Isolated liver disease in a patient with a CFTR genotype F508del/12TG-5T and 470MV: A new face of an old disease
Andrea D. Praticò
, Elena R. Praticò, Novella Rotolo, Stefania Salafia, Chiara Franzonello, Salvatore Leonardi
Corresponding author
Unit of Pediatric Pneumo-Allergology and Cystic Fibrosis, Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
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Praticò, Elena R. Praticò, Novella Rotolo, Stefania Salafia, Chiara Franzonello, Salvatore Leonardi" "autores" => array:6 [ 0 => array:5 [ "preGrado" => "M.D." "nombre" => "Andrea D." "apellidos" => "Praticò" "email" => array:1 [ 0 => "terrenere178@tin.it" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 1 => array:2 [ "nombre" => "Elena R." "apellidos" => "Praticò" ] 2 => array:2 [ "nombre" => "Novella" "apellidos" => "Rotolo" ] 3 => array:2 [ "nombre" => "Stefania" "apellidos" => "Salafia" ] 4 => array:2 [ "nombre" => "Chiara" "apellidos" => "Franzonello" ] 5 => array:2 [ "nombre" => "Salvatore" "apellidos" => "Leonardi" ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Unit of Pediatric Pneumo-Allergology and Cystic Fibrosis, Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy" "identificador" => "aff0005" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "*" "correspondencia" => "Correspondence and reprint request:" ] ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="s0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0015">Introduction</span><p id="p0005" class="elsevierStylePara elsevierViewall">Prevalence of liver disease in patients affected by cystic fibrosis (CF) is about 30-40% and it is the third cause of death in these patients.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a>,<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> Hypertransaminasemia and hyperbilirubinemia are the main biochemical manifestations, and usually occurs in 50% of patients,<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> while the most frequent hepatic disorders are hepatic steatotis (23-67%), focal biliary cirrhosis (11-72%), multilobar cirrhosis (5-10%), neonatal cholestasis and liver failure.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a>,<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a></p><p id="p0010" class="elsevierStylePara elsevierViewall">The exact pathogenesis of liver disease in CF seems to be related to the alteration of the cystic fibrosis transmembrane regulator (CFTR) channel, located on the apical side of the biliary ducts, resulting in a dehydrated and viscous bile secretion, which leads to obstruction of small biliary ducts. According to this etiopathogenetic hypothesis, cholestasis could activate an inflammatory cascade with production of fibrogenic molecules.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> Moreover liver damage could be modulated both by genes modifiers and environmental factors.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> A clear genotypephenotype correlation for the occurrence liver disorder in cystic fibrosis has not been demonstrated, even if liver disease is more frequent in patients carrying severe genotypes.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a></p><p id="p0015" class="elsevierStylePara elsevierViewall">In the last years, the discovery of new genetic mutations has allowed to explain many uncommon forms of CF<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a>,<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> and in many of these cases, genotypephenotype correlation is resulted difficult to clarify, especially when a CF-causing mutation is combined with one or more milder mutations or polymorphisms. Furthermore, the phenotype of patients affected by CF can be influenced by environmental factors (infections or pollution) or other gene modifiers, thus making almost unpredictable the course of the disease in subjects with rare genotypes.<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a></p><p id="p0020" class="elsevierStylePara elsevierViewall">In this setting, a new field of research is represented by the possible phenotypic expressions of patients carrying poly-5T variants in association with disease causing mutations, such as F508del. 5T is a widely expressed allelic polymorphism, approximately presented by 1 in 10 individuals, and when it is combined with another CF-causing mutation, it can lead either to CF phenotype or to a healthy condition,<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> in particular if associated with a longer (12 or 13) TG tract. The most common clinical feature presented by patients with this genotype is the congenital absence of vas deferens (CABVD), pancreatic sufficiency, and normal lung function.