Case report
TSC2/PKD1 contiguous gene syndrome, with emphasis on a case with an atypical mild polycystic kidney phenotype and a novel genetic variant
Síndrome de genes contiguos TSC2/PKD1 con énfasis en un caso con un fenotipo atípico de riñón poliquístico leve y una nueva variante genética
Miriam E. Reyna-Fabiána, Miguel A. Alcántara-Ortigozaa, Nancy L. Hernández-Martíneza, Jaime Berumenb,c, Raquel Jiménez-Garcíad, Gilberto Gómez-Garzae, Ariadna González-del Angela,?
Corresponding author
ariadnagonzalezdelangel@gmail.com
Corresponding author at: Laboratorio de Biología Molecular, Departamento de Genética Humana, Instituto Nacional de Pediatría, Secretaría de Salud, Insurgentes Sur 3700-C, Insurgentes-Cuicuilco, Del. Coyoacán, CP 04530, Ciudad de México, México.
Corresponding author at: Laboratorio de Biología Molecular, Departamento de Genética Humana, Instituto Nacional de Pediatría, Secretaría de Salud, Insurgentes Sur 3700-C, Insurgentes-Cuicuilco, Del. Coyoacán, CP 04530, Ciudad de México, México.
a Laboratorio de Biología Molecular, Departamento de Genética Humana, Instituto Nacional de Pediatría, Secretaría de Salud, Ciudad de México, México
b Departamento de Medicina Experimental, Facultad de Medicina, Universidad Nacional Autónoma de México, Ciudad de México, México
c Unidad de Medicina Genómica, Hospital General de México, Ciudad de México, México
d Servicio de Nefrología, Instituto Nacional de Pediatría, Secretaría de Salud, Ciudad de México, México
e Resonancia Magnética, Instituto Nacional de Pediatría, Secretaría de Salud, Ciudad de México, México
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"correspondencia" => "<span class="elsevierStyleItalic">Corresponding author at</span>: Laboratorio de Biología Molecular, Departamento de Genética Humana, Instituto Nacional de Pediatría, Secretaría de Salud, Insurgentes Sur 3700-C, Insurgentes-Cuicuilco, Del. Coyoacán, CP 04530, Ciudad de México, México." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Síndrome de genes contiguos <span class="elsevierStyleItalic">TSC2/PKD1</span> con énfasis en un caso con un fenotipo atípico de riñón poliquístico leve y una nueva variante genética" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0010" "etiqueta" => "Fig. 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1754 "Ancho" => 2514 "Tamanyo" => 186438 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Molecular PKDTS characterization in the three TSC patients. (A) Schematic representation of the deletions detected by MLPA in the three PKDTS cases (not drawn to scale). Vertical gray lines in the <span class="elsevierStyleItalic">TSC2</span> and <span class="elsevierStyleItalic">PKD1</span> genes indicate exons with proportional spacing. The long black lines above indicate the range of each heterozygous deletion. A short dotted arrow and a question mark represent the expected minimal deletion interval estimated by MLPA. (B) Schematic representation of the rearrangement detected in the 16p13.3 region by CMA in case 3 (not drawn to scale). Gray lines at the right indicate deleted coding genes (complete deletion of <span class="elsevierStyleItalic">TSC2</span> and deletion of exons 20–46 of <span class="elsevierStyleItalic">PKD1</span>) and double gray lines at the left indicate the duplicated coding genes (three copies), including <span class="elsevierStyleItalic">SSTR5</span>. <span class="elsevierStyleItalic">Abbreviations</span>: Cen: centromeric region, CMA: chromosomal microarray analysis, Ex: exon, MLPA: multiplex ligation-dependent probe amplification, Tel: telomeric region.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Tuberous sclerosis complex (TSC, MIM#191100) is an autosomal dominant disorder that is characterized by the development of multiple hamartomas and is caused by heterozygous pathogenic variants in the tumor suppressor genes, <span class="elsevierStyleItalic">TSC1</span> or <span class="elsevierStyleItalic">TSC2</span>. The most common renal lesions are angiomyolipomas, occurring in >80% of the patients and frequently presented as multiple and bilateral. Besides, approximately 14–32% of the TSC cases exhibit some degree of renal cyst formation, most of which occurs in the second decade of life.<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">1</span></a> Early development of multiple renal cysts with kidney enlargement in TSC patients is associated with the heterozygous contiguous deletion of <span class="elsevierStyleItalic">TSC2</span> and the adjacent <span class="elsevierStyleItalic">PKD1</span> gene; this last is the causative for autosomal dominant polycystic kidney disease (ADPKD, MIM#173900). The <span class="elsevierStyleItalic">TSC2/PKD1</span> contiguous gene syndrome (PKDTS, MIM #600273) reportedly comprises ~2–5% of all TSC cases.<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">2,3</span></a> These patients should be diagnosed as early as possible due to the <span class="elsevierStyleItalic">PKD1</span> deletion that increases the risk for ADPKD-related complications such as cystic kidney disease, hepatic and pancreatic cysts, arterial hypertension, intracranial aneurysm<a class="elsevierStyleCrossRefs" href="#bib0165"><span class="elsevierStyleSup">3–5</span></a> and to the probability of presenting an early end-stage renal disease (20–30 years).<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">6</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Molecular analysis is crucial for the early and confirmed diagnosis of PKDTS, which allows clinicians to assess for the progressive renal lesions and other potentially fatal ADPKD-related complications.<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">7</span></a> To date, more than 65 molecularly characterized cases of PKDTS have been reported (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 1</a>).