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array:24 [ "pii" => "S2387020623004667" "issn" => "23870206" "doi" => "10.1016/j.medcle.2023.06.031" "estado" => "S300" "fechaPublicacion" => "2023-12-07" "aid" => "6323" "copyright" => "Elsevier España, S.L.U.. All rights reserved" "copyrightAnyo" => "2023" "documento" => "simple-article" "crossmark" => 1 "subdocumento" => "crp" "cita" => "Med Clin. 2023;161:493-7" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "Traduccion" => array:1 [ "es" => array:19 [ "pii" => "S002577532300369X" "issn" => "00257753" "doi" => "10.1016/j.medcli.2023.06.009" "estado" => "S300" "fechaPublicacion" => "2023-12-07" "aid" => "6323" "copyright" => "Elsevier España, S.L.U." "documento" => "simple-article" "crossmark" => 1 "subdocumento" => "crp" "cita" => "Med Clin. 2023;161:493-7" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "es" => array:13 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Nota clínica</span>" "titulo" => "Deficiencia de vitamina D en la edad adulta: presentación de 2 casos familiares de seudohipoparatiroidismo" "tienePdf" => "es" "tieneTextoCompleto" => "es" "tieneResumen" => array:2 [ 0 => "es" 1 => "en" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "493" "paginaFinal" => "497" ] ] "titulosAlternativos" => array:1 [ "en" => array:1 [ "titulo" => "Vitamin D deficiency in adulthood: Presentation of 2<span class="elsevierStyleHsp" style=""></span>familial cases simulating pseudohypoparathyroidism" ] ] "contieneResumen" => array:2 [ "es" => true "en" => true ] "contieneTextoCompleto" => array:1 [ "es" => true ] "contienePdf" => array:1 [ "es" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figura 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1551 "Ancho" => 3341 "Tamanyo" => 577095 ] ] "descripcion" => array:1 [ "es" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Resultados de los estudios genéticos realizados a la familia 1. A) Identificación de la alteración en homocigosis en el exón 1 del gen <span class="elsevierStyleItalic">CYP27B1</span> mediante secuenciación masiva (NGS). Los archivos obtenidos del alineamiento de las lecturas NGS <span class="elsevierStyleItalic">paired-end</span> (rosa, sentido; azul, antisentido) está cargado en el visor del genoma interactivo, IGV para su visualización. La secuencia del gen está en la orientación inversa en el cromosoma (hebra –1). Se indica la posición de la mutación mediante una flecha roja. La raya negra representa deleción, posteriormente se muestra el cambio por una timina (rojo) en homocigosis. El panel superior corresponde a la persona índice, mientras que el inferior a una persona control. B) Confirmación mediante secuenciación Sanger de la presencia de la variante c.103_104delinsA (nombrada en la hebra<span class="elsevierStyleHsp" style=""></span>+1, según recomendaciones internacionales). El panel superior corresponde a la secuencia de la paciente índice, el intermedio a su padre y el inferior a una muestra control. Los resultados de la hermana y de la madre son idénticos a los mostrados en el panel superior y medio, respectivamente (datos no mostrados). Los nucleótidos alterados se muestran entre corchetes negros, la posición de la mutación se señala con una flecha roja.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "África Manero-Azua, Arrate Pereda, Natalia González Cabrera, M. Ángeles Martínez de Salinas Santamaría, Alejandro Cámara Balda, Guiomar Pérez de Nanclares" "autores" => array:6 [ 0 => array:2 [ "nombre" => "África" "apellidos" => "Manero-Azua" ] 1 => array:2 [ "nombre" => "Arrate" "apellidos" => "Pereda" ] 2 => array:2 [ "nombre" => "Natalia" "apellidos" => "González Cabrera" ] 3 => array:2 [ "nombre" => "M. Ángeles" "apellidos" => "Martínez de Salinas Santamaría" ] 4 => array:2 [ "nombre" => "Alejandro" "apellidos" => "Cámara Balda" ] 5 => array:2 [ "nombre" => "Guiomar" "apellidos" => "Pérez de Nanclares" ] ] ] ] ] "idiomaDefecto" => "es" "Traduccion" => array:1 [ "en" => array:9 [ "pii" => "S2387020623004667" "doi" => "10.1016/j.medcle.2023.06.031" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2387020623004667?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S002577532300369X?idApp=UINPBA00004N" "url" => "/00257753/0000016100000011/v1_202311261528/S002577532300369X/v1_202311261528/es/main.assets" ] ] "itemSiguiente" => array:19 [ "pii" => "S2387020623004746" "issn" => "23870206" "doi" => "10.1016/j.medcle.2023.06.034" "estado" => "S300" "fechaPublicacion" => "2023-12-07" "aid" => "6383" "copyright" => "The Author(s)" "documento" => "simple-article" "crossmark" => 1 "subdocumento" => "crp" "cita" => "Med Clin. 2023;161:498-9" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "en" => array:10 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Scientific letter</span>" "titulo" => "Hyperbaric oxygen therapy in long-COVID-19 disease" "tienePdf" => "en" "tieneTextoCompleto" => "en" "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "498" "paginaFinal" => "499" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Oxigenoterapia hiperbarica en la enfermedad por COVID-19 persistente" ] ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Daniel Apolinar García Estévez, Ángel López Pérez, Hugo Gómez Márquez" "autores" => array:3 [ 0 => array:2 [ "nombre" => "Daniel Apolinar" "apellidos" => "García Estévez" ] 1 => array:2 [ "nombre" => "Ángel" "apellidos" => "López Pérez" ] 2 => array:2 [ "nombre" => "Hugo" "apellidos" => "Gómez Márquez" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S0025775323004578" "doi" => "10.1016/j.medcli.2023.06.046" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0025775323004578?