<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a>,<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a></p><p id="p0025" class="elsevierStylePara elsevierViewall">Although quite common in the classic form of the disease,<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> apart from CBAVD, to date, liver disease has never been reported as manifestation of a F508del/ 12TG-5T-470MV genotype. We herein describe a young adult patient admitted to our unit because of a history of jaundice and hypertransaminasemia, and in whom a diagnosis of CF caused by this genotype was performed.</p></span><span id="s0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0020">Case Report</span><p id="p0030" class="elsevierStylePara elsevierViewall">The patient, a 15-year old boy was recovered at our unit, tertiary referral centre for Child Pneumoallergology and Cystic Fibrosis, with a two years history of chronic hypertransaminasemia and jaundice. The boy was born at-term with the weight of 3.4 kg. Family and personal history were negative and the patient did not report any exposure to toxic substances or drugs in the last two years. At physical examination, weight and height were respectively 42.7 kg (3rd percentile) and 160 cm (10-25th percentile) and, scleral jaundice was the only clinical sign. Blood tests showed aspartate aminotransferase (AST) value of 66 U/I (n.v. < 40 U/I) and alanine aminotransferase (ALT) of 200 U/I (n.v. < 40 U/I), increased alkaline phosphatase (646 U/I, n.v. = 300-400 U/I), and hyperbilirubinemia (total bilirubin 3.48 mg/dL, indirect bilirubin 1.84 mg/dL). All the other blood tests, including full blood count, glycaemia, lipid profile, electrolytes, protein electrophoresis, coagulation tests, renal and pancreatic function tests, blood iron subset and immunoglobulins, were within normal range. The results of bacterial and viral assessment were negative, and so the tests for Wilson disease, autoimmune hepatitis, non-alcoholic fatty liver disease, celiac disease and hereditary hemochromatosis.</p><p id="p0035" class="elsevierStylePara elsevierViewall">An abdominal ultrasound showed a slight increase in liver size and hyperechogenity of the parenchyma. A liver biopsy was performed, and there was no evidence of anomalies at the histological examination. A sweat chloride test was performed, with a result of 72 mEq/L (n.v. < 40 mEq/l). Two other tests were performed to confirm this result. The second showed a borderline result (47 mEq/L) and the third a positive result (60 mEq/L). For this reason, a genetic first level investigation for Cystic Fibrosis performed by reverse dot blot commercial kits (INNO-LIPA CFTR19, INNO-LIPA CFTR17+TnUpdate and INNO-LIPA Italian-Regional, Innogenetics, Ghent, Belgium) showed the presence of heterozygous mutation F508del and the presence of the 5T polymorphism. A second level investigation, performed by automated DNA sequencing using ABI Prism 3100 (Applied Biosystems, Warrington, UK), confirmed the presence of the haplotype TG12-5T plus the 470V variant in one allele and F508del and TG11-9T plus the 470M variant in the other. The same genetic analyses were performed in the parents and results are showed in <a class="elsevierStyleCrossRef" href="#t0005">table 1</a>. The presence of this genotype led to the diagnosis of CF.</p><elsevierMultimedia ident="t0005"></elsevierMultimedia><p id="p0040" class="elsevierStylePara elsevierViewall">The bacteriological analysis of sputum and a spirometry were performed, both with normal results. Chest X rays evaluation was normal. Pancreatic function was normal, as revealed by a fecal elastasys value of 400 <span class="elsevierStyleItalic">µ</span>g/g, and normal levels of amylase and lipase.</p><p id="p0045" class="elsevierStylePara elsevierViewall">Therapy with ursodeoxycholic acid at a dose of 15 mg/kg/day was initiated, with a slighter reduction of transaminases value (AST 60 U/L; ALT 110 U/L), but persistence of high bilirubin level (3.19 mg/dL). After six months of therapy, transaminases values decreased to normal levels (AST 30 U/L; ALT 35 U/L), and bilirubin level was further decreased 2.22 mg/dL. The presence of CBAVD was initially suggested by palpable scrotal vas on physical examination and by the results of a trans-rectal ultrasonography and subsequently confirmed by MRI examination of the seminal vesicle (SV) and intra-abdominal segment of vas deferens. The parents of the patient refused to sign the consent to perform a sperm count.