<a class="elsevierStyleCrossRefs" href="#bib0170"><span class="elsevierStyleSup">4,8–16</span></a> However, the precise deletion interval has only been identified in a few of these patients, and no clear genotype–phenotype correlation has been established. Hence, we need to describe more PKDTS patients and their responsible genotypes in order to identify possible genotype–phenotype correlations and/or the mechanisms underlying the phenotypic variability of PKDTS.</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Case presentation</span><p id="par0015" class="elsevierStylePara elsevierViewall">Herein we describe three unrelated Mexican pediatric patients who fulfilled the criteria of Northrup et al. for a definitive diagnosis of TSC (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 1</a>).<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">17</span></a> Written informed consent was obtained for all cases and the five available parents, besides, the study protocol was revised and approved by the local ethics committee (reference number 060/2014). DNA samples were acquired from peripheral blood leukocytes by standard <span class="elsevierStyleItalic">in silica</span> adsorption method. At the time of admission, cases 1 and 2 revealed multiple bilateral renal cysts on ultrasonography (US) (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 2</a>A and B). Since this suggested a classic PKDTS phenotype, these cases were subjected to a multiplex ligation-dependent probe amplification (MLPA) assay (SALSA MLPA® P337 TSC2 probemix, Lot 0510-A2; MRC-Holland Amsterdam, The Netherlands) that included 39 probes for <span class="elsevierStyleItalic">TSC2</span> and one probe for <span class="elsevierStyleItalic">PKD1</span> (exon 40). The MLPA results revealed a deletion involving exons 31–42 from <span class="elsevierStyleItalic">TSC2</span> and at least exons 40–46 from <span class="elsevierStyleItalic">PKD1</span> (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 1</a>, <a class="elsevierStyleCrossRef" href="#fig0010">Fig. 3</a>A) in both cases.</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0020" class="elsevierStylePara elsevierViewall">For case 3, a single cyst (<10<span class="elsevierStyleHsp" style=""></span>mm) in the right kidney was identified by US at 4 years of age, and follow-up US examinations yielded similar results (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 2</a>C). It should be noted that the molecular protocol carried out in this case 3 started with a direct Sanger sequencing (SS) of all coding exons and the exon–intron boundaries of <span class="elsevierStyleItalic">TSC1</span> and <span class="elsevierStyleItalic">TSC2</span> since there was no clinical suspicious of PKDTS due to the presence of a single renal cyst. As the SS results did not reveal any pathogenic variant a MLPA methodology was implemented and it revealed the presence of a large deletion that comprised all coding exons of <span class="elsevierStyleItalic">TSC2</span> and at least exons 40–46 of <span class="elsevierStyleItalic">PKD1</span> (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 3</a>A). Based on this genotype, a posteriori magnetic resonance imaging (MRI) was performed at age 15 to intentionally search for multiple renal cysts. The MRI results exposed more than 25 small cysts of variable size (9<span class="elsevierStyleHsp" style=""></span>mm<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>SD 5.39<span class="elsevierStyleHsp" style=""></span>mm) in both kidneys (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 2</a>D).</p><p id="par0025" class="elsevierStylePara elsevierViewall">To clarify the size and exact breakpoints of the deleted region in case 3, we performed chromosomal microarray (CMA) analysis (CytoScan™ High Density Microarray; Affymetrix, Inc., Santa Clara, CA, USA) using the Human Genome Assembly hg38 for the analysis. We detected a 230.8<span class="elsevierStyleHsp" style=""></span>kb heterozygous deletion that encompassed 13 coding genes, including all of <span class="elsevierStyleItalic">TSC2</span> and part of <span class="elsevierStyleItalic">PKD1</span> (exons 20–46), along with a neighboring heterozygous duplication of a previously undescribed CNV (242.9<span class="elsevierStyleHsp" style=""></span>kb) in the 16p13.3 region that included six coding genes (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 3</a>B).</p><p id="par0030" class="elsevierStylePara elsevierViewall">At the time of last evaluation, renal function was preserved in all three cases, although cases 2 and 3 had elevated glomerular filtration rates, and case 1 had microscopic hematuria without proteinuria (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 1</a>). None of the three cases presented intracranial aneurysm (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 1</a>). Both parents of all three patients had normal findings on clinical examination, cerebral computed tomography and renal US, while five had normal MLPA <span class="elsevierStyleItalic">TSC2</span> results. Thus, only two out of the three PKDTS cases identified herein were considered as <span class="elsevierStyleItalic">the novo</span> since DNA was not available for testing in the father of case 2.