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2387020623004746?idApp=UINPBA00004N" "url" => "/23870206/0000016100000011/v3_202406120712/S2387020623004746/v3_202406120712/en/main.assets" ] "itemAnterior" => array:19 [ "pii" => "S2387020623004679" "issn" => "23870206" "doi" => "10.1016/j.medcle.2023.06.032" "estado" => "S300" "fechaPublicacion" => "2023-12-07" "aid" => "6341" "copyright" => "Elsevier España, S.L.U." "documento" => "article" "crossmark" => 1 "subdocumento" => "rev" "cita" => "Med Clin. 2023;161:485-92" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "en" => array:13 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Review</span>" "titulo" => "Management of acute ischemic stroke" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "en" 1 => "es" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "485" "paginaFinal" => "492" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Abordaje y tratamiento del ictus isquémico en la fase aguda" ] ] "contieneResumen" => array:2 [ "en" => true "es" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1191 "Ancho" => 2410 "Tamanyo" => 182660 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0095" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Management and care of ischaemic stroke in the acute phase.</p> <p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">DVT, deep vein thrombosis; IVT, intravenous thrombolysis; LMWH, low molecular weight heparin; NGT, nasogastric tube; PE, pulmonary embolism; VRF, vascular risk factors.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Ricardo Rigual, Blanca Fuentes, Exuperio Díez-Tejedor" "autores" => array:3 [ 0 => array:2 [ "nombre" => "Ricardo" "apellidos" => "Rigual" ] 1 => array:2 [ "nombre" => "Blanca" "apellidos" => "Fuentes" ] 2 => array:2 [ "nombre" => "Exuperio" "apellidos" => "Díez-Tejedor" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S0025775323003974" "doi" => "10.1016/j.medcli.2023.06.022" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0025775323003974?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2387020623004679?idApp=UINPBA00004N" "url" => "/23870206/0000016100000011/v3_202406120712/S2387020623004679/v3_202406120712/en/main.assets" ] "en" => array:20 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Clinical report</span>" "titulo" => "Vitamin D deficiency in adulthood: Presentation of 2 familial cases simulating pseudohypoparathyroidism" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "493" "paginaFinal" => "497" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "África Manero-Azua, Arrate Pereda, Natalia González Cabrera, M. Ángeles Martínez de Salinas Santamaría, Alejandro Cámara Balda, Guiomar Pérez de Nanclares" "autores" => array:6 [ 0 => array:3 [ "nombre" => "África" "apellidos" => "Manero-Azua" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 1 => array:3 [ "nombre" => "Arrate" "apellidos" => "Pereda" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 2 => array:3 [ "nombre" => "Natalia" "apellidos" => "González Cabrera" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 3 => array:3 [ "nombre" => "M. Ángeles" "apellidos" => "Martínez de Salinas Santamaría" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] ] ] 4 => array:3 [ "nombre" => "Alejandro" "apellidos" => "Cámara Balda" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] ] ] 5 => array:4 [ "nombre" => "Guiomar" "apellidos" => "Pérez de Nanclares" "email" => array:1 [ 0 => "gnanclares@osakidetza.eus" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] ] "afiliaciones" => array:3 [ 0 => array:3 [ "entidad" => "Grupo de Investigación en Enfermedades Raras, Laboratorio de (epi) Genética Molecular, Instituto de Investigación Sanitaria Bioaraba, Hospital Universitario Araba-Txagorritxu, Vitoria-Gasteiz, Álava, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Servicio de Endocrinología y Nutrición, Hospital Universitario Araba-Txagorritxu, Vitoria-Gasteiz, Álava, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Servicio de Endocrinología y Nutrición, Hospital de San Pedro, Logroño, La Rioja, Spain" "etiqueta" => "c" "identificador" => "aff0015" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Deficiencia de vitamina D en la edad adulta: presentación de 2 casos familiares de seudohipoparatiroidismo" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1426 "Ancho" => 3341 "Tamanyo" => 543841 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0010" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Results of the sequencing studies performed on family 2. A) Visualisation in the IGV viewer of the results of the NGS in which the homozygous substitution of guanine for adenine (red arrow) appears in in the <span class="elsevierStyleItalic">CYP27B1</span> gene in the index patient (upper panel), with respect to a control (lower panel). The gene sequence is in the reverse orientation on the chromosome. B) Validation, by Sanger sequencing, of the presence of the pathogenic variant c.1226C>T (named on strand +1, according to international recommendations). The upper panel corresponds to the sequence of the index patient and the lower panel to a control sample. The arrow indicates the position of the substituted nucleotide.