</p></span><span id="s0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0025">Discussion</span><p id="p0050" class="elsevierStylePara elsevierViewall">Before the introduction of mandatory neonatal screening (in Sicily from 1999), CF was diagnosed at early age only if patients presented severe symptoms such as neonatal meconium ileus, recurrent <span class="elsevierStyleItalic">Pseudomonas aeruginosa</span> lung infections and pancreatic insufficiency.<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> At present, it is not rare, for patient born before 1999 or negative to the screening, or affected by atypical or milder form of cystic fibrosis, to be diagnosed in adolescence or adulthood, by the genetic evaluation.<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a>,<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a></p><p id="p0055" class="elsevierStylePara elsevierViewall">On this regard, complex genotypes are becoming a common finding in patients with these milder presentations, which usually consist in involvement of only one system (i.e. isolated pancreatic insufficiency, or CBAVD), in absence of severe symptoms. The genotypes of these patients can be characterized by one severe mutation plus one milder mutation, two or more milder mutation, one severe mutation plus one or more polymorphisms etc. Isolated liver disease is very rare and can represent an example of the role of genetic polymorphisms, which can express with a normal lung and pancreatic function, but with other organs dysfunction, such as CBAVD.</p><p id="p0060" class="elsevierStylePara elsevierViewall">Polymorphisms are common variant of a gene, usually found in > 1% of the population. Particular polymorphisms, such as 5T, or TG, M470V are commonly found in the healthy population, but if combined with severe CF-causing mutations, they can lead to unpredictable form of disease.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a></p><p id="p0065" class="elsevierStylePara elsevierViewall">The 5T allele in intron 8 (IVS8) is a mild variant of CFTR, resulting in mRNA lacking exon 9 and for this reason, 5T is thought to decrease the efficiency of intron 8 splicing.<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> The association F508del and 5T has been related to a less functional or even insufficient CFTR protein, leading to atypical CF or CBAVD in 60% of the cases.<a class="elsevierStyleCrossRefs" href="#bib0065"><span class="elsevierStyleSup">13</span></a><span class="elsevierStyleSup">–</span><a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> Other common variants of the IVS8, both considered polymorphic, are 7T and 9T, which differently from 5T do not cause atypical CF or CBAVD, even when associated to F508del or other severe mutations.<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a></p><p id="p0070" class="elsevierStylePara elsevierViewall">When a 5T mutation is present, the percentage of functioning protein is strictly related to the repetition of a TG tracts which lies in proximity to poly T and consists of a short string of TG repeats that commonly number 11, 12, or 13. A longer TG tract (12 or 13) in conjunction with a shorter poly T tract (5T) has the strongest adverse effect on proper intron 8 splicing and it is associated with higher values at IRT test.<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> Our patient presented a TG12-5T mutation, which has been reported to cause CF symptoms or CBAVD in 78% of affected patients.<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a></p><p id="p0075" class="elsevierStylePara elsevierViewall">A part from the higher risk of CBAVD, the presence of a IVS8 mutation in combination with a severe mutation on the other allele has been more rarely associated to severe lung disease,<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> and to recurrent acute pancreatitis.<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a></p><p id="p0080" class="elsevierStylePara elsevierViewall">The expressivity of poly-T and TG tract variant can be further complicated by the presence of 470M or 470V haplotype, which are both considered normal. M470V (1540A/G in exon 10) locus is polymorphic at amino acid level, and causes a different maturation and intrinsic chloride channel activity: 470M CFTR protein matures more slowly and has 1.7-fold increased channel activity compared to 470V protein.