</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Discussion</span><p id="par0035" class="elsevierStylePara elsevierViewall">The three studied cases displayed multiple renal cysts. Cases 1 and 2 were consistent with a classic PKDTS phenotype: large kidney cysts were identified by US at an early stage and predominated over angiomyolipomas (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 2</a>A and B, <a class="elsevierStyleCrossRef" href="#tbl0010">Table 1</a>). These two cases appeared to exhibit the same partial heterozygous deletion of <span class="elsevierStyleItalic">TSC2</span> and <span class="elsevierStyleItalic">PKD1</span>, although the exact 5´ deletion breakpoint in <span class="elsevierStyleItalic">PKD1</span> was not identified by the employed MLPA assay (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 3</a>A). To date, 30 PKDTS cases have been described in which the contiguous deletion affects parts of <span class="elsevierStyleItalic">TSC2</span> and <span class="elsevierStyleItalic">PKD1</span> (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 1</a>). In general, regardless of the extent of the deletion, the renal cysts were larger and the renal function fell below normal at a younger age than seen in typical TSC cases without any <span class="elsevierStyleItalic">PKD1</span> deletion.<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">10</span></a> Unexpectedly, case 3 exhibited small cysts that could only be detected by MRI, which is better able to detect small cysts (<1<span class="elsevierStyleHsp" style=""></span>cm) in ADPKD patients compared to US, although the latter is the initial test of choice in the polycystic kidney disease.<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">18</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">To date, at least 25 other PKDTS cases have been reported to include deletion of genes in addition to <span class="elsevierStyleItalic">TSC2</span> and <span class="elsevierStyleItalic">PKD1</span> (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 1</a>); among them, our case 3 appears to harbor the largest deletion upstream of <span class="elsevierStyleItalic">TSC2</span> (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 3</a>B). In three of the previously reported cases, (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 1</a>) the early PKD symptoms and end-stage renal disease were recognized fairly late (>20 years).<a class="elsevierStyleCrossRefs" href="#bib0190"><span class="elsevierStyleSup">8,11,12</span></a> This is similar to case 3, in which only a few small cysts were found at age 15 and renal function was preserved (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 1</a>). The previous authors speculated that the relatively mild kidney involvement could reflect somatic mosaicism or the presence of genetic modifiers, but these hypotheses were not tested.<a class="elsevierStyleCrossRefs" href="#bib0190"><span class="elsevierStyleSup">8,11</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">Other studies have suggested that a mild PKD phenotype (better preserved renal function, as evaluated by glomerular filtration rate, and cystic disease recognized only in adult life) is associated with low/high grade deletion mosaicism.<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">6,10,11</span></a> However, the apparently mild PKD phenotype in case 3 could not be explained by somatic mosaicism, as the MLPA results showed that the ratio values (STD<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>0.10) for each probe involved in the <span class="elsevierStyleItalic">TSC2/PKD1</span> contiguous deletion were reduced by 0.5, implying that 100% of the peripheral leukocyte cells were heterozygous for this genotype and in addition, we detected a smooth signal of 1.2 copies (heterozygous deletion genotype) in CMA data. However, a low-level mosaicism could not be totally ruled out by CMA data since the deletion size is very small and the CytoScan<span class="elsevierStyleSup">TM</span> algorithm is designed to discard mosaicism by the analysis of at least 5000 markers in deleted region.</p><p id="par0050" class="elsevierStylePara elsevierViewall">The variable progression of PKD in our patients and the reported cases plus the absence of a clear genotype–phenotype correlation suggest that the mechanisms underlying renal cyst formation in PKD are extremely complex and may involve environmental and/or genetic factors that are not solely related to the <span class="elsevierStyleItalic">PKD</span> genotype. The identified 296.7<span class="elsevierStyleHsp" style=""></span>kb CNV in the 16p13.3 region of case 3, which had not been previously reported as pathogenic in Decipher<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">19</span></a> or the Database of Genomic Variants,<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">20</span></a> included six coding genes and remarkable among them is the <span class="elsevierStyleItalic">SSTR5</span> (somatostatin receptor) gene. Although, small clinical trials showed that somatostatin analogs (SSAs) decreased total kidney volume in patients with ADPKD, larger trials are ongoing to know their final effect in kidney cysts, so at this time, they are only indicated in ADPKD patients with severe liver cystic disease.<a class="elsevierStyleCrossRefs" href="#bib0255"><span class="elsevierStyleSup">21–25</span></a> The precise mechanism through which SSAs (e.g., lanreotide and octreotide) inhibit cystogenesis is not fully understood, but SSAs can inhibit cAMP accumulation, which plays a crucial role in cystogenesis.<a class="elsevierStyleCrossRefs" href="#bib0280"><span class="elsevierStyleSup">26,27</span></a> We hypothesize that the triple gene dosage of <span class="elsevierStyleItalic">SSTR5</span> correlates with increased binding of the receptor's ligand, which would further reduce intracellular cAMP levels and decrease cellular proliferation through the Ras/Raf/MEK/ERK pathways.