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Peso percentil-75 y talla percentil-50&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">Se realizaron determinaciones en sangre de calcio total&#44; calcio i&#243;nico&#44; f&#243;sforo&#44; magnesio&#44; PTH&#44; 25-OH-vit&#46; D&#44; 1-25 &#40;OH&#41;<span class="elsevierStyleInf">2</span> vit&#46; D&#46; Tambi&#233;n se determin&#243; la creatinina &#40;Cr&#41;&#44; sodio&#44; potasio y cloro&#46; En orina se analizaron el calcio y la creatinina&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">En todas las muestras se constat&#243; hipercalcemia con calcio i&#243;nico elevado&#44; PTH normal o elevada y la calciuria disminuida&#46; Los valores anal&#237;ticos de las ni&#241;as&#44; seg&#250;n la edad&#44; se rese&#241;an en la <a class="elsevierStyleCrossRef" href="#tbl0005">tabla 1</a>&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0040" class="elsevierStylePara elsevierViewall">El estudio gen&#233;tico inicial se realiz&#243; 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es una causa poco frecuente de hipercalcemia&#44; que se produce por una mutaci&#243;n inactivante del gen que codifica para el CaSR&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">El CaSR se expresa en varios tejidos&#44; incluyendo las gl&#225;ndulas paratiroides&#44; los ri&#241;ones&#44; m&#233;dula &#243;sea&#44; osteoclastos y osteoblastos y en otros &#243;rganos&#46; Su principal funci&#243;n es regular el balance del calcio&#46; Un aumento en los niveles de calcio en plasma hace que&#44; detectado por el CaSR&#44; act&#250;e este&#44; disminuyendo la secreci&#243;n de PTH&#44; con la finalidad de normalizar la calcemia<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;2</span></a>&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">El CaSR es un receptor perteneciente a la familia de los receptores acoplados a prote&#237;nas G que se encuentra en la membrana de las c&#233;lulas de la gl&#225;ndula paratiroides<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a>&#46; El CaSR es un importante regulador de la excreci&#243;n urinaria de calcio&#46; El calcio se reabsorbe en el segmento cortical de la rama ascendente de Henle mediante un proceso pasivo&#46; Este mecanismo est&#225; regulado por el sensor del calcio&#44; que se encuentra en la superficie basocelular de estas c&#233;lulas y detecta los cambios en el calcio i&#243;nico sangu&#237;neo &#40;<a class="elsevierStyleCrossRef" href="#fig0010">fig&#46; 2</a>&#41;&#46; La activaci&#243;n del receptor CaSR&#44; por elevaci&#243;n del Ca i&#243;nico en plasma&#44; inhibe los mecanismos de transporte activo de sodio&#44; potasio y cloro y la reabsorci&#243;n activa de sodio&#44; disminuyendo as&#237; la diferencia de potencial transepitelial y&#44; de forma secundaria&#44; la reabsorci&#243;n pasiva de calcio<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#44;5</span></a>&#46; Las mutaciones inactivantes en el gen del receptor CaSR provocan un cierto grado de resistencia generalizada al calcio&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0060" class="elsevierStylePara elsevierViewall">Las alteraciones gen&#233;ticas implicadas con mayor frecuencia en la FHH se encuentran en el gen CASR&#44; localizado en el brazo largo del cromosoma 3&#46; La mayor&#237;a de las mutaciones producen un cambio en un &#250;nico amino&#225;cido que altera la funci&#243;n del receptor<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6-8</span></a>&#46; Los pacientes heterocigotos son diagnosticados de forma casual o por cribado de familiares afectados&#46; En familias con FHH y antecedentes de consanguinidad se han descrito formas de hiperparatiroidismo neonatal severo con hipercalcemias severas y trastornos &#243;seos graves cuando se heredan los dos alelos del gen portador de la FHH<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a>&#46; Todos nuestros casos presentaban en heterocigosis una mutaci&#243;n inactivante&#44; p&#46;Phe789del&#44; en el ex&#243;n 7 del gen del receptor sensible al calcio&#44; localizado en el cromosoma 3q 21&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">La escasa expresi&#243;n cl&#237;nica pone el punto de inter&#233;s del diagn&#243;stico de la FHH en la distinci&#243;n del hiperparatirodismo primario y en evitar tratamientos innecesarios&#46; El perfil bioqu&#237;mico de hipercalcemia-hipocalciuria se acompa&#241;a de tendencia a la hipermagnesemia&#44; niveles s&#233;ricos inapropiadamente normales o elevados de PTH y metabolitos de la vitamina