<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> Although 470M and 470V alleles differ functionally, there have been no reports that they alone could be associated with CF, but is much likely that they have synergistic effect with other sequence variants such as poly-T or TG tract. As reported by Noone and coll., the 5T polythymidine tract sequence on specific haplotype backgrounds (TG12-470M) may cause a low level of full-length functional CFTR protein and CF-like lung disease.<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> In a more recent paper it was showed that patients with 470V genotype had a 3.4-fold decreased risk of severe pulmonary disease.<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a></p><p id="p0085" class="elsevierStylePara elsevierViewall">Differently, the main symptom presented by our patient was an isolated liver involvement consisting in persistent hyperbilirubinemia and hypertransaminasemia, never reported as isolated feature in patients carrying these mutations.</p><p id="p0090" class="elsevierStylePara elsevierViewall">In our case, the presence of the severe mutation F508del associated with TG11-9T-470M on one allele and a pattern of milder polymorphism TG12-5T-470V on the other chromosome, represents a never reported genotypic profile, in which lung and pancreas do not seem to be affected, CBAVD is probably present and liver involvement is mild with no specific pathological findings at liver biopsy.</p></span><span id="s0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0030">Conclusions</span><p id="p0095" class="elsevierStylePara elsevierViewall">Although a clear genotype-phenotype correlation for liver disease is still missing for CF patients, it is possible to state that this isolated clinical presentation could represent an unusual phenotype of CF, related to a complex genotype characterized by a severe mutation and one (or more) polymorphism.</p></span><span id="s0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0035">Authors’ Contribution</span><p id="p0100" class="elsevierStylePara elsevierViewall">ADP wrote the entire manuscript, ERP and SS revised the literature, NR and CF followed up the patient, SL revised the entire manuscript.</p><p id="p0105" class="elsevierStylePara elsevierViewall">Andrea D. Praticò is responsible for the integrity of the work as a whole.</p></span><span id="s0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0040">Conflict of Interests</span><p id="p0110" class="elsevierStylePara elsevierViewall">The authors have nothing to disclose.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:9 [ 0 => array:3 [ "identificador" => "xres1199888" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abs0010" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1118324" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "s0005" "titulo" => "Introduction" ] 3 => array:2 [ "identificador" => "s0010" "titulo" => "Case Report" ] 4 => array:2 [ "identificador" => "s0015" "titulo" => "Discussion" ] 5 => array:2 [ "identificador" => "s0020" "titulo" => "Conclusions" ] 6 => array:2 [ "identificador" => "s0025" "titulo" => "Authors’ Contribution" ] 7 => array:2 [ "identificador" => "s0030" "titulo" => "Conflict of Interests" ] 8 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2015-01-18" "fechaAceptado" => "2015-03-16" "PalabrasClave" => array:1 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1118324" "palabras" => array:6 [ 0 => "Liver disease" 1 => "Cystic fibrosis" 2 => "CFTR" 3 => "F508del" 4 => "IVS8 5T" 5 => "M470V" ] ] ] ] "tieneResumen" => true "resumen" => array:1 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<span id="abs0010" class="elsevierStyleSection elsevierViewall"><p id="sp0010" class="elsevierStyleSimplePara elsevierViewall">Today the knowledge of genotype-phenotype correlation in cystic fibrosis is enriched by the growing discoveries of new mutations of the <span class="elsevierStyleItalic">CFTR</span> gene. Although the combination of two severe mutations usually leads to the classic disease (pulmonary and pancreatic insufficiency, sterility, nasal polyposis), the presence of a complex genotype characterized by severe and milder mutations or polymorphism can cause a hidden disease, which is often asymptomatic at early ages. We report on a case of a 15 years old boy, in whom the only clinical signs of CF were chronic hypertransaminasemia and hyperbilirubinemia, and in whom it was demonstrated the presence of the mutations F508del associated with TG11-9T-470M in one allele and TG12-5T-470V in the other allele. Although a clear genotype-phenotype correlation for liver disease is still missing for CF patients, it is possible to state that this isolated clinical presentation could represent an unusual phenotype of CF, related to a complex genotype characterized by a severe mutation and one (or more) polymorphism.