<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">27</span></a> Modifier genes have previously been proposed to be present within CNVs of monogenic disorders. For example, Artuso et al.,<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">28</span></a> detected a CNV containing a candidate modifier gene for Rett syndrome (MIM#312750). In two sisters with the same pathogenic genotype of <span class="elsevierStyleItalic">MECP2</span> (the gene responsible for Rett syndrome), the three copies of <span class="elsevierStyleItalic">CROCC</span> (1p36.13) was associated with a milder phenotype, while a single gene copy was associated with the classic phenotype of Rett syndrome. Thus, it can be hypothesized that the presence of the CNV with the three <span class="elsevierStyleItalic">SSTR5</span> copies in our case 3 may counteract the <span class="elsevierStyleItalic">TSC2</span> and <span class="elsevierStyleItalic">PKD1</span> deletion and modulate the PKD severity. However, future work is warranted to examine this possibility.</p><p id="par0055" class="elsevierStylePara elsevierViewall">In the other hand, we can neither rule out that in case 3 the heterozygous loss of any of the 13 coding genes, others than <span class="elsevierStyleItalic">TSC2</span> and <span class="elsevierStyleItalic">PKD1</span>, could act as disease modifier. In fact, it has been shown that some of these genes are expressed in the kidney,<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">29</span></a> although none has been involved in a syndrome associating with kidney alterations in OMIM.<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">30</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusions</span><p id="par0060" class="elsevierStylePara elsevierViewall">The cystic phenotype in PKDTS cases varies considerable among individuals; this suggests that a combination of factors besides the <span class="elsevierStyleItalic">TSC2/PKD1</span> genotype, as modifying genes could be implied in the progression of the disease. Given the reported effect of SSAs in cystogenesis and the presence of three copies of <span class="elsevierStyleItalic">SSTR5</span> in the patient who exhibited the mildest PKD phenotype (case 3) we hypothesize that an increased gene dosage of <span class="elsevierStyleItalic">SSTR5</span> could counteract the PKD phenotype and its progression. The main limitation of our work relies on the fact that the exact 5'<span class="elsevierStyleItalic">PKD1</span> breakpoint in cases 1 and 2 could not be determined, however, these two cases presented multiple cysts in both kidneys at early age as expected with a classic PKDTS. Considering that no previous studies have reported possible modifier genetic variants in other PKDTS patients, future work that includes functional analyses, frequency population studies in healthy individuals and more PKDTS cases will be necessary to determine the role of the 16p13.3 CNV, that contains <span class="elsevierStyleItalic">SSTR5</span> in case 3 which apparently harbors the largest <span class="elsevierStyleItalic">TSC2/PKD1</span> deletion and the mildest PKDTS phenotype.</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Funding</span><p id="par0065" class="elsevierStylePara elsevierViewall">This study was supported by the research funding from the National Institute of Pediatrics, Ciudad de México, México (Recursos Fiscales del Programa E022), as well as funding from Consejo Nacional de Ciencia y Tecnología, México (CONACyT FONSEC SSA/IMSS/ISSSTE, S0008, 2016–2018, Project #261404), Fundación “Miguel Alemán” 2012 and Novartis (2013).</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Conflict of interest</span><p id="par0070" class="elsevierStylePara elsevierViewall">The authors declare no conflicts of interests.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:14 [ 0 => array:3 [ "identificador" => "xres1318558" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1216597" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "xpalclavsec1216595" "titulo" => "Abbreviations" ] 3 => array:3 [ "identificador" => "xres1318559" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 4 => array:2 [ "identificador" => "xpalclavsec1216594" "titulo" => "Palabras clave" ] 5 => array:2 [ "identificador" => "xpalclavsec1216596" "titulo" => "Abreviaturas" ] 6 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 7 => array:2 [ "identificador" => "sec0010" "titulo" => "Case presentation" ] 8 => array:2 [ "identificador" => "sec0015" "titulo" => "Discussion" ] 9 => array:2 [ "identificador" => "sec0020" "titulo" => "Conclusions" ] 10 => array:2 [ "identificador" => "sec0025" "titulo" => "Funding" ] 11 => array:2 [ "identificador" => "sec0030" "titulo" => "Conflict of interest" ] 12 => array:2 [ "identificador" => "xack454579" "titulo" => "Acknowledgements" ] 13 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2018-08-10" "fechaAceptado" => "2019-03-26" "PalabrasClave" => array:2 [ "en" => array:2 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1216597" "palabras" => array:5 [ 0 => "Tuberous sclerosis complex" 1 => "Polycystic kidney disease" 2 => "Copy number variant" 3 => "<span class="elsevierStyleItalic">TSC2</span>/<span class="elsevierStyleItalic">PKD1</span> contiguous gene syndrome" 4 => "<span class="elsevierStyleItalic">SSTR5</span> gene" ] ] 1 => array:4 [ "clase" => "abr" "titulo" => "Abbreviations" "identificador" => "xpalclavsec1216595" "palabras" => array:8 [ 0 => "ADPKD" 1 => "CNV" 2 => "CMA" 3 => "MLPA" 4 => "PKD" 5 => "PKDTS" 6 => "SSAs" 7 => "TSC" ] ] ] "es" => array:2 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1216594" "palabras" => array:5 [ 0 => "Complejo de esclerosis tuberosa" 1 => "Enfermedad del riñón poliquístico" 2 => "Variante del número de copias" 3 => "Síndrome de genes contiguos <span class="elsevierStyleItalic">TSC2</span>/<span class="elsevierStyleItalic">PKD1</span>" 4 => "Gen <span class="elsevierStyleItalic">SSTR5</span>" ] ] 1 => array:4 [ "clase" => "abr" "titulo" => "Abreviaturas" "identificador" => "xpalclavsec1216596" "palabras" => array:3 [ 0 => "CET" 1 => "ERP" 2 => "PKDTS" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">About 