#237;picas y genot&#237;picas&#44; formas de presentaci&#243;n&#44; t&#233;cnicas de VM utilizadas y evoluci&#243;n de los pacientes espa&#241;oles diagnosticados de SHCC incluidos en el Registro europeo&#44; y <span class="elsevierStyleItalic">b&#41;</span> identificar aspectos relevantes en el cuidado de estos pacientes&#44; subsidiarios de mejora&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">M&#233;todo</span><p id="par0030" class="elsevierStylePara elsevierViewall">La implantaci&#243;n del Registro europeo en Espa&#241;a fue autorizada por un Comit&#233; &#201;tico de Investigaci&#243;n Cl&#237;nica espa&#241;ol de referencia y se divulg&#243; a trav&#233;s de sociedades cient&#237;ficas y de la Asociaci&#243;n Ondine&#44; que integra a familiares y pacientes espa&#241;oles con SHCC &#40;<a href="http://www.sindromedeondine.es/">www&#46;sindromedeondine&#46;es</a>&#41;&#46; Se comenz&#243; el reclutamiento de pacientes en marzo del 2012&#46; Cuatro familias declinaron participar&#46; Los responsables legales y&#47;o pacientes firmaron el consentimiento informado para participar&#46; Los m&#233;dicos espa&#241;oles responsables de los pacientes&#44; uno de ellos coordinador nacional&#44; recibieron acceso al Registro online&#59; cada investigador introdujo los datos&#44; obtenidos mediante revisi&#243;n de la historia cl&#237;nica y entrevista a los afectados&#44; supervisados posteriormente por el coordinador&#46; Los datos se actualizan peri&#243;dicamente&#44; la &#250;ltima fecha&#44; el 31 de diciembre del 2015&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">Se recogieron los siguientes datos&#58; fecha y pa&#237;s de nacimiento&#44; sexo&#44; raza&#44; datos del embarazo&#44; parto y periodo neonatal&#46; Manifestaciones cl&#237;nicas iniciales y evolutivas &#40;respiratorias&#44; gastrointestinales&#44; neurol&#243;gicas&#44; cardiovasculares&#44; oculares&#44; endocrinas&#44; tumores&#44; otras&#41;&#59; patolog&#237;as asociadas&#46; Diagn&#243;stico&#58; fecha&#44; pruebas realizadas&#44; estudio gen&#233;tico&#44; mutaci&#243;n encontrada&#46; Tratamientos&#58; t&#233;cnicas de ventilaci&#243;n y cambios&#59; cirug&#237;as&#46; Tiempo de ingreso hospitalario&#46; Aspectos sociales&#58; escolarizaci&#243;n&#44; grado acad&#233;mico alcanzado&#44; primer trabajo&#46; Datos del fallecimiento&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">Se trata de un estudio observacional transversal&#46; La descripci&#243;n de los datos se realiz&#243; mediante la media&#44; la mediana&#44; la desviaci&#243;n t&#237;pica y el rango de las variables cuantitativas&#44; as&#237; como mediante las frecuencias absoluta y relativa de las variables cualitativas&#46; Cuando los datos lo permitieron&#44; se realizaron contrastes de hip&#243;tesis&#59; las medias de los d&#237;as de ingreso se compararon mediante el test de Mann-Whitney y la relaci&#243;n entre la frecuencia de patolog&#237;as asociadas y las diversas mutaciones se estudi&#243; mediante regresi&#243;n lineal&#46; Los datos relevantes se presentaron en tablas y figuras&#46; Se utiliz&#243; el programa SPSS versi&#243;n 15 para el an&#225;lisis estad&#237;stico&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Resultados</span><p id="par0045" class="elsevierStylePara elsevierViewall">Durante el periodo del estudio &#40;desde marzo del 2012 hasta diciembre del 2015&#41; se registraron y actualizaron los datos de 38 pacientes&#44; nacidos entre 1987 y 2013&#44; de edad media 13&#44;6 &#177; 7&#44;45 a&#241;os&#59; mediana 11&#44;35 meses&#59; rango de edad&#58; 5 meses y 28&#44;6 a&#241;os&#46; Trece pacientes &#40;34&#44;2&#37;&#41; eran mayores de 18 a&#241;os&#46; Diecisiete &#40;44&#44;7&#37;&#41; eran varones y 21 &#40;55&#44;3&#37;&#41; mujeres&#46; La distribuci&#243;n de pacientes por comunidad aut&#243;noma de residencia fue la siguiente&#58; Madrid 7 pacientes&#44; Andaluc&#237;a 6&#44; Castilla-La Mancha 5&#44; Catalu&#241;a 5&#44; Murcia 3&#44; Pa&#237;s Vasco 3&#44; Arag&#243;n 2&#44; Valencia 2&#44; Canarias 1&#44; Castilla-Le&#243;n 1&#44; Extremadura 1&#44; Islas Baleares 1 y Navarra 1 paciente&#46; En el estudio han participado 22 investigadores&#44; pertenecientes a 19 hospitales espa&#241;oles&#44; referidos en la lista de autores&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">Han fallecido 3 pacientes &#40;7&#44;8&#37;&#41;&#44; todos de forma inesperada fuera del hospital&#44; 2 durante el sue&#241;o y otro por accidente&#59; sus edades de defunci&#243;n fueron 5 meses&#44; 13 meses y 15 a&#241;os&#44; respectivamente&#46;</p><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Genotipos&#44; fenotipos y correlaci&#243;n genotipo&#47;fenotipo</span><p id="par0055" class="elsevierStylePara elsevierViewall">Treinta y siete pacientes aportaban estudio del gen <span class="elsevierStyleItalic">PHOX2B</span>&#44; realizado en 32 ni&#241;os &#40;86&#44;4&#37;&#41; en el Instituto de Gen&#233;tica M&#233;dica y Molecular del Hospital La Paz de Madrid&#44; laboratorio de referencia en Espa&#241;a para el diagn&#243;stico de SHCC&#46; Treinta y dos pacientes &#40;86&#44;4&#37;&#41; presentaban mutaci&#243;n&#59; 30 mutaciones &#40;93&#37;&#41; eran PARM y 2 &#40;6&#44;6&#37;&#41; eran NPARM &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">tabla 1</a>&#41;&#46; Los genotipos 20&#47;25&#44; 20&#47;26 y 20&#47;27 representan el 84&#44;3&#37; de las mutaciones encontradas&#46; El estudio gen&#233;tico fue negativo en 4 ni&#241;os&#58; 2 estaban diagnosticados de s&#237;ndrome de ROHHAD por el cuadro cl&#237;nico asociado&#59; uno inici&#243; hipoventilaci&#243;n a los 10 a&#241;os&#59; uno&#44; con comienzo neonatal&#44; presentaba hipoventilaci&#243;n en sue&#241;o tranquilo&#46; Se desconoce el resultado del estudio en un paciente y no fue realizado en otro&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0060" class="elsevierStylePara elsevierViewall">La <a class="elsevierStyleCrossRef" href="#tbl0005">tabla 1</a> muestra las patolog&#237;as asociadas y su relaci&#243;n con las diferentes mutaciones&#59; destacan las alteraciones oculares por su alta frecuencia &#40;47&#44;3&#37;&#41;&#46; Dos pacientes fueron intervenidos de urgencia por v&#243;lvulo gastrointestinal&#46; Cinco pacientes &#40;13&#44;1&#37;&#41; presentaron hipoglucemias&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">En esta serie no es posible comparar los tipos de patolog&#237;as del SNA encontrados en ambos tipos de mutaciones &#40;PARM vs&#46; NPARM&#41; porque solo 2 pacientes presentan mutaci&#243;n NPARM&#46; Sin embargo&#44; las patolog&#237;as estructurales &#40;tumores del SNA&#44; Hirschsprung&#41; tienden a asociarse con mutaciones NPARM y las patolog&#237;as funcionales &#40;alteraci&#243;n del ritmo cardiaco&#44; hipoglucemias&#44; etc&#46;&#41; se asocian con las mutaciones PARM &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">tabla 1</a>&#41;&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">Dentro de las mutaciones PARM&#44; las patolog&#237;as del SNA son m&#225;s frecuentes y m&#225;s graves en pacientes con