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Pseudohypoparathyroidism (PHP), recently renamed iPPSD2 and 3 (<span class="elsevierStyleItalic">inactivating PTH/PTHrP signalling disorders</span>),<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> describes a heterogeneous group of rare genetic or epigenetic diseases characterised by the presence of hypocalcaemia and hyperphosphatemia resulting from the resistance of certain tissues to the biological actions of parathyroid hormone (PTH).<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">However, elevated PTH levels are not specific to iPPSD, as other physiological conditions such as hyperparathyroidism, benign parathyroid tumours, renal disease, calcium and phosphorus metabolism disorders or vitamin D deficiency must be ruled out before such a diagnosis.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">We report the cases of 2 pairs of siblings who were diagnosed with pseudohypoparathyroidism in childhood or adolescence. The causal mutation was identified in the <span class="elsevierStyleItalic">CYP27B1</span> gene after genetic testing in adulthood using next-generation sequencing of a panel of genes associated with iPPSD and other differential diagnoses, suggesting a diagnosis of vitamin D-dependent rickets type 1A.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Patients and methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Family 1</span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Case 1</span><p id="par0020" class="elsevierStylePara elsevierViewall">A 59-year-old Caucasian woman was referred for genetic counselling due to clinical suspicion of type 2 pseudohypoparathyroidism, diagnosed in childhood, due to the incidental finding of elevated PTH values after an accident with trauma. Currently undergoing treatment with calcium and calcitriol, with elevated PTH associated with vitamin D alterations (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>). The patient is short (142 cm;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Case 2</span><p id="par0025" class="elsevierStylePara elsevierViewall">A 57-year-old woman, sister of the previous patient, with clinical suspicion of PHP type 2. Despite treatment, she had elevated PTH with normal levels of 1.25(OH)<span class="elsevierStyleInf">2</span>D<span class="elsevierStyleInf">3</span> and 25(OH)D<span class="elsevierStyleInf">3</span> (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>). Phenotypically, she is at the lower limit of normal height (152 cm; p3–p10) and overweight (61.2 kg; BMI: 26.5). X-rays show a slight shortening of metacarpals II and III (Appendix B Fig. B of the Supplementary material).</p></span></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Family 2</span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Case 3</span><p id="par0030" class="elsevierStylePara elsevierViewall">A 62-year-old man who visited the endocrinology clinic with a clinical diagnosis of pseudohypoparathyroidism at the age of 23 due to hypocalcaemia (5.8 mg/dL; normal range 8−11 mg/dL), hyperphosphatemia (5.4 mg/dL; normal range 2.7–4.5 mg/dL) with normal PTH levels (values not available). Physical examination revealed short stature (150 cm; >p3), normal weight (54.7 kg; BMI: 24.31) and absence of subcutaneous ossifications and brachydactyly.</p><p id="par0035" class="elsevierStylePara elsevierViewall">At the time of medical consultation, the patient was receiving oral treatment with calcidiol and calcium supplements. Laboratory tests revealed normal biochemical parameters (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Case 4</span><p id="par0040" class="elsevierStylePara elsevierViewall">A 65-year-old woman with clinical suspicion of familial pseudohypoparathyroidism visited an endocrinology clinic at the age of 21 for tetany secondary to hypocalcaemia (5.2 mg/dL), stiffness of hands and circumoral contracture. In addition, bilateral shortening of metacarpals II, III and IV was detected on radiography (Appendix B Fig. C of the Supplementary material) and opacities in the posterior capsule of the lens in both eyes. Throughout the follow-up, elevated PTH levels (101 pg/mL) were occasionally detected.</p><p id="par0045" class="elsevierStylePara elsevierViewall">The existence of the same condition in a sibling (case 3), the biochemical characteristics, and the presence of short stature (136 cm;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).</p></span></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Molecular studies</span><p id="par0050" class="elsevierStylePara elsevierViewall">Epigenetic and genetic alterations at the <span class="elsevierStyleItalic">GNAS</span> locus were analysed in both families, as already described.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> This was followed by the in-house designed iPPSD-v1 NGS panel testing, in which 92 genes (see Appendix B Supplementary material) associated with iPPSDs and other differential diagnoses were studied. Analysis of the NGS data as well as filtering and prioritisation of variants was carried out as described above.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> Subsequent confirmation and co-segregation studies were performed by Sanger sequencing.