Scientific Letter
X-linked hypophosphatemic rickets due to mutations in PHEX: Clinical and evolutionary variability
Raquitismo hipofosfatémico ligado a X por mutaciones en PHEX: variabilidad clínica y evolutiva
Gabriel Á. Martos Morenoa,b,c, Cristina Apariciod, Carmen de Lucasd, Helena Gil Peñae, Jesús Argentea,b,c,
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a Servicio de Endocrinología, Hospital Infantil Universitario Niño Jesús, Madrid, Spain
b Departamento de Pediatría, Universidad Autónoma de Madrid, Madrid, Spain
c CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain
d Sección de Nefrología, Hospital Infantil Universitario Niño Jesús, Madrid, Spain
e Servicio de Pediatría, Hospital Universitario Central de Asturias, Estudio colaborativo RenalTube, Oviedo, Asturias, Spain
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Martos Moreno, Cristina Aparicio, Carmen de Lucas, Helena Gil Peña, Jesús Argente" "autores" => array:5 [ 0 => array:3 [ "nombre" => "Gabriel Á." "apellidos" => "Martos Moreno" "referencia" => array:3 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] 2 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] ] ] 1 => array:3 [ "nombre" => "Cristina" "apellidos" => "Aparicio" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">d</span>" "identificador" => "aff0020" ] ] ] 2 => array:3 [ "nombre" => "Carmen" "apellidos" => "de Lucas" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">d</span>" "identificador" => "aff0020" ] ] ] 3 => array:3 [ "nombre" => "Helena" "apellidos" => "Gil Peña" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">e</span>" "identificador" => "aff0025" ] ] ] 4 => array:4 [ "nombre" => "Jesús" "apellidos" => "Argente" "email" => array:1 [ 0 => "jesus.argente@uam.es" ] "referencia" => array:4 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] 2 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] 3 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] ] "afiliaciones" => array:5 [ 0 => array:3 [ "entidad" => "Servicio de Endocrinología, Hospital Infantil Universitario Niño Jesús, Madrid, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Departamento de Pediatría, Universidad Autónoma de Madrid, Madrid, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain" "etiqueta" => "c" "identificador" => "aff0015" ] 3 => array:3 [ "entidad" => "Sección de Nefrología, Hospital Infantil Universitario Niño Jesús, Madrid, Spain" "etiqueta" => "d" "identificador" => "aff0020" ] 4 => array:3 [ "entidad" => "Servicio de Pediatría, Hospital Universitario Central de Asturias, Estudio colaborativo RenalTube, Oviedo, Asturias, Spain" "etiqueta" => "e" "identificador" => "aff0025" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Raquitismo hipofosfatémico ligado a X por mutaciones en <span class="elsevierStyleItalic">PHEX</span>: variabilidad clínica y evolutiva" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1758 "Ancho" => 1350 "Tamanyo" => 209554 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Physical and radiographic characteristics of the lower extremities of Case 2 at diagnosis (A and B) and after two years of treatment (C and D).</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">The term hypophosphatemic rickets (HR) encompasses a group of genetic diseases characterised by impairment of bone mineralisation, hyperphosphaturia and hypophosphatemia in the absence of vitamin D deficiency.<a class="elsevierStyleCrossRefs" href="#bib0035"><span class="elsevierStyleSup">1,2</span></a> These features are caused by increased levels of fibroblast growth factor 23 (FGF23), which, through interaction with its receptor α-klotho, prevents adequate reabsorption of phosphate in the proximal tubule and interferes with the hydroxylation of vitamin D in the kidney.<a class="elsevierStyleCrossRefs" href="#bib0035"><span class="elsevierStyleSup">1–3</span></a> Based on this, the current treatment for HR consists in supplementation with phosphate and bioactive forms of vitamin D.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">4</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">The inheritance patterns and genes involved in these syndromes vary. The syndrome that has been described most thoroughly to date is X-linked dominant HR, which results from inactivating mutations of <span class="elsevierStyleItalic">PHEX</span> (phosphate regulating endopeptidase homolog, X-linked), a gene encoding a cell-surface metalloprotease that regulates the expression and degradation of FGF23.