expansiones mayores &#40;20&#47;27 y 20&#47;33&#59; p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;014 y p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;003&#44; respectivamente&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">tabla 1</a>&#41;&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Formas cl&#237;nicas de presentaci&#243;n inicial</span><p id="par0075" class="elsevierStylePara elsevierViewall">Treinta pacientes &#40;79&#37;&#41; comenzaron de forma t&#237;pica&#44; necesitando VM desde el periodo neonatal &#40;29 desde el primer d&#237;a de vida&#44; 1 despu&#233;s&#41;&#44; sin patolog&#237;a cardiopulmonar u otra justificaci&#243;n &#40;inicio precoz&#41;&#59; de ellos&#44; 28 &#40;93&#44;3&#37;&#41; presentaban mutaci&#243;n&#44; uno no&#44; y se desconoce en otro&#46; Ocho pacientes &#40;21&#37;&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">tabla 2</a>&#41; comenzaron con otros s&#237;ntomas y&#47;o la necesidad de VM se detect&#243; o apareci&#243; en edad posterior &#40;inicio-diagn&#243;stico tard&#237;o&#41;&#44; 4 de ellos &#40;50&#37;&#41; presentaban mutaci&#243;n&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Tipo de ventilaci&#243;n mec&#225;nica</span><p id="par0080" class="elsevierStylePara elsevierViewall">T&#233;cnicas ventilatorias en la Unidad de Cuidados Intensivos pedi&#225;trica o neonatal&#58; Durante el comienzo de la enfermedad&#44; 35 pacientes &#40;92&#44;1&#37;&#41; recibieron intubaci&#243;n y ventilaci&#243;n invasiva&#44; y 18 &#40;47&#37;&#41; ventilaci&#243;n no invasiva &#40;VNI&#41;&#44; usada por primera vez en el a&#241;o 2000&#46; Quince ni&#241;os &#40;39&#44;5&#37;&#41; utilizaron ambos modos&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">T&#233;cnicas ventilatorias en domicilio&#58; <span class="elsevierStyleItalic">a&#41; traqueostom&#237;a</span> &#40;TQ&#41;&#58; 32 pacientes &#40;84&#44;2&#37;&#41; han sido ventilados con TQ&#59; 6 &#40;15&#44;8&#37;&#41; nunca fueron traqueostomizados&#59; la edad media del procedimiento quir&#250;rgico fue de 7&#44;8 meses &#177; 1&#44;1&#59; mediana&#44; 2&#44;6 meses&#59; rango 24 d&#237;as<span class="elsevierStyleHsp" style=""></span>-<span class="elsevierStyleHsp" style=""></span>5&#44;75 a&#241;os&#46; Han sido decanulados 11 pacientes &#40;34&#44;3&#37;&#41;&#59; la edad media de decanulaci&#243;n y transferencia a VNI fue de 13&#44;7 a&#241;os &#177; 1&#44;89&#59; mediana&#44; 12&#44;66 a&#241;os&#59; rango 6&#44;12<span class="elsevierStyleHsp" style=""></span>-<span class="elsevierStyleHsp" style=""></span>20&#44;5 a&#241;os&#46; Solo un paciente era menor de 10 a&#241;os cuando fue decanulado<span class="elsevierStyleItalic">&#46; b&#41; Ventilaci&#243;n con mascarilla</span>&#58; fue usada en domicilio por 19 pacientes &#40;50&#37;&#41;&#44; la primera vez en 1998&#44; evento publicado por sus autores<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">26</span></a>&#46; La <a class="elsevierStyleCrossRef" href="#tbl0015">tabla 3</a> muestra las caracter&#237;sticas de los 8 ni&#241;os ventilados con mascarilla en el momento de su primer alta a domicilio tras el diagn&#243;stico&#59; 5 eran lactantes con comienzo neonatal de la enfermedad&#44; 2 de los cuales precisaron cambio a TQ tras presentar parada cardiorrespiratoria en domicilio por ventilaci&#243;n ineficaz &#40;genotipos&#58; 20&#47;33&#44; NPARM&#41;&#46; <span class="elsevierStyleItalic">c&#41; Marcapasos fr&#233;nico</span> &#40;MF&#41;&#58; se implant&#243; en 4 pacientes &#40;11&#37;&#41;&#44; en el Hospital de Parapl&#233;jicos de Toledo&#44; a la edad&#47;a&#241;o de implantaci&#243;n de&#58; 1&#44;2 a&#241;os&#47;1992 &#40;que fracas&#243;&#41;&#44; 8&#44;8 a&#241;os&#47;2000&#44; 23 a&#241;os&#47;2013 y 24 a&#241;os&#47;2014&#59; los 3 pacientes ventilados con MF en diciembre del 2015 eran adultos dependientes de VM 24 h&#44; que en vigilia usaban el MF y por la noche&#44; la TQ &#40;un paciente&#41; o la mascarilla &#40;2 pacientes&#41;&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0090" class="elsevierStylePara elsevierViewall">A lo largo de su vida en domicilio&#44; 22 pacientes han recibido un s&#243;lo modo de ventilaci&#243;n&#44; 13&#44; 2 modos&#44; y 3&#44; 3 modos&#46; Ning&#250;n paciente fue ventilado con presi&#243;n negativa&#46; La <a class="elsevierStyleCrossRef" href="#fig0005">figura 1</a> muestra las t&#233;cnicas ventilatorias aplicadas en la primera alta a domicilio y en diciembre del 2015&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0095" class="elsevierStylePara elsevierViewall">Estancias&#58; en las <a class="elsevierStyleCrossRefs" href="#tbl0005">tablas 1 y 4</a> se describe la duraci&#243;n del ingreso que origin&#243; la VM a domicilio&#46; El tiempo fue significativamente m&#225;s largo en pacientes con genotipo 20&#47;27 &#40;p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;016&#41;&#44; dados de alta con TQ &#40;p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;004&#41; y en ingresados antes del a&#241;o 2000 &#40;p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;000&#41;&#46;</p><elsevierMultimedia ident="tbl0020"></elsevierMultimedia></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Aspectos sociales</span><p id="par0100" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">a&#46; Escolarizaci&#243;n</span>&#58; de los 34 pacientes en edad escolar&#44; 3 &#40;8&#44;8&#37;&#41; recibieron educaci&#243;n especial y 31 &#40;91&#37;&#41; acudieron a colegio normal&#44; aunque 10 de estos &#40;29&#44;4&#37;&#41; necesitaron refuerzo educativo continuado&#46; La <a class="elsevierStyleCrossRef" href="#fig0010">figura 2</a> muestra el grado acad&#233;mico alcanzado seg&#250;n la edad&#44; menor o mayor de 18 a&#241;os&#46; Cuatro pacientes mayores de 18 a&#241;os &#40;30&#37;&#41; recibieron educaci&#243;n superior &#40;3&#44; universidad y 1&#44; grado formativo superior&#41;&#44; <span class="elsevierStyleItalic">b&#41; trabajo</span>&#58; 4 pacientes mayores de 18 a&#241;os &#40;30&#37;&#41; iniciaron actividad laboral remunerada&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia></span></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Discusi&#243;n</span><p id="par0105" class="elsevierStylePara elsevierViewall">Este estudio agrupa por primera vez a los pacientes espa&#241;oles con SHCC&#46; La implementaci&#243;n del Registro europeo en Espa&#241;a ha requerido el esfuerzo y la colaboraci&#243;n de 19 hospitales y 22 profesionales sanitarios para reclutar a 38 pacientes&#44; al tratarse de una enfermedad muy rara y no existir a&#250;n centros de referencia nacionales para el seguimiento multidisciplinar&#44; coordinado con los m&#233;dicos regionales&#44; como se recomienda<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">2</span></a>&#44; y se lleva a cabo internacionalmente &#40;Francia<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">24</span></a>&#44; EE&#46; UU&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">27</span></a>&#41;&#46; La puesta en marcha del laboratorio de referencia espa&#241;ol para diagn&#243;stico