D<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a>&#46; La ausencia de s&#237;ntomas de hipercalcemia &#40;debilidad muscular&#44; anorexia&#44; v&#243;mitos&#44; estre&#241;imiento&#44; polidipsia-poliuria&#44; p&#233;rdida de peso&#41; y el hallazgo de hipercalcemia-hipocalciuria en otros miembros de la familia nos orientan hacia el diagnostico de FHH<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a>&#46; La determinaci&#243;n de la calciuria se entorpece por el problema que supone la recogida de orina de 24 horas en los ni&#241;os&#59; el cociente o &#237;ndice Ca&#47;Cr en micci&#243;n aislada s&#243;lo es v&#225;lido para valorar la hipercalciuria&#44; pero no la hipocalciuria&#46; Por este motivo&#44; se utiliza el &#237;ndice de excreci&#243;n de calcio&#44; que se calcula dividiendo el aclaramiento de calcio entre el aclaramiento de creatinina&#44; y se expresan en mg&#47;100<span class="elsevierStyleHsp" style=""></span>ml de GFR<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a>&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">El an&#225;lisis mutacional se debe realizar&#58; a&#41; en los lactantes y ni&#241;os menores de 10 a&#241;os&#44; en los cuales el hiperparatiroidismo primario y la FHH son las causas m&#225;s frecuentes de hipercalcemia cuando la PTH est&#225; elevada o normal&#59; b&#41; en los casos at&#237;picos en los que no se demuestra la hipocalciuria&#44; pacientes con fenotipo FHH cuyos padres son normocalc&#233;micos &#40;mutaci&#243;n del CASR <span class="elsevierStyleItalic">de novo</span>&#41;&#59; y c&#41; cuando no hay miembros de la familia disponibles para pruebas<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a>&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">En resumen&#44; en presencia de una hipercalcemia con PTH elevada o inapropiadamente normal es importante realizar el estudio familiar y determinar la calciuria&#46; La aparici&#243;n de alg&#250;n miembro afecto en la familia&#44; o la aparici&#243;n de hipocalciuria es suficiente para sospechar esta entidad e indicar el an&#225;lisis mutacional para establecer el diagn&#243;stico diferencial con el hiperparatiroidismo primario y evitar tratamientos innecesarios&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Conflicto de intereses</span><p id="par0085" class="elsevierStylePara elsevierViewall">Los autores declaran no tener ning&#250;n conflicto de intereses&#46;</p></span></span>"
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    "fechaRecibido" => "2010-06-14"
    "fechaAceptado" => "2010-10-07"
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          "identificador" => "xpalclavsec93363"
          "palabras" => array:3 [
            0 => "Hipercalcemia hipocalci&#250;rica familiar"
            1 => "Hiperparatiroidismo"
            2 => "Rreceptor sensible al calcio"
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        0 => array:4 [
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            1 => "Hyperparathyroidism"
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        "resumen" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">La hipercalcemia hipocalci&#250;rica familiar &#40;FHH&#41; es una de las causas de hipercalcemia&#59; se hereda de forma autos&#243;mica dominante&#44; y posee alta penetrancia&#46; Es el resultado de una mutaci&#243;n inactivante en el gen del receptor sensible al calcio &#40;CaSR&#41;&#46; Los casos heterocigotos no suelen presentar s&#237;ntomas y se diagnostican de forma incidental&#46;</p><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Presentamos los casos de tres ni&#241;as afectas de una mutaci&#243;n inactivante en heterocigosis&#44; p&#46;Phe789del&#44; en el ex&#243;n 7 del gen del receptor sensible al calcio &#40;gen CASR&#41; localizado en el cromosoma 3q21 &#40;Ensembl ENSG00000036828&#41;&#46; En las muestras sangu&#237;neas se constat&#243; hipercalcemia con calcio i&#243;nico elevado&#44; hormona paratiroidea normal o elevada&#44; y la calciuria disminuida&#46;</p><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Es importante establecer el diagnostico-diferencial con el hiperparatiroidismo primario&#46; Por lo tanto&#44; en presencia de una hipercalcemia con hormona paratiroidea elevada o normal&#44; se debe realizar el estudio familiar y determinar la calciuria&#46; La aparici&#243;n de alg&#250;n miembro afecto en la familia o la aparici&#243;n de hipocalciuria es suficiente para sospechar esta entidad e indicar el an&#225;lisis mutacional&#44; para establecer el diagn&#243;stico diferencial con el hiperparatiroidismo primario y evitar tratamientos innecesarios&#46;</p>"