<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">5</span></a> Still, there is considerable variability in clinical manifestations and outcomes within this subgroup, and patients respond differently to treatment, which is illustrated by the cases presented here:</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Case 1</span><p id="par0015" class="elsevierStylePara elsevierViewall">Girl aged 21 months born full term with normal anthropometric measurements to healthy, nonconsanguineous parents and with no family history of skeletal disease.</p><p id="par0020" class="elsevierStylePara elsevierViewall">The physical examination found a symmetrical genu varum (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>A) associated with a waddling gait, confirmed by radiographic findings: varus of the tibias, fraying of the distal metaphyseal region of both femurs and tibias, and cupping of both fibulas (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>B), the ulnas and the radii (with a mild widening of the distal end of the forearms).</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0025" class="elsevierStylePara elsevierViewall">The blood chemistry panel (in the absence of protein deficiency) showed normal calcium and magnesium levels (ionised and total), along with severe hypophosphatemia (2.3<span class="elsevierStyleHsp" style=""></span>mg/dL; normal range, 4.5–6.7) and increased alkaline phosphatase activity (528<span class="elsevierStyleHsp" style=""></span>U/L; normal range, 122–290). The value of the rate of tubular phosphate reabsorption (TPR) obtained from a single-void urine sample was not indicative (83.2%), as opposed to the value obtained from the 24-h urine sample, which was clearly decreased (67.1%).</p><p id="par0030" class="elsevierStylePara elsevierViewall">The panel showed normal levels of 25-hidroxyvitamin D (27.1<span class="elsevierStyleHsp" style=""></span>ng/dL) and elevated levels of 1,25-dihidroxyvitamin D (123<span class="elsevierStyleHsp" style=""></span>pg/dL; normal range, 16–56) and intact PTH (106<span class="elsevierStyleHsp" style=""></span>pg/mL; normal range, 11–67). Hypophosphatemic rickets was suspected, leading to the determination of the serum FGF23 level, which exceeded the upper detection limit of the assay (>426<span class="elsevierStyleHsp" style=""></span>U/mL).</p><p id="par0035" class="elsevierStylePara elsevierViewall">The etiological diagnosis was made after gene sequencing found a de novo heterozygous mutation in exon 22 of <span class="elsevierStyleItalic">PHEX</span> (c.2445G>A [W627X]) that had not been previously described in the literature.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Case 2</span><p id="par0040" class="elsevierStylePara elsevierViewall">Girl aged 25 months born full term with normal anthropometric measurements to healthy nonconsanguineous parents and no family history of skeletal disease.</p><p id="par0045" class="elsevierStylePara elsevierViewall">The patient presented with severe asymmetrical genu varum with the right side more affected than the left (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>A), a waddling gait and radiographic findings similar to those of case 1 (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>B), with a greater widening of the distal ends of the forearms.</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0050" class="elsevierStylePara elsevierViewall">The patient had normal calcium and magnesium levels, hypophosphatemia (2.9<span class="elsevierStyleHsp" style=""></span>mg/dL, normal range, 4.5–6.7), hyperphosphatasemia (446<span class="elsevierStyleHsp" style=""></span>U/L, normal range, 122–290), a normal rate of TPR in a single-void urine test (93.9%), and a clearly decreased TPR rate in the 24-h urine test (67.5%).</p><p id="par0055" class="elsevierStylePara elsevierViewall">Also consistently with case 1, the patient had elevated levels of intact PTH (116<span class="elsevierStyleHsp" style=""></span>pg/mL; normal range, 11–67) and normal levels of 25-hidroxyvitamin D (37.2<span class="elsevierStyleHsp" style=""></span>ng/dL), although her levels of 1,25-dihidroxyvitamin D were also normal (55<span class="elsevierStyleHsp" style=""></span>pg/dL; normal range, 16–56). The presence of an elevated serum FGF23 level (253<span class="elsevierStyleHsp" style=""></span>U/mL; normal range <146) and the detection of a c.2301G>A (G579R) heterozygous mutation in exon 17 of <span class="elsevierStyleItalic">PHEX</span> confirmed the diagnosis.