gen&#233;tico de SHCC es el primer paso dado en ese proyecto&#44; que constituye un &#225;rea de mejora&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">Un tercio de los pacientes espa&#241;oles son mayores de 18 a&#241;os &#40;todos diagnosticados en la infancia&#44; muchos al nacer&#41;&#44; lo que demuestra su larga supervivencia gracias a la VM domiciliaria y al cuidado continuado de sus familias&#46; La entrada en la edad adulta plantea la dif&#237;cil transici&#243;n de estos ni&#241;os cr&#243;nicos desde los servicios de Pediatr&#237;a &#40;donde generalmente han recibido seguimiento estrecho&#41; a Unidades de adultos&#44; que desconocen esta patolog&#237;a&#44; pudiendo quedar insuficientemente protegidos&#46; Por ello&#44; algunos pa&#237;ses extienden la atenci&#243;n a pacientes mayores de edad en sus centros de referencia&#44; en colaboraci&#243;n con especialistas de adultos<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">27</span></a>&#46; La vida independiente y aut&#243;noma&#44; las relaciones de pareja y la inserci&#243;n en la vida laboral suponen un desaf&#237;o para estos j&#243;venes que duermen con respirador&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">El desarrollo neurocognitivo de los pacientes con SHCC est&#225; condicionado por aspectos relacionados con la propia enfermedad&#44; por procesos intercurrentes y por el riesgo permanente de hipoxemia e hipercapnia&#44; especialmente durante el sue&#241;o<a class="elsevierStyleCrossRefs" href="#bib0340"><span class="elsevierStyleSup">28-30</span></a>&#46; Aun as&#237;&#44; la mayor&#237;a de los ni&#241;os espa&#241;oles han sido escolarizados en centros normales y 4 han alcanzado el nivel superior educativo&#44; aunque un tercio han precisado refuerzo educativo mantenido&#46; Por ello&#44; la optimizaci&#243;n de la atenci&#243;n de los ni&#241;os espa&#241;oles con SHCC implica su valoraci&#243;n psicopedag&#243;gica y curricular peri&#243;dica&#44; para detectar y tratar precozmente deficiencias de aprendizaje&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">La frecuencia de mutaciones del presente estudio se corresponde con otras series publicadas y aparentemente tambi&#233;n la correlaci&#243;n genotipo-fenotipo<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">14</span></a>&#44; aunque&#44; como se se&#241;ala anteriormente&#44; el escaso n&#250;mero de pacientes NPARM impide estudios comparativos&#59; no obstante&#44; en esta serie&#44; los tumores del SNA est&#225;n ausentes en pacientes PARM y la enfermedad de Hirschsprung predomina en pacientes 20&#47;33 y NPARM&#46; Por ello&#44; el an&#225;lisis gen&#233;tico es fundamental para diagnosticar la enfermedad y orientar en el tratamiento multidisciplinar y el seguimiento peri&#243;dico protocolizado seg&#250;n genotipo&#44; como recomienda la American Thoracic Society &#40;ATS&#41;<a class="elsevierStyleCrossRefs" href="#bib0210"><span class="elsevierStyleSup">2&#44;15</span></a>&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">Respecto a otras patolog&#237;as asociadas&#44; las hipoglucemias aparecen en 5 pacientes &#40;13&#37;&#41;&#44; frente al 8&#37; de la serie de Vanderlaan et al&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">8</span></a>&#59; se trata de una complicaci&#243;n poco rese&#241;ada en la literatura&#44; incluso no mencionada en publicaciones de expertos<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">2</span></a>&#59; sin embargo&#44; comporta gran relevancia cl&#237;nica&#44; porque las hipoglucemias perturban enormemente la vida diaria del ni&#241;o y familia&#44; tanto por los s&#237;ntomas como por las medidas necesarias para su dif&#237;cil control<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">31</span></a>&#46; Dos pacientes &#40;genotipos 20&#47;27&#44; 20&#47;33&#41; precisaron laparotom&#237;a urgente por presentar v&#243;lvulo gastrointestinal&#44; complicaci&#243;n no descrita anteriormente por otros autores&#44; aunque pudiera haberse englobado en las alteraciones de motilidad intestinal&#46; Las patolog&#237;as oculares&#44; sin precisar tipo&#44; son muy frecuentes&#44; present&#225;ndose en casi la mitad de los pacientes espa&#241;oles&#44; al igual que en la serie de Vaderlaan et al&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">8</span></a>&#46; Patwari et al&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">5</span></a> describen alteraci&#243;n de la capacidad de adaptaci&#243;n pupilar a la luz&#46; Por tanto&#44; la exploraci&#243;n oftalmol&#243;gica peri&#243;dica incluyendo pupilometr&#237;a es necesaria para prevenir la repercusi&#243;n negativa de la alteraci&#243;n visual sobre el aprendizaje y desarrollo&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">Los s&#237;ntomas de hipoventilaci&#243;n central pueden pasar desapercibidos o ser malinterpretados y diagnosticarse tard&#237;amente&#44; sobre todo en mutaciones menos graves&#44; como ocurri&#243; en 3 de nuestros pacientes con genotipo 20&#47;25&#44; aunque tambi&#233;n sucedi&#243; en un lactante 20&#47;33&#44; diagnosticado inicialmente de enfermedad de Hirschsprung&#46; El retraso diagn&#243;stico implica hipoxia e hipercapnia cr&#243;nicas&#44; que entorpecen el neurodesarrollo<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">20</span></a>&#59; su prevenci&#243;n representa un &#225;rea de mejora que conlleva mantener alto &#237;ndice de sospecha ante hallazgos cl&#237;nicos no aclarados&#44; tales como episodios de cianosis&#44; letargia&#44; hipertensi&#243;n pulmonar&#44; necesidad de VM por infecciones leves o tras anestesia&#44; convulsiones o retraso del neurodesarrollo&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">La elecci&#243;n del modo ventilatorio en cada paciente y momento supone un aspecto muy relevante en la optimizaci&#243;n del tratamiento&#46; La TQ es la t&#233;cnica m&#225;s usada en los ni&#241;os espa&#241;oles con SHCC en la primera d&#233;cada de la vida&#44; como en otras series<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">8</span></a>&#46; Diversos autores y la ATS recomiendan la TQ en los primeros a&#241;os de la vida&#44; por seguridad y para garantizar un &#243;ptimo neurodesarrollo&#44; evitando el cambio a VNI antes de los 6-8 a&#241;os<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">15</span></a>&#46; Sin embargo&#44; es un asunto controvertido porque no hay estudios que analicen la influencia de la t&#233;cnica ventilatoria sobre el neurodesarrollo&#46; Costa Orvay et al&#46;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">32</span></a> describen el fracaso de la VNI en 2 lactantes con SHCC frente a la experiencia positiva de otros autores<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">33</span></a>&#59; en la serie de Vanderlaan et al&#46;&#44; de 196 pacientes&#44; el 14&#44;3&#37; nunca us&#243; TQ<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">8</span></a>&#44; porcentaje similar al obtenido en el presente estudio &#40;15&#44;8&#37;&#41;&#46; Este muestra a 8 pacientes tratados desde el inicio y dados de alta a