</p><p id="par0055" class="elsevierStylePara elsevierViewall">All the studies have been reviewed and approved by the Basque Clinical Research Ethics Committee (CEI-E) and, in addition, the patients have signed the corresponding informed consent for the study to be conducted.</p></span></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Results</span><p id="par0060" class="elsevierStylePara elsevierViewall">After ruling out epigenetic and genetic alterations at the <span class="elsevierStyleItalic">GNAS</span> locus, the iPPSD-v1 NGS panel testing identified a variant potentially associated with the phenotype in each of the families.</p><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Family 1</span><p id="par0065" class="elsevierStylePara elsevierViewall">A probably homozygous variant was identified in exon 1 of the <span class="elsevierStyleItalic">CYP27B1</span> gene (NM_000785.4: c.103_104delinsA; p.(Ser36Alafs*42)) (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). Sanger sequencing in both case 1 and case 2 and in their parents confirmed the presence of the familial variant in homozygosity in both patients and in heterozygosity in their parents. Consanguinity was ruled out.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0070" class="elsevierStylePara elsevierViewall">This is a novel variant, not present in population databases such as gnomAD, ExAC or 1000 Genomes, nor described in the literature associated with the disease. Bioinformatic analysis indicates that the truncated protein is not functional, as the ligand binding sites have been completely eliminated and the vitamin 1α-hydroxylase activity domain has been broken. Therefore, according to ACMG guidelines, this variant is classified as probably pathogenic (PVS1, PM2, PP4).</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Family 2</span><p id="par0075" class="elsevierStylePara elsevierViewall">A probably homozygous variant was identified in exon 8 of the <span class="elsevierStyleItalic">CYP27B1</span> gene (NM_000785.4: c.1226C>T; p.(Thr409Ile)) (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>). The algorithm for copy number alteration analysis (<span class="elsevierStyleItalic">VarSeq CNV Caller,</span> Golden Helix, Varseq 2.2.5) showed a ratio of ∼1 (computed based on normalised average coverage versus control samples), which rules out deletions in this gene. The presence of this variant was subsequently confirmed by Sanger sequencing in both patients. No segregation studies were performed as no progenitor sample was available.</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0080" class="elsevierStylePara elsevierViewall">This variant has already been described as pathogenic in several independent families.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a></p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Clinical reassessment</span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Family 1</span><p id="par0085" class="elsevierStylePara elsevierViewall">When informed of the genetic result, patient 1 revealed that, in her adolescence, she was bow-legged, had hypocalcaemia and elevated PTH. Currently, she suffers from bone pain, especially in the feet and knees. Bone densitometry shows low bone density in the lumbar spine and proximal femur. The amount and frequency of calcitriol treatment has been modified to 0.5 μg/day to return PTH, 25(OH)D<span class="elsevierStyleInf">3</span> and 1,25(OH)<span class="elsevierStyleInf">2</span>D<span class="elsevierStyleInf">3</span> levels to normal and bone pain is currently treated with tapentadol.</p><p id="par0090" class="elsevierStylePara elsevierViewall">Her sister mentions that, in adolescence, she suffered 2 episodes of tetany, had dysplastic teeth and bowed legs. In addition, several blood tests showed hypocalcaemia, hyperphosphatemia, high levels of alkaline phosphatase, PTH and vitamin D deficiency. Tetany was no longer present and vitamin D levels, both 25(OH)D<span class="elsevierStyleInf">3</span> and 1,25(OH)<span class="elsevierStyleInf">2</span>D<span class="elsevierStyleInf">3</span>, returned to normal after treatment with calcitriol.</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Family 2</span><p id="par0095" class="elsevierStylePara elsevierViewall">Based on the genetic results, patient 3 was switched from calcidiol to calcitriol (0.25 μg/day), maintaining calcium supplementation. A review of the medical record showed that the patient had suffered seizures at the age of 10, classified as febrile, and at 14 years of age, hypertonia symptoms associated with generalised hypocalcaemia. A bone series study at the age of 23 revealed diffuse osteosclerosis of the spine and femurs with bowing. He currently reports knee osteopenia.</p><p id="par0100" class="elsevierStylePara elsevierViewall">His sister’s treatment was also switched from calcidiol to calcitriol (0.25 μg/day) and she was insisted on the need to take calcium supplements continuously, without success. At 46 years of age, she was suffering from bilateral and intermittent coxofemoral joint pain with no detectable alteration in the bone densitometry study.</p></span></span></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Discussion</span><p id="par0105" class="elsevierStylePara elsevierViewall">Vitamin D-dependent rickets (VDDR1) is an autosomal recessive disease characterised by deficiency of 1α-hydroxylase activity.