</p><p id="par0060" class="elsevierStylePara elsevierViewall">Both cases were treated with oral phosphate and bioactive forms of vitamin D. After two years of treatment, case 1 had shown gradual normalisation of serum levels of phosphorus (3.6<span class="elsevierStyleHsp" style=""></span>mg/dL), PTH and 1,25-dihidroxyvitamin D, along with evident clinical and radiographic improvement (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>C and D), although the patient started to show sonographic signs suggestive of nephrocalcinosis. Conversely, in case 2, despite the self-reported adherence to treatment, the hypophosphoremia worsened (with values repeatedly below 2.5<span class="elsevierStyleHsp" style=""></span>mg/dL; lowest value, 2.3<span class="elsevierStyleHsp" style=""></span>mg/dL) and persistently elevated alkaline phosphatase activity (greater than 400<span class="elsevierStyleHsp" style=""></span>U/L) despite the gradual increase of the sodium phosphate dose to a maximum of 960<span class="elsevierStyleHsp" style=""></span>mg of phosphorus a day (81<span class="elsevierStyleHsp" style=""></span>mg/kg). Furthermore, the clinical and radiographic outcomes were poor (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>C and D), and the patient required lateral external hemyepiphysiodesis in the tibial and femoral metaphyses of both knees.</p><p id="par0065" class="elsevierStylePara elsevierViewall">Given the different response to treatment and the possibility of developing nephrocalcinosis, the new therapeutic approach based on the use of anti-FGF23 monoclonal antibodies is very attractive, and it has showed promising results<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">4</span></a> in adult patients and in ongoing trials (Phase II and III) in paediatric patients, as explained in the editorial that accompanies this scientific letter.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">6</span></a></p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Case 1" ] 1 => array:2 [ "identificador" => "sec0010" "titulo" => "Case 2" ] 2 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Martos Moreno GÁ, Aparicio C, de Lucas C, Gil Peña H, Argente J. Raquitismo hipofosfatémico ligado a X por mutaciones en <span class="elsevierStyleItalic">PHEX</span>: variabilidad clínica y evolutiva. An Pediatr (Barc). 2016;85:41–43</p>" ] ] "multimedia" => array:2 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1690 "Ancho" => 1400 "Tamanyo" => 194776 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Physical and radiographic characteristics of the lower extremities of Case 1 at diagnosis (A and B) and after two years of treatment (C and D).</p>" ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1758 "Ancho" => 1350 "Tamanyo" => 209554 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Physical and radiographic characteristics of the lower extremities of Case 2 at diagnosis (A and B) and after two years of treatment (C and D).</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:6 [ 0 => array:3 [ "identificador" => "bib0035" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Hypophosphatemic rickets: revealing novel control points for phosphate homeostasis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "K.E. 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Carpenter" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s11914-015-0259-y" "Revista" => array:6 [ "tituloSerie" => "Curr Osteoporos Rep" "fecha" => "2015" "volumen" => "13" "paginaInicial" => "88" "paginaFinal" => "97" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25620749" "web" => "Medline" ] ] ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0045" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Regulation of serum phosphate" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "E. Lederer" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "J Physiol" "fecha" => "2014" "volumen" => "594" "paginaInicial" => "3985" "paginaFinal" => "3995" ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib0050" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The changing face of hypophosphatemic disorders in the FGF-23 era" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "J.Y. Lee" 1 => "E.A. Imel" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Pediatr Endocrinol Rev" "fecha" => "2013" "volumen" => "10" "numero" => "Suppl. 2" "paginaInicial" => "S367" "paginaFinal" => "S379" ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib0055" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "FGF23, PHEX, and MEPE regulation of phosphate homeostasis and skeletal mineralization" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "L.D. 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| Year/Month | Html | Total | |
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