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        "resumen" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Familial hypocalciuric hypercalcemia &#40;FHH&#41; is a cause of hypercalcemia with autosomal dominant pattern of inheritance and high penetrance&#46; In most of the cases it can be shown to be due to an inactivating mutation on the gene coding for the calcium-sensing receptor &#40;CaSR&#41;&#46; Heterozygous cases usually do not present symptoms and they are diagnosed as an incidental finding&#46;</p><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">We report three affected children with an inactivating heterozygous mutation&#44; p&#46;Phe789del&#44; in exon 7 of the calcium-sensing receptor gene &#40;CASR gene&#41;&#44; situated in chromosome 3q21 &#40;Ensembl ENSG00000036828&#41;&#44; which results in elevated serum calcium&#44; normal o high level of parathyroid hormone &#40;PTH&#41; and reduced urinary excretion with hypocalciuria&#46;</p><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">It is very important to determine the difference between FHH and primary hyperparathyroidism&#46; Therefore&#44; in a mild to moderate PTH-dependent hypercalcemia we must perform a family study and determine the urinary excretion of calcium&#46; The presence of any other affected family member or reduced urinary calcium excretion is enough to suspect FHH&#44; and this should be confirmed by the mutational analysis of the CASR gene&#44; in order to establish the correct diagnosis&#44; differentiated from primary hyperparathyroidism&#44; to avoid unnecessary investigations or operations&#46;</p>"
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          "es" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">&#193;rbol geneal&#243;gico de la familia&#58; en azul&#44; casos en la familia&#59; flecha&#44; probandos&#46;</p>"
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          "leyenda" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">25-&#40;OH&#41; vit D&#58; 25 hidroxi vitamina D s&#233;rica&#59; 1&#44;25- &#40;OH&#41;<span class="elsevierStyleInf">2</span> vit D&#58; 1&#44;25 dihidroxi vitamina D s&#233;rica&#59; Ca&#58; calcio&#59; Cr P&#58; creatinina plasm&#225;tica&#59; IECa&#58; &#237;ndice de excreci&#243;n urinaria de calcio&#59; Mg&#58; magnesio plasm&#225;tico&#59; P&#58; f&#243;sforo plasm&#225;tico&#59; PTH&#58; hormona paratiroidea&#46;</p>"
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                  <table border="0" frame="\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Edad &#40;a&#241;os&#41;&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">Ca total &#40;mg&#47;dl&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Ca i&#243;nico &#40;mMol&#47;l&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">PTH &#40;pg&#47;ml&#41;&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">25-OH vit D &#40;ng&#47;ml&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">1&#44;25-&#40;OH&#41;<span class="elsevierStyleInf">2</span> vit D &#40;pg&#47;ml&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Cr P &#40;mg&#47;dl&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">P &#40;mg&#47;dl&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Mg &#40;mg&#47;dl&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">IECa &#40;mg&#47;100ml&#41;GFR&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">&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" style="border-bottom: 2px solid black">9&#44;05&#8211;10&#44;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td 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" style="border-bottom: 2px solid black">1&#44;12&#8211;1&#44;32&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">10&#8211;65&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td 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" style="border-bottom: 2px solid black">25&#8211;35&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td 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" style="border-bottom: 2px solid black">20&#8211;80&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td 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" style="border-bottom: 2px solid black">0&#44;3&#8211;0&#44;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td 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" style="border-bottom: 2px solid black">3&#44;5&#8211;5&#44;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">1&#44;7&#8211;2&#44;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">0&#44;03&#8211;0&#44;06&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><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 &#189; meses&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">12&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&#44;6&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">30&#44;6&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">35&#44;7&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">80&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">0&#44;24&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">5&#44;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