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> Pathogenic variants in the <span class="elsevierStyleItalic">CYP27B1</span> gene are associated with VDDR1A (OMIM #264700), characterised by hypotonia, growth retardation and seizures or tetany. It can also lead to tooth enamel hypoplasia during infancy<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> and mild to moderate rickets findings on radiographs. Biochemically, it presents with low serum calcium and phosphorus concentrations together with increased PTH and alkaline phosphatase levels. They associate normal or elevated 25(OH)D<span class="elsevierStyleInf">3</span> concentrations with low 1,25(OH)<span class="elsevierStyleInf">2</span>D<span class="elsevierStyleInf">3</span> levels.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">We have identified 2 homozygous variants in the <span class="elsevierStyleItalic">CYP27B1</span> gene in the present study. Both involve a defect in the enzymatic activity of 1α-hydroxylase, in 2 adult sibling pairs, with intra- and interfamilial clinical variability, which coincide with the doubtful phenotype-genotype correlation in VDDR1A,<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> for which it is proposed that factors such as early treatment with variable doses of calcium may mitigate the symptoms.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">Moreover, rPTH is one of the major criteria for the diagnosis of iPPSD.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> However, elevated PTH levels are not always due to resistance, but may be the consequence of a compensatory mechanism triggered by vitamin D deficiency since, when a patient starts to have insufficient or deficient vitamin D levels, there is a compensatory increase in PTH until serum 1,25(OH)<span class="elsevierStyleInf">2</span>D<span class="elsevierStyleInf">3</span> levels return to normal.<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> However, in patients with impaired vitamin D metabolism, serum 1,25(OH)<span class="elsevierStyleInf">2</span>D<span class="elsevierStyleInf">3</span> concentrations do not return to normal and PTH values remain elevated.<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> For this reason, rPTH is defined as the association of hypocalcaemia, hyperphosphatemia and elevated PTH levels in the absence of vitamin D deficiency.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1,2</span></a></p><p id="par0120" class="elsevierStylePara elsevierViewall">The patients described in this study had clinical suspicion of PHP/iPPSD because, similar to VDDR1A, they had brachydactyly, hypocalcaemia and elevated PTH levels, and vitamin D concentrations were the differentiating analyte between the two diseases.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1,2</span></a> Furthermore, in patients with VDDR1A, vitamin D deficiency usually appears after birth and clinical manifestations are usually detected during the first years of life.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> However, severe vitamin D deficiency in adults is less common and usually involves nonspecific clinical manifestations related to osteomalacia, diffuse bone pain and muscle weakness.<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> Since there are recommendations that vitamin D levels should not be routinely requested<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> and guidelines on optimal vitamin D levels for proper body function have only recently been agreed,<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> the differential diagnosis between VDDR1A and iPPSD is complicated.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> However, it has been demonstrated that, in certain cases, the biochemical determination of serum levels of both 1,25(OH)<span class="elsevierStyleInf">2</span>D<span class="elsevierStyleInf">3</span> and 25(OH)D<span class="elsevierStyleInf">3</span> can be used to guide and make an appropriate diagnosis.</p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">Ethical considerations</span><p id="par0125" class="elsevierStylePara elsevierViewall">The studies have been reviewed and approved by the Basque Clinical Research Ethics Committee (CEI-E).</p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0150">Funding</span><p id="par0130" class="elsevierStylePara elsevierViewall">This study has been funded with partial support from the <span class="elsevierStyleGrantSponsor" id="gs0005">Instituto de Salud Carlos III</span> of the Ministry of Economy and Competitiveness (Spain), co-financed by the <span class="elsevierStyleGrantSponsor" id="gs0010">European Regional Development</span> Fund (grant number <span class="elsevierStyleGrantNumber" refid="gs0010">PI20/00950</span>) and the <span class="elsevierStyleGrantSponsor" id="gs0015">Department of Health of the Basque Government</span> (grant number <span class="elsevierStyleGrantNumber" refid="gs0015">GV2021/111056</span>).</p></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0155">Conflict of interest</span><p id="par0135" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflicts of interest.