domicilio con ventilaci&#243;n con mascarilla&#44; sin TQ&#44; 5 de los cuales hab&#237;an presentado comienzo neonatal&#58; los 2 con genotipo m&#225;s grave &#40;20&#47;33&#44; NPARM&#41; precisaron transferir a TQ por presentar parada cardiorrespiratoria en su domicilio&#44; frente a los 3 restantes&#44; con mutaciones m&#225;s leves &#40;20&#47;25&#44; 20&#47;25&#44; no mutaci&#243;n&#41;&#44; que han mantenido la mascarilla&#46; Cuando se usa VNI en ni&#241;os peque&#241;os&#44; adem&#225;s de la gravedad del genotipo&#44; otro aspecto a considerar es el efecto negativo a largo plazo de la interfase sobre el crecimiento del macizo facial<a class="elsevierStyleCrossRefs" href="#bib0370"><span class="elsevierStyleSup">34&#44;35</span></a>&#44; hecho no analizado en nuestro estudio&#46; Por todo lo anterior&#44; parece prudente utilizar la TQ como opci&#243;n inicial en ni&#241;os con SHCC de comienzo precoz&#44; planteando la VNI como opci&#243;n inicial solo en pacientes muy seleccionados&#44; como pueden ser algunos beb&#233;s con genotipo menos grave determinante de menor hipoventilaci&#243;n y no comorbilidad&#44; o en pacientes con comienzo tard&#237;o&#46; El uso de la VNI siempre debe acompa&#241;arse de vigilancia estrecha y de medidas preventivas dirigidas a evitar deformidades faciales &#40;alternancia de interfases&#44; uso de mascarilla facial total o de presi&#243;n negativa&#41;<a class="elsevierStyleCrossRefs" href="#bib0380"><span class="elsevierStyleSup">36&#44;37</span></a>&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">El MF asociado a otros modos es utilizado por solo 3 pacientes espa&#241;oles&#44; todos dependientes de VM 24 h&#44; como otros autores refieren<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">38</span></a>&#46; No obstante&#44; el MF aislado se usa por adolescentes o adultos ventilados solo durante el sue&#241;o<a class="elsevierStyleCrossRefs" href="#bib0240"><span class="elsevierStyleSup">8&#44;27</span></a>&#44; liberados de TQ y mascarilla&#46; Los inconvenientes del MF est&#225;n en relaci&#243;n con su implantaci&#243;n quir&#250;rgica y con complicaciones t&#233;cnicas o infecciosas<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">39</span></a>&#46; Un nuevo sistema de marcapasos que estimula directamente el diafragma podr&#237;a mejorar el procedimiento&#44; aunque la experiencia a&#250;n es muy escasa<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">40</span></a>&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">El paso de TQ a VNI se llev&#243; a cabo en nuestros pacientes a la edad media de 13&#44;7 a&#241;os&#44; el doble de la edad m&#237;nima de seguridad recomendada &#40;6-8 a&#241;os&#41;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">15</span></a>&#59; solo un ni&#241;o cambi&#243; antes de los 10 a&#241;os&#59; diversos factores no analizados en este estudio influyen en la decisi&#243;n personalizada del momento de cambio&#58; ventajas&#47;inconvenientes&#44; disposici&#243;n y deseo del paciente o padres&#44; experiencia del equipo m&#233;dico&#46;</p><p id="par0150" class="elsevierStylePara elsevierViewall">La principal limitaci&#243;n del presente estudio es que el Registro no ha reclutado a todos los pacientes espa&#241;oles con SHCC&#44; porque algunas familias han rechazado participar y porque probablemente existen pacientes no diagnosticados o desconocidos&#46; Con los pacientes conocidos y los datos demogr&#225;ficos publicados por el Instituto Nacional de Estad&#237;stica &#40;<a href="http://www.ine.es/inebmenu/mnu_dinamicapob.htm">http&#58;&#47;&#47;www&#46;ine&#46;es&#47;inebmenu&#47;mnu&#95;dinamicapob&#46;htm</a>&#41;&#44; la incidencia estimada en Espa&#241;a del SHCC ser&#237;a de 0&#44;35&#47;100&#46;000 RN vivos&#59; sin embargo&#44; tomando como referencia la incidencia francesa<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">24</span></a>&#44; en Espa&#241;a nacer&#237;an cada a&#241;o unos 2 pacientes con SHCC y sumar&#237;an unos 17 los a&#250;n no identificados&#46; Ser&#237;a necesario aumentar los esfuerzos colaborativos para identificarlos&#46;</p><p id="par0155" class="elsevierStylePara elsevierViewall">En resumen&#44; la puesta en funcionamiento del Registro europeo de pacientes con SHCC en Espa&#241;a ha permitido reconocer aspectos relevantes para optimizar sus cuidados&#58; ausencia de centros de referencia en Espa&#241;a&#44; importancia del estudio gen&#233;tico y del refuerzo educativo y algunas limitaciones de los modos ventilatorios&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Financiaci&#243;n</span><p id="par0160" class="elsevierStylePara elsevierViewall">Estudio financiado parcialmente por Proyecto FIS08&#47;90233 &#40;Angel Campos Barros&#41;&#46; El dise&#241;o&#44; elaboraci&#243;n y mantenimiento del Registro europeo fueron financiados por la Agencia Ejecutiva de Sanidad y Consumo de la Uni&#243;n Europea&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Conflicto de intereses</span><p id="par0165" class="elsevierStylePara elsevierViewall">Los autores declaran no tener ning&#250;n conflicto de intereses&#46;</p></span></span>"
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          "titulo" => "Abstract"
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            0 => array:2 [
              "identificador" => "abst0030"
              "titulo" => "Introduction"
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            1 => array:2 [
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              "titulo" => "Aim"
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              "titulo" => "Results"
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              "titulo" => "Conclusion"
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          "identificador" => "xpalclavsec828932"
          "titulo" => "Keywords"
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        4 => array:2 [
          "identificador" => "sec0005"
          "titulo" => "Introducci&#243;n"
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          "titulo" => "M&#233;todo"
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          "titulo" => "Resultados"
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            0 => array:2 [
              "identificador" => "sec0020"
              "titulo" => "Genotipos&#44; fenotipos y correlaci&#243;n genotipo&#47;fenotipo"
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            1 => array:2 [
              "identificador" => "sec0025"
              "titulo" => "Formas cl&#237;nicas de presentaci&#243;n inicial"
            ]
            2 => array:2 [
              "identificador" => "sec0030"
              "titulo" => "Tipo de ventilaci&#243;n mec&#225;nica"
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            3 => array:2 [
              "identificador" => "sec0035"
              "titulo" => "Aspectos sociales"
            ]
          ]
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          "identificador" => "sec0040"
          "titulo" => "Discusi&#243;n"
        ]
        8 => array:2 [