80% of patients with tuberous sclerosis complex (TSC) present renal involvement, usually as angiomyolipomas followed by cystic disease. An early diagnosis of polycystic kidney disease (PKD) in such patients is frequently related to the <span class="elsevierStyleItalic">TSC2/PKD1</span> contiguous gene syndrome (PKDTS). Molecular confirmation of PKDTS is important for a prompt diagnosis, which can be complicated by the phenotypic heterogeneity of PKD and the absence of a clear phenotype–genotype correlation. Herein, we report three PKDTS pediatric patients. The case 3 did not present a classic PKDTS phenotype, having only one observable cyst on renal ultrasound at age 4 and multiple small cysts on magnetic resonance imaging at age 15. In this patient, chromosomal microarray analysis showed a gross deletion of 230.8<span class="elsevierStyleHsp" style=""></span>kb that involved <span class="elsevierStyleItalic">TSC2</span>, <span class="elsevierStyleItalic">PKD1</span> and 13 other protein-coding genes, plus a heterozygous duplication of a previously undescribed copy number variant of 242.9<span class="elsevierStyleHsp" style=""></span>kb that involved six protein-coding genes, including <span class="elsevierStyleItalic">SSTR5</span>, in the 16p13.3 region. Given the observations that the case 3 presented the mildest renal phenotype, harbored three copies of <span class="elsevierStyleItalic">SSTR5,</span> and the reported inhibition of cystogenesis (specially in liver) observed with somatostatin analogs in some patients with autosomal dominant PKD, it can be hypothesized that other genetic factors as the gene dosage of <span class="elsevierStyleItalic">SSTR5</span> may influence the PKD phenotype and the progression of the disease; however, future work is needed to examine this possibility.</p></span>" ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Un 80% de los pacientes con complejo de esclerosis tuberosa (CET) presentan afectación renal, generalmente angiomiolipomas, seguidos de enfermedad quística. Un diagnóstico temprano de la enfermedad renal poliquística (ERP) en estos pacientes se relaciona con frecuencia con el síndrome de genes contiguos <span class="elsevierStyleItalic">TSC2/PKD1</span> (PKDTS). La confirmación molecular de PKDTS es importante para establecer un diagnóstico oportuno, que puede complicarse por la heterogeneidad fenotípica de PKD y la ausencia de una clara correlación entre fenotipo y genotipo. En este artículo presentamos los casos de 3 pacientes pediátricos con PKDTS. El caso 3 no presentó un fenotipo PKDTS clásico, con solo un quiste observable en la ecografía renal a los 4 años y numerosos quistes pequeños en la resonancia magnética a los 15 años. En este paciente, el análisis de microarreglos para análisis cromosómico global mostró una eliminación total de 230,8<span class="elsevierStyleHsp" style=""></span>kb que involucró a <span class="elsevierStyleItalic">TSC2,</span><span class="elsevierStyleItalic">PKD1</span> y otros 13 genes codificantes de proteínas, más una duplicación heterocigota para una variante de número de copias no descrita previamente de 242,9<span class="elsevierStyleHsp" style=""></span>kb que involucró a 6 genes codificantes de proteínas, entre ellos <span class="elsevierStyleItalic">SSTR5,</span> en la región 16p13.3. Dado que el caso 3 mostraba el fenotipo renal menos severo, contaba con tres copias del gen <span class="elsevierStyleItalic">SSTR5</span> y a que se ha observado una inhibición en la cistogénesis (especialmente en el hígado) con los análogos de somatostatina en algunos pacientes con ERP autosómica dominante, podemos hipotetizar que existen otros factores genéticos como la dosis génica de <span class="elsevierStyleItalic">SSTR5</span> que pudieran influir en el fenotipo y la progresión de la ERP; sin embargo, se necesitan estudios adicionales para investigar esta posibilidad.</p></span>" ] ] "multimedia" => array:6 [ 0 => array:7 [ "identificador" => "fig0015" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 3808 "Ancho" => 2934 "Tamanyo" => 656108 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">TS</span>C2 and <span class="elsevierStyleItalic">PKD1</span> deletions characterized by various molecular techniques in the reported PKDTS cases.</p> <p id="spar0050" class="elsevierStyleSimplePara elsevierViewall"><elsevierMultimedia ident="202003180710049251"></elsevierMultimedia>, Complete deletion of the gene; <elsevierMultimedia ident="202003180710049252"></elsevierMultimedia>, partial deletion of the gene; ?, Unknown breakpoint. <span class="elsevierStyleItalic">Abbreviations</span>: aCGH: microarray-based comparative genomic hybridization; CMA: chromosomal microarray; FISH: fluorescence <span class="elsevierStyleItalic">in situ</span> hybridization; MLPA: multiplex ligation-dependent probe amplification; qPCR: quantitative PCR, *Cases in which PKD symptoms and end-stage renal disease were recognized fairly late (>20 years).</p>" ] ] 1 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1777 "Ancho" => 2126 "Tamanyo" => 296331 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Renal image studies in the three TSC patients. (A and B) Polycystic kidney disease detected by US in cases 1 and 2. (C) Single cyst in the right kidney detected by US in case 3 (arrows). (D) Polycystic kidney disease detected by MRI in case 3.</p>" ] ] 2 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Fig. 