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                  \t\t\t\t">2&#44;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
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                  \t\t\t\t">0&#44;002&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
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                  """
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          "es" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Valores anal&#237;ticos de las tres ni&#241;as afectas de mutaci&#243;n&#46;</p>"
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          "leyenda" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">25-&#40;OH&#41; vit D&#58; 25 hidroxi vitamina D s&#233;rica&#59; 1&#44;25- &#40;OH&#41;<span class="elsevierStyleInf">2</span> vit D&#58; 1&#44;25 dihidroxi vitamina D s&#233;rica&#59; Ca&#58; calcio&#59; Cr P&#58; creatinina plasm&#225;tica&#59; IECa&#58; &#237;ndice de excreci&#243;n urinaria de calcio&#59; Mg&#58; magnesio plasm&#225;tico&#59; P&#58; f&#243;sforo plasm&#225;tico&#59; PTH&#58; hormona paratiroidea&#46;</p>"
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Original breve
Hipercalcemia hipocalciúrica familiar: a propósito de una nueva mutación
Familial hypocalciuric hypercalcemia: a new mutation
M. Ubetagoyena Arrietaa,
Autor para correspondencia
, L. Castaño Gonzálezb,c, G. Pérez de Nanclares Lealb, D. Arruebarrena Lizarragaa,d, M. Imaz Murguiondoa, R. Areses Trapotea
a Sección de Nefrología Pediátrica, Osakidetza, Hospital Universitario Donostia, San Sebastián, España
b Unidad de Investigación. Laboratorio de Genética Molecular, CIBERER (Ciber de enfermedades raras) Osakidetza, Hospital de Cruces, Baracaldo, Vizcaya, España
c Departamento de Pediatría, Facultad de Medicina (U.D. de Cruces), Universidad del País Vasco, España
d Departamento de Pediatría, Facultad de Medicina (U.D. de San Sebastián), Universidad del País Vasco, España
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Introducci&#243;n</span><p id="par0005" class="elsevierStylePara elsevierViewall">La hipercalcemia hipocalci&#250;rica familiar &#40;FHH&#41; es una de las causas de hipercalcemia&#59; se hereda de forma autos&#243;mica dominante&#44; y posee alta penetrancia&#46; Los efectos del calcio sobre la hormona paratiroidea &#40;PTH&#41; y los ri&#241;ones est&#225;n mediados por su receptor espec&#237;fico&#44; receptor-sensible al calcio &#40;CaSR&#41;&#44; que se encuentra en la membrana de las c&#233;lulas de la gl&#225;ndula paratiroides y en las c&#233;lulas renales<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;2</span></a>&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">La mayor&#237;a de los casos de FHH son el resultado de una mutaci&#243;n inactivante en el CaSR&#44; cuyo gen &#40;CASR&#41; se encuentra en el brazo largo del cromosoma 3&#46; Estas mutaciones inactivantes se manifiestan por una hipercalcemia leve o moderada&#44; con PTH normal o elevada y disminuci&#243;n de la excreci&#243;n de calcio urinario&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Pacientes</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Caso 1</span><p id="par0015" class="elsevierStylePara elsevierViewall">Ni&#241;a de 1 mes&#44; remitida a la consulta para despistaje de FHH&#46; Primera gestaci&#243;n sin incidencias&#46; Parto a t&#233;rmino&#44; eut&#243;cico&#46; Peso natal &#40;PN&#41;&#58; 2&#46;950<span class="elsevierStyleHsp" style=""></span>g&#46; Padres no consangu&#237;neos&#46; Hasta la &#250;ltima revisi&#243;n realizada a los dos a&#241;os se ha mantenido asintom&#225;tica con desarrollo psicomotor y p&#243;ndero-estatural normales &#40;peso percentil-10 y talla percentil-50&#41;&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Caso 2</span><p id="par0020" class="elsevierStylePara elsevierViewall">Ni&#241;a de 2 a&#241;os y 8 meses&#46; Prima del caso anterior&#46; Tambi&#233;n