          "identificador" => "sec0045"
          "titulo" => "Financiaci&#243;n"
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        9 => array:2 [
          "identificador" => "sec0050"
          "titulo" => "Conflicto de intereses"
        ]
        10 => array:1 [
          "titulo" => "Bibliograf&#237;a"
        ]
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    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "fechaRecibido" => "2016-03-11"
    "fechaAceptado" => "2016-05-17"
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          "palabras" => array:5 [
            0 => "S&#237;ndrome de hipoventilaci&#243;n central cong&#233;nita"
            1 => "Registro"
            2 => "Asistencia sanitaria"
            3 => "Enfermedad rara"
            4 => "<span class="elsevierStyleItalic">PHOX2B</span>"
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          "clase" => "keyword"
          "titulo" => "Keywords"
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          "palabras" => array:5 [
            0 => "Congenital central hypoventilation syndrome"
            1 => "Registry"
            2 => "Health care"
            3 => "Rare disease"
            4 => "<span class="elsevierStyleItalic">PHOX2B</span>"
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    "resumen" => array:2 [
      "es" => array:3 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Introducci&#243;n</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">El s&#237;ndrome de hipoventilaci&#243;n central cong&#233;nita &#40;SHCC&#41; es una enfermedad gen&#233;tica muy rara causada por mutaciones en <span class="elsevierStyleItalic">PHOX2B</span>&#59; en 2010 se cre&#243; el Consorcio Europeo del S&#237;ndrome de Hipoventilaci&#243;n Central&#44; que en 2012 implant&#243; un Registro online de pacientes para optimizar su cuidado&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Objetivo</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Conocer las caracter&#237;sticas y la evoluci&#243;n de los pacientes espa&#241;oles con SHCC y detectar &#225;reas de mejora&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Materiales y m&#233;todo</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Se analizaron los datos actualizados en diciembre del 2015 de los pacientes espa&#241;oles del Registro europeo&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Resultados</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Se registr&#243; a 38 pacientes&#44; nacidos entre 1987 y 2013&#44; procedentes de 18 hospitales&#46; El 34&#44;2&#37; eran mayores de 18 a&#241;os&#46; Han fallecido 3 pacientes&#46; Aportaban estudio del gen <span class="elsevierStyleItalic">PHOX2B</span> 37 &#40;97&#44;3&#37;&#41;&#44; 32 &#40;86&#44;5&#37;&#41; con mutaci&#243;n&#46; Los genotipos 20&#47;25&#44; 20&#47;26 y 20&#47;27 representaron el 84&#44;3&#37; de las mutaciones&#46; Las disautonom&#237;as fueron m&#225;s frecuentes y graves en portadores de genotipos con mayores expansiones de polialaninas&#46; El 47&#37; de pacientes asociaba alteraciones oculares&#44; el 16&#37; Hirschsprung&#44; el 13&#37; hipoglucemias y el 5&#37; tumores&#46; Treinta pacientes &#40;79&#37;&#41; debutaron en el periodo neonatal y 8 &#40;21&#37;&#41; posteriormente &#40;inicio&#47;diagn&#243;stico tard&#237;o&#41;&#46; Ocho ni&#241;os &#40;21&#37;&#41; recibieron inicialmente ventilaci&#243;n domiciliaria con mascarilla&#59; 5 eran lactantes con comienzo neonatal&#44; 2 de ellos precisaron cambio a traqueostom&#237;a tras presentar parada cardiorrespiratoria&#59; ambos ten&#237;an mutaciones graves&#46; Han sido decanulados y transferidos a mascarilla el 34&#44;3&#37; de los pacientes &#40;edad media&#58; 13&#44;7 a&#241;os&#41;&#46; El 29&#44;4&#37; de los ni&#241;os escolarizados precisaron refuerzo educativo&#46;</p></span> <span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Conclusi&#243;n</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">La implementaci&#243;n del Registro en Espa&#241;a de pacientes con SHCC ha permitido identificar aspectos relevantes para optimizar sus cuidados&#44; tales como la importancia del estudio gen&#233;tico para el diagn&#243;stico y la estimaci&#243;n de gravedad&#44; la frecuencia elevada de alteraciones oculares y de necesidad de refuerzo educativo&#44; y algunas limitaciones de las t&#233;cnicas ventilatorias&#46;</p></span>"
        "secciones" => array:5 [
          0 => array:2 [
            "identificador" => "abst0005"
            "titulo" => "Introducci&#243;n"
          ]
          1 => array:2 [
            "identificador" => "abst0010"
            "titulo" => "Objetivo"
          ]
          2 => array:2 [
            "identificador" => "abst0015"
            "titulo" => "Materiales y m&#233;todo"
          ]
          3 => array:2 [
            "identificador" => "abst0020"
            "titulo" => "Resultados"
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          4 => array:2 [
            "identificador" => "abst0025"
            "titulo" => "Conclusi&#243;n"
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      "en" => array:3 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Introduction</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Congenital Central Hypoventilation Syndrome &#40;CCHS&#41; is a very rare genetic disease&#46; In 2012 the European Central Hypoventilation Syndrome &#40;EuCHS&#41; Consortium created an online patient registry in order to improve care&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Aim</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">To determine the characteristics and outcomes of Spanish patients with CCHS&#44; and detect clinical areas for improvement&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Materials and method</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">An assessment was made on the data from Spanish patients in the European Registry&#44; updated on December 2015&#46;</p></span> <span id="abst0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Results</span><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">The Registry contained 38 patients&#44; born between 1987 and 2013&#44; in 18 hospitals&#46; Thirteen &#40;34&#46;2&#37;&#41; were older than 18 years&#46; Three patients had died&#46; Genetic analysis identified <span class="elsevierStyleItalic">PHOX2B</span> mutations in 32 &#40;86&#46;5&#37;&#41; out of 37 patients assessed&#46; The 20&#47;25&#44; 20&#47;26 and 20&#47;27 polyalanine repeat mutations &#40;PARMs&#41; represented 84&#46;3&#37; of all mutations&#46; Longer PARMs had more&#44; as well as more severe&#44; autonomic dysfunctions&#46; Eye diseases were present in 47&#37;&#44; with 16&#37; having Hirschsprung disease&#44; 13&#37; with hypoglycaemia&#44; and 5&#37; with tumours&#46; Thirty patients &#40;79&#37;&#41; required ventilation from the neonatal period onwards&#44; and 8 &#40;21&#37;&#41; later on in life &#40;late onset&#47;presentation&#41;&#46; Eight children &#40;21&#37;&#41; were using mask ventilation at the first home discharge&#46; Five of them were infants with neonatal onset&#44; two of them&#44; both having a severe mutation&#44; were switched to tracheostomy after cardiorespiratory arrest at home&#46; Approximately one-third &#40;34&#46;3&#37;&#41; of patients were de-cannulated and switched to mask ventilation at a mean age of 13&#46;7 years&#46; Educational reinforcement was required in 29&#46;4&#37; of children attending school&#46;</p></span> <span id="abst0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Conclusion</span><p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">The implementation of the EuCHS Registry in Spain has identified some relevant issues for optimising healthcare&#44; such as the importance of genetic study for diagnosis and assessment of severity&#44; the high frequency of eye disease and educational reinforcement&#44; as well as some limitations in ventilatory techniques&#46;</p></span>"