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:12 [ 0 => array:3 [ "identificador" => "xres2164236" "titulo" => "Abstract" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Background and objective" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Patients and methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1835814" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres2164237" "titulo" => "Resumen" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Antecedentes y objetivo" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Pacientes y métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusiones" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1835815" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Patients and methods" "secciones" => array:3 [ 0 => array:3 [ "identificador" => "sec0015" "titulo" => "Family 1" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0020" "titulo" => "Case 1" ] 1 => array:2 [ "identificador" => "sec0025" "titulo" => "Case 2" ] ] ] 1 => array:3 [ "identificador" => "sec0030" "titulo" => "Family 2" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0035" "titulo" => "Case 3" ] 1 => array:2 [ "identificador" => "sec0040" "titulo" => "Case 4" ] ] ] 2 => array:2 [ "identificador" => "sec0045" "titulo" => "Molecular studies" ] ] ] 6 => array:3 [ "identificador" => "sec0050" "titulo" => "Results" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0055" "titulo" => "Family 1" ] 1 => array:2 [ "identificador" => "sec0060" "titulo" => "Family 2" ] 2 => array:3 [ "identificador" => "sec0065" "titulo" => "Clinical reassessment" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0070" "titulo" => "Family 1" ] 1 => array:2 [ "identificador" => "sec0075" "titulo" => "Family 2" ] ] ] ] ] 7 => array:2 [ "identificador" => "sec0080" "titulo" => "Discussion" ] 8 => array:2 [ "identificador" => "sec0085" "titulo" => "Ethical considerations" ] 9 => array:2 [ "identificador" => "sec0090" "titulo" => "Funding" ] 10 => array:2 [ "identificador" => "sec0095" "titulo" => "Conflict of interest" ] 11 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2023-04-03" "fechaAceptado" => "2023-06-18" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1835814" "palabras" => array:6 [ 0 => "Vitamin D-dependent rickets" 1 => "Inactivating PTH/PTHrP signaling disorders" 2 => "Pseudohypoparathyroidism" 3 => "Vitamin D" 4 => "<span class="elsevierStyleItalic">CYP27B1</span>" 5 => "Adults" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1835815" "palabras" => array:6 [ 0 => "Raquitismo dependiente de vitamina D" 1 => "Enfermedades por inactivación de la vía de señalización PTH/PTHrP" 2 => "Seudohipoparatiroidismo" 3 => "Vitamina D" 4 => "<span class="elsevierStyleItalic">CYP27B1</span>" 5 => "Adultos" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Background and objective</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">The clinical and biochemical overlap of various pathologies of phosphocalcic metabolism can lead to misdiagnosis and consequent clinical management. One example is pseudohypoparathyroidism, which can be confused with vitamin D-dependent rickets (VDDR1) if appropriate biochemical determinations are not performed.</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Patients and methods</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Two pairs of siblings, from independent families, were clinically diagnosed in adolescence with pseudohypoparathyroidism due to hypocalcaemia, elevated parathyroid hormone levels and normal or elevated phosphorus values. After ruling out alterations in <span class="elsevierStyleItalic">GNAS</span>, a massive sequencing study of genes associated with other differential diagnoses was carried out.</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Two genetic variants in the <span class="elsevierStyleItalic">CYP27B1</span> gene potentially associated with the phenotype were identified. Pathogenic variants in this gene are associated with VDDR1A. Clinical-biochemical re-evaluation of the patients confirmed this diagnosis and treatment was adapted.</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Although VDDR1A is an infrequently diagnosed pathology in adulthood, in cases of hypocalcaemia with elevated PTH values, determination of the 1,25(OH)<span class="elsevierStyleInf">2</span>D<span class="elsevierStyleInf">3</span> and 25(OH)D<span class="elsevierStyleInf">3</span> forms of vitamin D is relevant to reach a correct diagnosis.</p></span>" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Background and objective" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Patients and methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] "es" => array:3 [ "titulo" => "Resumen" "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Antecedentes y objetivo</span><p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">El solapamiento clínico y bioquímico de diversas enfermedades del metabolismo fosfocálcico puede conllevar un erróneo diagnóstico y su consecuente abordaje clínico. Un ejemplo es el seudohipoparatiroidismo, que puede confundirse con el raquitismo dependiente de vitamina D (VDDR1) si no se hacen las determinaciones bioquímicas adecuadas.</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Pacientes y métodos</span><p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Dos parejas de hermanos, de familias independientes, fueron diagnosticados clínicamente en la adolescencia de seudohipoparatiroidismo al presentar hipocalcemia, niveles elevados de hormona paratiroidea y valores normales o elevados de fósforo. Tras descartar alteraciones en <span class="elsevierStyleItalic">GNAS</span>, se realizó un estudio, mediante secuenciación masiva, de genes asociados a otros diagnósticos diferenciales.