acudi&#243; a la consulta para despistaje de FHH&#46; Parto a t&#233;rmino&#44; eut&#243;cico&#46; PN&#58; 3&#46;600<span class="elsevierStyleHsp" style=""></span>g&#46; Padres no consangu&#237;neos&#46; Sus antecedentes personales carec&#237;an de inter&#233;s y presentaba un desarrollo psicomotor y p&#243;ndero-estatural normales&#46; La &#250;ltima consulta se realiz&#243; a los tres a&#241;os y seis meses manteni&#233;ndose asintom&#225;tica con crecimiento en peso y talla en percentil 90&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Caso 3</span><p id="par0025" class="elsevierStylePara elsevierViewall">Ni&#241;a de 11 a&#241;os&#46; Prima de las dos anteriores&#46; Parto a t&#233;rmino&#44; eut&#243;cico&#46; Parto normal&#46; PN&#58; 3&#46;870<span class="elsevierStyleHsp" style=""></span>g&#46; Antecedentes personales sin inter&#233;s&#46; Desarrollo psicomotor y p&#243;ndero-estatural normales&#46; Peso percentil-75 y talla percentil-50&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">Se realizaron determinaciones en sangre de calcio total&#44; calcio i&#243;nico&#44; f&#243;sforo&#44; magnesio&#44; PTH&#44; 25-OH-vit&#46; D&#44; 1-25 &#40;OH&#41;<span class="elsevierStyleInf">2</span> vit&#46; D&#46; Tambi&#233;n se determin&#243; la creatinina &#40;Cr&#41;&#44; sodio&#44; potasio y cloro&#46; En orina se analizaron el calcio y la creatinina&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">En todas las muestras se constat&#243; hipercalcemia con calcio i&#243;nico elevado&#44; PTH normal o elevada y la calciuria disminuida&#46; Los valores anal&#237;ticos de las ni&#241;as&#44; seg&#250;n la edad&#44; se rese&#241;an en la <a class="elsevierStyleCrossRef" href="#tbl0005">tabla 1</a>&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0040" class="elsevierStylePara elsevierViewall">El estudio gen&#233;tico inicial se realiz&#243; en la abuela de las ni&#241;as &#40;66 a&#241;os&#41; tras el hallazgo de hipercalcemia durante una evaluaci&#243;n de rutina por osteoporosis&#46; Se estudi&#243; molecularmente a la abuela&#44; a sus cinco hijas y a sus tres nietas&#46; Todas&#44; menos una de las hijas&#44; presentaban a nivel del ADN codificante &#40;cADN&#41; cuya nomenclatura ser&#237;a c&#46;2367&#95;2369 del CTT&#44; la mutaci&#243;n p&#46;Phe789del en heterocigosis &#40;<a class="elsevierStyleCrossRef" href="#fig0005">fig&#46; 1</a>&#41;&#46; Los datos anal&#237;ticos se resumen en la <a class="elsevierStyleCrossRef" href="#tbl0010">tabla 2</a>&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Discusi&#243;n</span><p id="par0045" class="elsevierStylePara elsevierViewall">La FHH&#44; tambi&#233;n denominada hipercalcemia familiar benigna&#44; es una causa poco frecuente de hipercalcemia&#44; que se produce por una mutaci&#243;n inactivante del gen que codifica para el CaSR&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">El CaSR se expresa en varios tejidos&#44; incluyendo las gl&#225;ndulas paratiroides&#44; los ri&#241;ones&#44; m&#233;dula &#243;sea&#44; osteoclastos y osteoblastos y en otros &#243;rganos&#46; Su principal funci&#243;n es regular el balance del calcio&#46; Un aumento en los niveles de calcio en plasma hace que&#44; detectado por el CaSR&#44; act&#250;e este&#44; disminuyendo la secreci&#243;n de PTH&#44; con la finalidad de normalizar la calcemia<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;2</span></a>&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">El CaSR es un receptor perteneciente a la familia de los receptores acoplados a prote&#237;nas G que se encuentra en la membrana de las c&#233;lulas de la gl&#225;ndula paratiroides<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a>&#46; El CaSR es un importante regulador de la excreci&#243;n urinaria de calcio&#46; El calcio se reabsorbe en el segmento cortical de la rama ascendente de Henle mediante un proceso pasivo&#46; Este mecanismo est&#225; regulado por el sensor del calcio&#44; que se encuentra en la superficie basocelular de estas c&#233;lulas y detecta los cambios en el calcio i&#243;nico sangu&#237;neo &#40;<a class="elsevierStyleCrossRef" href="#fig0010">fig&#46; 2</a>&#41;&#46; La activaci&#243;n del receptor CaSR&#44; por elevaci&#243;n del Ca i&#243;nico en plasma&#44; inhibe los mecanismos de transporte activo de sodio&#44; potasio y cloro y la reabsorci&#243;n activa de sodio&#44; disminuyendo as&#237; la diferencia de potencial transepitelial y&#44; de forma secundaria&#44; la reabsorci&#243;n pasiva de calcio<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#44;5</span></a>&#46; Las