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            "titulo" => "Materials and method"
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            "titulo" => "Results"
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          "es" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Diferentes t&#233;cnicas de ventilaci&#243;n y n&#250;mero de pacientes ventilados con cada una de ellas en la primera alta a domicilio &#40;izquierda y en diciembre del 2015 &#40;derecha&#41;&#46;</p> <p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">MF&#58; marcapasos fr&#233;nico&#59; TQ&#58; traqueostom&#237;a&#59; VNI&#58; ventilaci&#243;n no invasiva con mascarilla&#46;</p>"
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          "es" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">N&#250;mero de pacientes que han alcanzado cada nivel de escolarizaci&#243;n&#46; Se diferencian 2 grupos&#44; seg&#250;n la edad&#58; &#60; 18 a&#241;os &#40;25 pacientes&#41; y &#8805; 18 a&#241;os &#40;13 pacientes&#41;&#46; Diez ni&#241;os precisaron refuerzo educativo&#46;</p>"
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;6&#44;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " colspan="2" align="left" valign="top">&#8211;</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;5&#44;2&#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="table-entry ; entry_with_role_rowhead " align="left" valign="top">S&#237;ncopes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;13&#44;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " colspan="2" align="left" valign="top">&#8211;</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;10&#44;5&#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="table-entry ; entry_with_role_rowhead " align="left" valign="top">Mareos&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;10&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " colspan="2" align="left" valign="top">&#8211;</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;7&#44;9&#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="table-entry ; entry_with_role_rowhead " align="left" valign="top">Marcapasos cardiaco&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;6&#44;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " colspan="2" align="left" valign="top">&#8211;</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;5&#44;2&#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="table-entry ; entry_with_role_rowhead " align="left" valign="top">Convulsiones&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;40&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " colspan="2" align="left" valign="top">&#8211;</td><td class="td" title="table-entry  " align="left" valign="top">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">14&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;36&#44;8&#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="table-entry ; entry_with_role_rowhead " align="left" valign="top">Espasmos del sollozo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;13&#44;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " colspan="2" align="left" valign="top">&#8211;</td><td class="td" title="table-entry  " align="left" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;13&#44;1&#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="table-entry ; entry_with_role_rowhead " align="left" valign="top">Hipoglucemias&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;16&#44;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " colspan="2" align="left" valign="top">&#8211;</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;13&#44;1&#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="table-entry ; entry_with_role_rowhead " align="left" valign="top">Alteraciones oculares&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">17&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;56&#44;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " colspan="2" align="left" valign="top">&#8211;</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">18&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;47&#44;3&#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="table-entry ; entry_with_role_rowhead " align="left" valign="top">Media n&#46;&#176; patolog&#237;as&#47;pac<br>p<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#44;2<br>&#60; 0&#44;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&#44;36<br>&#60; 0&#44;014&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3&#44;33<br>&#60; 0&#44;003&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " colspan="2" align="center" valign="middle"></td><td class="td" title="table-entry  " colspan="2" align="center" valign="middle"></td><td class="td" title="table-entry  " colspan="2" align="center" valign="middle"></td><td class="td" title="table-entry  " colspan="2" align="center" valign="middle"></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Media de d&#237;as de estancia<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a> p&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">228<br>&#60; 0&#44;46&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">215<br>&#60; 0&#44;46&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">429<br>&#60; 0&#44;016&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">87<br>&#60; 0&#44;07&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " colspan="2" align="center" valign="middle">282</td><td class="td" title="table-entry  " colspan="2" align="center" valign="middle">425<br>&#60; 0&#44;94</td><td class="td" title="table-entry  " align="left" valign="top">165<br>&#60; 0&#44;98&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">152<br>&#60; 0&#44;92&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " colspan="2" align="center" valign="middle">271</td></tr></tbody></table>
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          "leyenda" => "<p id="spar0085" class="elsevierStyleSimplePara elsevierViewall">ddv&#58; d&#237;as de vida&#59; E&#58; enfermedad&#59; NPT&#58; nutrici&#243;n parenteral total&#59; PCR&#58; parada cardiorrespiratoria&#59; RM&#58; resonancia magn&#233;tica&#59; RN&#58; reci&#233;n nacido&#59; ROHHAD&#58; rapid-onset obesity with hypoventilation&#44; hypothalamic dysfunction and autonomic dysregulation&#59; TQ&#58; traqueostom&#237;a&#59; VM&#58; ventilaci&#243;n mec&#225;nica&#59; VNI&#58; ventilaci&#243;n no invasiva con mascarilla&#46;</p>"