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1754 "Ancho" => 2514 "Tamanyo" => 186438 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Molecular PKDTS characterization in the three TSC patients. (A) Schematic representation of the deletions detected by MLPA in the three PKDTS cases (not drawn to scale). Vertical gray lines in the <span class="elsevierStyleItalic">TSC2</span> and <span class="elsevierStyleItalic">PKD1</span> genes indicate exons with proportional spacing. The long black lines above indicate the range of each heterozygous deletion. A short dotted arrow and a question mark represent the expected minimal deletion interval estimated by MLPA. (B) Schematic representation of the rearrangement detected in the 16p13.3 region by CMA in case 3 (not drawn to scale). Gray lines at the right indicate deleted coding genes (complete deletion of <span class="elsevierStyleItalic">TSC2</span> and deletion of exons 20–46 of <span class="elsevierStyleItalic">PKD1</span>) and double gray lines at the left indicate the duplicated coding genes (three copies), including <span class="elsevierStyleItalic">SSTR5</span>. <span class="elsevierStyleItalic">Abbreviations</span>: Cen: centromeric region, CMA: chromosomal microarray analysis, Ex: exon, MLPA: multiplex ligation-dependent probe amplification, Tel: telomeric region.</p>" ] ] 3 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:3 [ "leyenda" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">All cases are definitive according to the criteria of Northrup et al.<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">17</span></a> Seizures are well controlled in all three cases.</p><p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">CMA: chromosomal microarray; eGFR: estimated glomerular filtration rate; m: months; MLPA: multiple ligation probe amplification; NA: not analyzed; y: years; +: present; -: absent.</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="" 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="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Case 1 \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="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Case 2 \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="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Case 3 \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Age at hospital admission/PKD diagnosis</span> \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">11y \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">7m \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">4y \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Current age</span> \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">18y, 5m \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">18y, 9m \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">15y, 8m \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Gender</span> \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">Female \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">Male \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">Male \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 " colspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">TSC major features</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Hypomelanotic macules \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">+ \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">+ \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">+ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Angiofibromas (=3) or fibrous cephalic plaque \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">+ \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">+ \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">+ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Ungual fibromas (=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">- \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">- \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">- \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Shagreen patch \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">+ \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">+ \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">+ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Multiple retinal hamartomas \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">+ \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">- \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">- \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Cortical dysplasias \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">+ \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">+ \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">+ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Subependymal nodules \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">+ \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">+ \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">+ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Subependymal giant cell astrocytoma \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">- \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">- \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">- \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Cardiac rhabdomyoma \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">- \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">- \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">- \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Lymphangioleiomyomatosis \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">NA \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">NA \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">NA \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Angiomyolipomas (=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">- \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">- \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">- \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 " colspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">TSC minor features</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Confetti skin lesions \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">- \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">- \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">- \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Dental enamel pits (>3) \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">- \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">+ \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">- \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Intraoral fibromas (=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">- \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">- \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">- \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Retinal achromic patch \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">- \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">- \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">- \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Multiple renal cysts \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">+ \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">+ \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">+ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Nonrenal hamartomas \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">- \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">- \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">- \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 " colspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Other clinical findings</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Seizures \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">+<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a> \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">+<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a> \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">+<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">c</span></a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Intellectual disability \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">+ \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">- \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">+ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Central nervous system alterations, aneurysms \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">Absent at 16y, 1m \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">Absent at 15y, 1m \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">Absent at 11y, 7m \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Liver cysts \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">Absent at 14y \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">Absent at 18y \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">Absent at 13y, 7m \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Kidney findings at last evaluation age \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">16y, 7m \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">10y, 9m \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">13y, 2m \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>eGFR<a class="elsevierStyleCrossRef" href="#tblfn0020">*</a> (normal 90–120<span class="elsevierStyleHsp" style=""></span>mL/min/1.73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>) \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">110 \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">146 \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">223 \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 " colspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Blood pressure (systolic/diastolic PC</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic"><</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">90)</span> \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"><90 \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"><90 \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">Not measured \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Hemoglobin (12–15</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">mg/dL)</span> \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">14.4 \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">Not measured \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">Not measured \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Uric acid (2.4–5.9</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">mg/dL)</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4.4 \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">5.4 \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">Not measured \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Proteinuria (urinary protein to creatinine ratio</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic"><</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">0.2)</span> \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">0.08 \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">0.04 \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">Not measured \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Hematuria (2–5 RBCs/high power field)</span> \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">34 (positive) \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">Not measured \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">Not measured \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">% Kidney growth per year</span> \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">9.6% \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">22% \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">5.6% \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 " colspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Molecular studies</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Deleted region by MLPA \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"><span