mutaciones inactivantes en el gen del receptor CaSR provocan un cierto grado de resistencia generalizada al calcio&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0060" class="elsevierStylePara elsevierViewall">Las alteraciones gen&#233;ticas implicadas con mayor frecuencia en la FHH se encuentran en el gen CASR&#44; localizado en el brazo largo del cromosoma 3&#46; La mayor&#237;a de las mutaciones producen un cambio en un &#250;nico amino&#225;cido que altera la funci&#243;n del receptor<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6-8</span></a>&#46; Los pacientes heterocigotos son diagnosticados de forma casual o por cribado de familiares afectados&#46; En familias con FHH y antecedentes de consanguinidad se han descrito formas de hiperparatiroidismo neonatal severo con hipercalcemias severas y trastornos &#243;seos graves cuando se heredan los dos alelos del gen portador de la FHH<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a>&#46; Todos nuestros casos presentaban en heterocigosis una mutaci&#243;n inactivante&#44; p&#46;Phe789del&#44; en el ex&#243;n 7 del gen del receptor sensible al calcio&#44; localizado en el cromosoma 3q 21&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">La escasa expresi&#243;n cl&#237;nica pone el punto de inter&#233;s del diagn&#243;stico de la FHH en la distinci&#243;n del hiperparatirodismo primario y en evitar tratamientos innecesarios&#46; El perfil bioqu&#237;mico de hipercalcemia-hipocalciuria se acompa&#241;a de tendencia a la hipermagnesemia&#44; niveles s&#233;ricos inapropiadamente normales o elevados de PTH y metabolitos de la vitamina D<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a>&#46; La ausencia de s&#237;ntomas de hipercalcemia &#40;debilidad muscular&#44; anorexia&#44; v&#243;mitos&#44; estre&#241;imiento&#44; polidipsia-poliuria&#44; p&#233;rdida de peso&#41; y el hallazgo de hipercalcemia-hipocalciuria en otros miembros de la familia nos orientan hacia el diagnostico de FHH<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a>&#46; La determinaci&#243;n de la calciuria se entorpece por el problema que supone la recogida de orina de 24 horas en los ni&#241;os&#59; el cociente o &#237;ndice Ca&#47;Cr en micci&#243;n aislada s&#243;lo es v&#225;lido para valorar la hipercalciuria&#44; pero no la hipocalciuria&#46; Por este motivo&#44; se utiliza el &#237;ndice de excreci&#243;n de calcio&#44; que se calcula dividiendo el aclaramiento de calcio entre el aclaramiento de creatinina&#44; y se expresan en mg&#47;100<span class="elsevierStyleHsp" style=""></span>ml de GFR<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a>&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">El an&#225;lisis mutacional se debe realizar&#58; a&#41; en los lactantes y ni&#241;os menores de 10 a&#241;os&#44; en los cuales el hiperparatiroidismo primario y la FHH son las causas m&#225;s frecuentes de hipercalcemia cuando la PTH est&#225; elevada o normal&#59; b&#41; en los casos at&#237;picos en los que no se demuestra la hipocalciuria&#44; pacientes con fenotipo FHH cuyos padres son normocalc&#233;micos &#40;mutaci&#243;n del CASR <span class="elsevierStyleItalic">de novo</span>&#41;&#59; y c&#41; cuando no hay miembros de la familia disponibles para pruebas<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a>&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">En resumen&#44; en presencia de una hipercalcemia con PTH elevada o inapropiadamente normal es importante realizar el estudio familiar y determinar la calciuria&#46; La aparici&#243;n de alg&#250;n miembro afecto en la familia&#44; o la aparici&#243;n de hipocalciuria es suficiente para sospechar esta entidad e indicar el an&#225;lisis mutacional para establecer el diagn&#243;stico diferencial con el hiperparatiroidismo primario y evitar tratamientos innecesarios&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Conflicto de intereses</span><p id="par0085" class="elsevierStylePara elsevierViewall">Los autores declaran no tener ning&#250;n conflicto de intereses&#46;</p></span></span>"