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                  \t\t\t\t\tvoid\n
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                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Edad de inicio VM&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">S&#237;ntomas al comienzo &#40;modo de ventilaci&#243;n&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Mutaci&#243;n&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">1&#46; RN sano&#44; alta a domicilio<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">19 d&#237;as&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Cianosis&#44; hipercapnia sin distr&#233;s&#44; necesidad de VM &#40;TQ&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">20&#47;26&nbsp;\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">2&#46; RN sano&#44; alta a domicilio&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">40 d&#237;as&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Letargia&#44; rechazo de tomas&#44; cianosis&#44; hipercapnia sin distr&#233;s respiratorio&#44; necesidad de VM &#40;TQ&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">20&#47;25&nbsp;\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">3&#46; RN 1&#46;<span class="elsevierStyleSup">er</span> ddv&#58; episodios de cianosis&#59; diagn&#243;stico sepsis cl&#237;nica&#44; antibi&#243;ticos&#44; alta a domicilio&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">46 d&#237;as&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Reingresa por cianosis&#44; hipercapnia sin distr&#233;s&#44; necesidad de VM &#40;TQ&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">20&#47;25&nbsp;\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">4&#46; RN 1&#46;<span class="elsevierStyleSup">er</span> ddv&#58; episodios de cianosis&#44; hipoglucemias&#44; sepsis cl&#237;nica&#44; antibi&#243;ticos&#44; alta a domicilio&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">50 d&#237;as&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Reingresa por letargia&#44; rechazo de tomas&#44; cianosis&#44; hipercapnia sin distr&#233;s respiratorio&#44; edemas&#44; hepatopat&#237;a&#44; necesidad de VM &#40;TQ&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">20&#47;25&nbsp;\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">5&#46; RN 3&#46;<span class="elsevierStyleSup">er</span> ddv s&#237;ntomas digestivos&#44; necesita NPT&#59; un mes&#58; hipercapnia no valorada&#59; 3 meses&#58; diagnosticado de enfermedad de Hirschsprung&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5&#44;8 meses&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Bronquiolitis&#44; necesidad de VM &#40;VNI&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">20&#47;33&nbsp;\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">6<a class="elsevierStyleCrossRef" href="#tblfn0020"><span class="elsevierStyleSup">b</span></a>&#46; Trastornos del sue&#241;o<br>14 meses&#58; hipertensi&#243;n pulmonar primaria&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5&#44;6 a&#241;os&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Neumon&#237;a&#44; hipoxemia&#44; crisis convulsivas&#44; necesidad de VM &#40;TQ&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No realizado&nbsp;\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">7<a class="elsevierStyleCrossRef" href="#tblfn0020"><span class="elsevierStyleSup">b</span></a>&#46; Sano hasta 7 meses antes&#44; cuando inicia polifagia&#44; r&#225;pida ganancia de peso&#44; enuresis&#44; alteraciones del sue&#241;o&#44; sudoraci&#243;n profusa&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3&#44;9 a&#241;os&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Apnea&#44; cianosis&#44; PCR&#46; ROHHAD&#58; obesidad&#44; hipoventilaci&#243;n central&#44; disfunci&#243;n hipotal&#225;mica&#44; ganglioneuroblastoma tor&#225;cico&#44; necesidad de VM &#40;TQ&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No mutaci&#243;n&nbsp;\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">8&#46; Sano hasta los 3 a&#241;os&#44; cuando inicia polifagia&#44; gana 14<span class="elsevierStyleHsp" style=""></span>kg en pocos meses&#44; poliuria&#44; sudoraci&#243;n profusa&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5&#44;2 a&#241;os&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Apneas centrales y obstructivas&#46; Bradicardias&#44; Raynaud&#44; ROHHAD&#58; obesidad&#44; hipoventilaci&#243;n central&#44; disfunci&#243;n hipotal&#225;mica &#40;TSH elevada&#41;&#44; necesidad de VM &#40;VNI&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No mutaci&#243;n&nbsp;\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">9&#46; Sano&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">10&#44;4 a&#241;os&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Coma&#44; hipercapnia&#44; &#171;encefalitis&#187; resuelta con VM&#44; RM normal&#44; persiste hipoventilaci&#243;n central&#44; necesidad de VM &#40;VNI&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No mutaci&#243;n&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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            0 => array:3 [
              "identificador" => "tblfn0015"
              "etiqueta" => "a"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0015">Se incluye a un paciente con comienzo neonatal&#44; sucedido despu&#233;s de ser dado de alta a domicilio&#46;</p>"
            ]
            1 => array:3 [
              "identificador" => "tblfn0020"
              "etiqueta" => "b"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0020">Referencia S&#225;nchez et al&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">17</span></a>&#46;</p>"
            ]
          ]
        ]
        "descripcion" => array:1 [
          "es" => "<p id="spar0080" class="elsevierStyleSimplePara elsevierViewall">Pacientes con inicio o diagn&#243;stico tard&#237;o del s&#237;ndrome de hipoventilaci&#243;n central</p>"
        ]
      ]
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        "identificador" => "tbl0015"
        "etiqueta" => "Tabla 3"
        "tipo" => "MULTIMEDIATABLA"
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        "detalles" => array:1 [
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            "identificador" => "at3"
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        "tabla" => array:2 [
          "leyenda" => "<p id="spar0095" class="elsevierStyleSimplePara elsevierViewall">ddv&#58; d&#237;a de vida&#59; MF&#58; marcapasos fr&#233;nico&#59; NPARM&#58; nonpolyalanine repeat expansion mutation&#59; PCR&#58; parada cardiorrespiratoria&#59; ROHHAD&#58; rapid-onset obesity with hypoventilation&#44; hypothalamic dysfunction and autonomic dysregulation&#59; TQ&#58; traqueostom&#237;a&#59; VM&#58; ventilaci&#243;n mec&#225;nica&#46;</p>"