class="elsevierStyleItalic">TSC2</span> (Exons 31–42), <span class="elsevierStyleItalic">PKD1</span> (Exons 46–40) \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"><span class="elsevierStyleItalic">TSC2</span> (Exons 31–42), <span class="elsevierStyleItalic">PKD1</span> (Exons 46–40) \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"><span class="elsevierStyleItalic">TSC2</span> (whole gene deletion), <span class="elsevierStyleItalic">PKD1</span> (Exons 20–46), exact breakpoint further delineated by CMA \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Deleted region by CMA/deleted genes \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="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \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="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \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"><span class="elsevierStyleItalic">arr[hg38] 16p13.3(1,875,332–2,106,147)x1/HS3ST6, MSRB1, RPL3L, NDUFB10, RPS2, RNF151, NOXO1, GFER, SYNGR3, ZNF598, NPW, SLC9A3R2, NTHL1</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Duplicated region by CMA/duplicated genes \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="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \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="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \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"><span class="elsevierStyleItalic">arr[hg38] 16p13.3(1,002,307-1,245,192)x3/SSTR5, C1QTNF8, CACNA1H, TPSG1, TPSB2, TPSAB1.</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2260100.png" ] ] ] "notaPie" => array:4 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">One seizure per month, treated with three antiepileptic drugs.</p>" ] 1 => array:3 [ "identificador" => "tblfn0010" "etiqueta" => "b" "nota" => "<p class="elsevierStyleNotepara" id="npar0010">One seizure per month, treated with two antiepileptic drugs.</p>" ] 2 => array:3 [ "identificador" => "tblfn0015" "etiqueta" => "c" "nota" => "<p class="elsevierStyleNotepara" id="npar0015">No seizure in past 4 years, treated with two antiepileptic drugs.</p>" ] 3 => array:3 [ "identificador" => "tblfn0020" "etiqueta" => "*" "nota" => "<p class="elsevierStyleNotepara" id="npar0020">The glomerular filtration rate was calculated using the Schwartz formula and classified according to the Kidney Disease Improving Global Outcomes (KDIGO) guidelines.</p>" ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Clinical features of the three studied cases of PKDTS.</p>" ] ] 4 => array:5 [ "identificador" => "202003180710049251" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => false "mostrarDisplay" => true "figura" => array:1 [ 0 => array:4 [ "imagen" => "fx1.jpeg" "Alto" => 22 "Ancho" => 30 "Tamanyo" => 315 ] ] ] 5 => array:5 [ "identificador" => "202003180710049252" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => false "mostrarDisplay" => true "figura" => array:1 [ 0 => array:4 [ "imagen" => "fx2.jpeg" "Alto" => 21 "Ancho" => 37 "Tamanyo" => 680 ] ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:30 [ 0 => array:3 [ "identificador" => "bib0155" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Renal manifestations of tuberous sclerosis complex: incidence, prognosis, and predictive factors" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "S.K. 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This study makes use of data generated by the DECIPHER community. A full list of centers that contributed to the generation of the data is available from <a target="_blank" href="http://decipher.sanger.ac.uk/">http://decipher.sanger.ac.uk</a> and via email from <a target="_blank" href="http://www.decipher.sanger.ac.uk/">www.decipher.sanger.ac.uk</a>.</p>" "vista" => "all" ] ] ] "idiomaDefecto" => "en" "url" => "/20132514/0000004000000001/v1_202003180708/S2013251420300195/v1_202003180708/en/main.assets" "Apartado" => array:4 [ "identificador" => "35422" "tipo" => "SECCION" "en" => array:2 [ "titulo" => "Case Reports" "idiomaDefecto" => true ] "idiomaDefecto" => "en" ] "PDF" => "https://static.elsevier.es/multimedia/20132514/0000004000000001/v1_202003180708/S2013251420300195/v1_202003180708/en/main.pdf?idApp=UINPBA000064&text.app=https://revistanefrologia.com/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2013251420300195?idApp=UINPBA000064" ]
| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 13 | 6 | 19 |
| 2024 October | 75 | 60 | 135 |
| 2024 September | 70 | 29 | 99 |
| 2024 August | 71 | 75 | 146 |
| 2024 July | 54 | 39 | 93 |
| 2024 June | 48 | 37 | 85 |
| 2024 May | 40 | 29 | 69 |
| 2024 April | 53 | 40 | 93 |
| 2024 March | 36 | 29 | 65 |
| 2024 February | 32 | 36 | 68 |
| 2024 January | 34 | 29 | 63 |
| 2023 December | 42 | 39 | 81 |
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| 2023 October | 74 | 40 | 114 |
| 2023 September | 72 | 28 | 100 |
| 2023 August | 59 | 31 | 90 |
| 2023 July | 53 | 22 | 75 |
| 2023 June | 46 | 23 | 69 |
| 2023 May | 51 | 34 | 85 |
| 2023 April | 46 | 17 | 63 |
| 2023 March | 74 | 28 | 102 |
| 2023 February | 48 | 19 | 67 |
| 2023 January | 41 | 40 | 81 |
| 2022 December | 50 | 34 | 84 |
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| 2021 December | 71 | 36 | 107 |
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| 2021 October | 84 | 56 | 140 |
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| 2021 February | 53 | 33 | 86 |
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| 2020 December | 37 | 19 | 56 |
| 2020 November | 24 | 14 | 38 |
| 2020 October | 23 | 24 | 47 |
| 2020 September | 23 | 17 | 40 |
| 2020 August | 23 | 16 | 39 |
| 2020 July | 28 | 19 | 47 |
| 2020 June | 18 | 14 | 32 |
| 2020 May | 77 | 29 | 106 |
| 2020 April | 34 | 29 | 63 |
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