</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Se identificaron 2 variantes genéticas en el gen <span class="elsevierStyleItalic">CYP27B1</span> potencialmente asociadas con el fenotipo. Variantes patogénicas en este gen se asocian con VDDR1A. La reevaluación clínica-bioquímica de los pacientes confirmó dicho diagnóstico y se adecuó el tratamiento.</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusiones</span><p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Si bien la VDDR1A es un trastorno del metabolismo de diagnóstico infrecuente en la edad adulta, en casos de hipocalcemia con valores elevados de PTH es relevante la determinación de las formas 1,25(OH)<span class="elsevierStyleInf">2</span>D<span class="elsevierStyleInf">3</span> y 25(OH)D<span class="elsevierStyleInf">3</span> de la vitamina D para alcanzar un diagnóstico correcto.</p></span>" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Antecedentes y objetivo" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Pacientes y métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusiones" ] ] ] ] "apendice" => array:1 [ 0 => array:1 [ "seccion" => array:1 [ 0 => array:4 [ "apendice" => "<p id="par0145" class="elsevierStylePara elsevierViewall">The following is Supplementary data to this article:<elsevierMultimedia ident="upi0005"></elsevierMultimedia></p>" "etiqueta" => "Appendix A" "titulo" => "Supplementary data" "identificador" => "sec0105" ] ] ] ] "multimedia" => array:4 [ 0 => array:8 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1551 "Ancho" => 3341 "Tamanyo" => 578446 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0005" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Genetic testing results performed on family 1. A) Identification of the homozygous mutation in exon 1 of the <span class="elsevierStyleItalic">CYP27B1</span> gene by next-generation sequencing (NGS). The files obtained from the alignment of the <span class="elsevierStyleItalic">paired-end</span> NGS reads (pink, sense; blue, antisense) are uploaded to the interactive genome viewer, IGV for visualisation. The gene sequence is in the reverse orientation on the chromosome (strand-1). The position of the mutation is indicated by a red arrow. The black stripe represents deletion, subsequently the change is shown by a homozygous thymine (red). The upper panel corresponds to the index person, while the lower panel corresponds to a control person. B) Confirmation by Sanger sequencing of the presence of the c.103_104delinsA variant (named on strand +1, according to international recommendations). The upper panel corresponds to the sequence of the index patient, the middle panel to her father and the lower panel to a control sample. The results for the sister and the mother are identical to those shown in the top and middle panel, respectively (data not shown). Altered nucleotides are shown in black brackets, the position of the mutation is indicated by a red arrow.</p>" ] ] 1 => array:8 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1426 "Ancho" => 3341 "Tamanyo" => 543841 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0010" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Results of the sequencing studies performed on family 2. A) Visualisation in the IGV viewer of the results of the NGS in which the homozygous substitution of guanine for adenine (red arrow) appears in in the <span class="elsevierStyleItalic">CYP27B1</span> gene in the index patient (upper panel), with respect to a control (lower panel). The gene sequence is in the reverse orientation on the chromosome. B) Validation, by Sanger sequencing, of the presence of the pathogenic variant c.1226C>T (named on strand +1, according to international recommendations). The upper panel corresponds to the sequence of the index patient and the lower panel to a control sample. The arrow indicates the position of the substituted nucleotide.</p>" ] ] 2 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0015" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">The treatment they were taking at the time is included.</p><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">1,25(OH)<span class="elsevierStyleInf">2</span>D<span class="elsevierStyleInf">3</span>: serum levels of 1-alpha,25-dihydroxycholecalciferol or calcitriol; 25(OH)D<span class="elsevierStyleInf">3</span>: serum levels of 25-hydroxyvitamin D or calcidiol; Ca: serum calcium levels; F: female; mg: milligrams; M: male; NA: not available; P: serum phosphorus levels; PTH: serum parathyroid hormone levels; μg: micrograms, normal range shown in brackets.