</p></span>" ] ] "multimedia" => array:1 [ 0 => array:7 [ "identificador" => "t0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:1 [ "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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">F508Del \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">PolyT-TG \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">M470V \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" 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">Father allele #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">F508del \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">TG11-9T \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">470M \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">Father allele #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">Null \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">TG11-7T \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">470V \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">Mother allele #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">Null \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">TG12-5T \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">470V \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">Mother allele #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">Null \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">TG11-7T \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">470V \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">Patient Paternal allele \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">F508del \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">TG11-9T \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">470M \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">Patient Maternal allele \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">Null \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">TG12-5T \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">470V \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2049673.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="sp0005" class="elsevierStyleSimplePara elsevierViewall">Genotype of the patients and of his parents.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bs0010" "bibliografiaReferencia" => array:20 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1." 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 1 | 0 | 1 |
| 2024 October | 16 | 2 | 18 |
| 2024 September | 30 | 3 | 33 |
| 2024 August | 32 | 4 | 36 |
| 2024 July | 24 | 7 | 31 |
| 2024 June | 20 | 9 | 29 |
| 2024 May | 14 | 3 | 17 |
| 2024 April | 16 | 2 | 18 |
| 2024 March | 31 | 4 | 35 |
| 2024 February | 24 | 4 | 28 |
| 2024 January | 11 | 2 | 13 |
| 2023 December | 25 | 6 | 31 |
| 2023 November | 25 | 1 | 26 |
| 2023 October | 24 | 3 | 27 |
| 2023 September | 15 | 0 | 15 |
| 2023 August | 5 | 2 | 7 |
| 2023 July | 21 | 2 | 23 |
| 2023 June | 19 | 3 | 22 |
| 2023 May | 24 | 1 | 25 |
| 2023 April | 22 | 0 | 22 |
| 2023 March | 19 | 4 | 23 |
| 2023 February | 17 | 5 | 22 |
| 2023 January | 12 | 3 | 15 |
| 2022 December | 25 | 5 | 30 |
| 2022 November | 13 | 4 | 17 |
| 2022 October | 9 | 4 | 13 |
| 2022 September | 8 | 4 | 12 |
| 2022 August | 13 | 8 | 21 |
| 2022 July | 8 | 4 | 12 |
| 2022 June | 9 | 9 | 18 |
| 2022 May | 17 | 7 | 24 |
| 2022 April | 13 | 12 | 25 |
| 2022 March | 10 | 9 | 19 |
| 2022 February | 8 | 3 | 11 |
| 2022 January | 16 | 4 | 20 |
| 2021 December | 16 | 9 | 25 |
| 2021 November | 8 | 5 | 13 |
| 2021 October | 59 | 11 | 70 |
| 2021 September | 64 | 12 | 76 |
| 2021 August | 12 | 8 | 20 |
| 2021 July | 9 | 8 | 17 |
| 2021 June | 9 | 6 | 15 |
| 2021 May | 16 | 13 | 29 |
| 2021 April | 7 | 18 | 25 |
| 2021 March | 11 | 11 | 22 |
| 2021 February | 3 | 10 | 13 |
| 2021 January | 3 | 8 | 11 |
| 2020 December | 3 | 8 | 11 |
| 2020 November | 3 | 9 | 12 |
| 2020 October | 2 | 7 | 9 |
| 2020 September | 5 | 6 | 11 |
| 2020 August | 8 | 8 | 16 |
| 2020 July | 8 | 6 | 14 |
| 2020 June | 2 | 3 | 5 |
| 2020 May | 4 | 4 | 8 |
| 2020 April | 0 | 4 | 4 |
| 2020 March | 3 | 2 | 5 |
| 2020 February | 5 | 3 | 8 |
| 2020 January | 8 | 5 | 13 |
| 2019 December | 7 | 5 | 12 |
| 2019 November | 6 | 5 | 11 |
| 2019 October | 4 | 0 | 4 |
| 2019 September | 3 | 0 | 3 |
| 2019 August | 1 | 2 | 3 |
| 2019 July | 6 | 1 | 7 |
| 2019 June | 6 | 18 | 24 |
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