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        "resumen" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">La hipercalcemia hipocalci&#250;rica familiar &#40;FHH&#41; es una de las causas de hipercalcemia&#59; se hereda de forma autos&#243;mica dominante&#44; y posee alta penetrancia&#46; Es el resultado de una mutaci&#243;n inactivante en el gen del receptor sensible al calcio &#40;CaSR&#41;&#46; Los casos heterocigotos no suelen presentar s&#237;ntomas y se diagnostican de forma incidental&#46;</p><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Presentamos los casos de tres ni&#241;as afectas de una mutaci&#243;n inactivante en heterocigosis&#44; p&#46;Phe789del&#44; en el ex&#243;n 7 del gen del receptor sensible al calcio &#40;gen CASR&#41; localizado en el cromosoma 3q21 &#40;Ensembl ENSG00000036828&#41;&#46; En las muestras sangu&#237;neas se constat&#243; hipercalcemia con calcio i&#243;nico elevado&#44; hormona paratiroidea normal o elevada&#44; y la calciuria disminuida&#46;</p><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Es importante establecer el diagnostico-diferencial con el hiperparatiroidismo primario&#46; Por lo tanto&#44; en presencia de una hipercalcemia con hormona paratiroidea elevada o normal&#44; se debe realizar el estudio familiar y determinar la calciuria&#46; La aparici&#243;n de alg&#250;n miembro afecto en la familia o la aparici&#243;n de hipocalciuria es suficiente para sospechar esta entidad e indicar el an&#225;lisis mutacional&#44; para establecer el diagn&#243;stico diferencial con el hiperparatiroidismo primario y evitar tratamientos innecesarios&#46;</p>"
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        "resumen" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Familial hypocalciuric hypercalcemia &#40;FHH&#41; is a cause of hypercalcemia with autosomal dominant pattern of inheritance and high penetrance&#46; In most of the cases it can be shown to be due to an inactivating mutation on the gene coding for the calcium-sensing receptor &#40;CaSR&#41;&#46; Heterozygous cases usually do not present symptoms and they are diagnosed as an incidental finding&#46;</p><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">We report three affected children with an inactivating heterozygous mutation&#44; p&#46;Phe789del&#44; in exon 7 of the calcium-sensing receptor gene &#40;CASR gene&#41;&#44; situated in chromosome 3q21 &#40;Ensembl ENSG00000036828&#41;&#44; which results in elevated serum calcium&#44; normal o high level of parathyroid hormone &#40;PTH&#41; and reduced urinary excretion with hypocalciuria&#46;</p><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">It is very important to determine the difference between FHH and primary hyperparathyroidism&#46; Therefore&#44; in a mild to moderate PTH-dependent hypercalcemia we must perform a family study and determine the urinary excretion of calcium&#46; The presence of any other affected family member or reduced urinary calcium excretion is enough to suspect FHH&#44; and this should be confirmed by the mutational analysis of the CASR gene&#44; in order to establish the correct diagnosis&#44; differentiated from primary hyperparathyroidism&#44; to avoid unnecessary investigations or operations&#46;</p>"
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          "leyenda" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">25-&#40;OH&#41; vit D&#58; 25 hidroxi vitamina D s&#233;rica&#59; 1&#44;25- &#40;OH&#41;<span class="elsevierStyleInf">2</span> vit D&#58; 1&#44;25 dihidroxi vitamina D s&#233;rica&#59; Ca&#58; calcio&#59; Cr P&#58; creatinina plasm&#225;tica&#59; IECa&#58; &#237;ndice de excreci&#243;n urinaria de calcio&#59; Mg&#58; magnesio plasm&#225;tico&#59; P&#58; f&#243;sforo plasm&#225;tico&#59; PTH&#58; hormona paratiroidea&#46;</p>"
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                  """
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Información del artículo
ISSN: 16954033
Idioma original: Español
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2018 Octubre 224 25 249
2018 Septiembre 95 12 107
2018 Agosto 6 0 6
2018 Julio 9 0 9
2018 Junio 11 0 11
2018 Mayo 17 0 17
2018 Abril 64 0 64
2018 Marzo 69 0 69
2018 Febrero 69 0 69
2018 Enero 73 1 74
2017 Diciembre 78 0 78
2017 Noviembre 65 0 65
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2017 Septiembre 71 1 72
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2017 Julio 62 0 62
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2017 Mayo 101 31 132
2017 Abril 62 20 82
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2016 Julio 48 9 57
2016 Junio 3 0 3
2016 Mayo 2 0 2
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2016 Marzo 4 8 12
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2013 Noviembre 209 12 221
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2013 Septiembre 114 23 137
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2013 Junio 1 5 6
2013 Mayo 1 5 6
2013 Abril 3 3 6
2013 Marzo 2 8 10
2013 Febrero 17 6 23
2013 Enero 7 1 8
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