</p>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">Patient \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">Sex \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">Current age (years) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " colspan="5" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Biochemical parameters of calcium and phosphorus metabolism</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">Initial treatment \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">Ca \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">P \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">PTH \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">25(OH)D<span class="elsevierStyleInf">3</span> (ng/mL) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">1,25(OH)<span class="elsevierStyleInf">2</span>D<span class="elsevierStyleInf">3</span> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">(mg/dL) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">(mg/dL) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">(pg/mL) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">Deficit < 10 \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">(ng/mL) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">[8–10.5] \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">[2.5–4.5] \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">[14–100] \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Sub-optimal N 10–30 \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">[20–54] \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead rowgroup " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Family 1-case 1</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">F</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">59</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">8.9</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3.7</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">259</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">19</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">15</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Calcium: 500 mg/d \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 \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Calcitriol: 0.25 μg 3 d/wk \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Family 1-case 2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">F \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">57 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">9.4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3.1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">134 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">42 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">32 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Calcitriol: 0.5 μg 2 d/wk and 0.25 μg 5 d/wk \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead rowgroup " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Family 2-case 3</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">M</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">62</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">9.2</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3.6</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">40</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">90</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NA</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Calcium: 500 mg 2 times/d \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 \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Calcidiol: 0.25 g/dμ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead rowgroup " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Family 2-case 4</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">F</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">65</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">9.7</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3.5</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">51</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">37.1</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NA</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Calcium, intermittently \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 \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Calcidiol: 0.266 μg 2 d/wk \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab3566092.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Summary of calcium and phosphorus metabolism data at the time of the patients’ visit to the clinic.</p>" ] ] 3 => array:5 [ "identificador" => "upi0005" "tipo" => "MULTIMEDIAECOMPONENTE" "mostrarFloat" => false "mostrarDisplay" => true "Ecomponente" => array:2 [ "fichero" => "mmc1.docx" "ficheroTamanyo" => 1075048 ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:10 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "From pseudohypoparathyroidism to inactivating PTH/PTHrP signalling disorder (iPPSD), a novel classification proposed by the EuroPHP network" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "S. Thiele" 1 => "G. Mantovani" 2 => "A. Barlier" 3 => "V. Boldrin" 4 => "P. Bordogna" 5 => "L. de Sanctis" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1530/EJE-16-0107" "Revista" => array:6 [ "tituloSerie" => "Eur J Endocrinol" "fecha" => "2016" "volumen" => "175" "paginaInicial" => "P1" "paginaFinal" => "P17" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27401862" "web" => "Medline" ] ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0010" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Diagnosis and management of pseudohypoparathyroidism and related disorders: first International Consensus Statement" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "G. Mantovani" 1 => "M. Bastepe" 2 => "D. Monk" 3 => "L. de Sanctis" 4 => "S. Thiele" 5 => "A. 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