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                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Edad de inicio de ventilaci&#243;n&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Edad de alta a domicilio&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Patolog&#237;a asociada&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Mutaci&#243;n&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Cambio a otro modo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Edad de cambio&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Motivo de cambio&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#46;<span class="elsevierStyleSup">er</span> ddv&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&#44;7 meses&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">20&#47;25&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\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">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#46;<span class="elsevierStyleSup">er</span> ddv&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&#44;17 meses&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">20&#47;25&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\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">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#46;<span class="elsevierStyleSup">er</span> ddv&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#44;7 meses&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No mutaci&#243;n&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\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">4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#46;<span class="elsevierStyleSup">er</span> ddv&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&#44;43 meses&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Hirschsprung<br>Espasmos del sollozo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">20&#47;33&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">S&#237;&#44; a TQ&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5&#44; 7 meses&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">PCR en casa&nbsp;\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">5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#46;<span class="elsevierStyleSup">er</span> ddv&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&#44;23 meses&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">NPARM&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">S&#237;&#44; a TQ&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#44; 6 a&#241;os&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">PCR en casa&nbsp;\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">6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5&#44;7 meses&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">7&#44;3 meses&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Hirschsprung&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">20&#47;33&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\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">7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5&#44;2 a&#241;os&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5&#44; 3 a&#241;os&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ROHHAD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No mutaci&#243;n&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\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">8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">10&#44;4 a&#241;os&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">10&#44;9 a&#241;os&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Neuropat&#237;a perif&#233;rica&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No mutaci&#243;n&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">S&#237;&#44; asocia MF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">22&#44;9 a&#241;os&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Necesidad de VM 24 h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "es" => "<p id="spar0090" class="elsevierStyleSimplePara elsevierViewall">Pacientes en los que la ventilaci&#243;n no invasiva con mascarilla se us&#243; como primera opci&#243;n y se mantuvo en el primer alta a domicilio</p>"
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      ]
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        "tabla" => array:3 [
          "leyenda" => "<p id="spar0105" class="elsevierStyleSimplePara elsevierViewall">TQ&#58; traqueostom&#237;a&#59; VNI&#58; ventilaci&#243;n no invasiva con mascarilla&#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="table-head  " align="" valign="top" scope="col">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col">Todos&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " colspan="2" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Modo de ventilaci&#243;n</th><th class="td" title="table-head  " colspan="2" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Tipo de comienzo</th><th class="td" title="table-head  " colspan="2" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">A&#241;o de inicio del ingreso</th></tr><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">&#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>38&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">VNI<br>&#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>8&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">304<a class="elsevierStyleCrossRef" href="#tblfn0025"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">566<a class="elsevierStyleCrossRef" href="#tblfn0030"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">118&nbsp;\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">Desviaci&#243;n t&#237;pica&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">313&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">336&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">51&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">69&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">392&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">53&nbsp;\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">Mediana&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">153&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">181&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">70&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">153&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">162&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">332&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">103&nbsp;\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">Rango&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">49-1165&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">62-1165&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">49-175&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">51-1165&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">49-259&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">154-1165&nbsp;\t\t\t\t\t\t\n
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                      "doi" => "10.1038/ng1130"
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