Letter to the Editor
A novel case of diabetes MODY1 and chronic hereditary pancreatitis: coexistence of two infrequent genetic mutations
Un nuevo caso de diabetes MODY1 y pancreatitis crónica hereditaria: coexistencia de dos mutaciones genéticas poco frecuentes
Efrain Cordero-Vázqueza, Francesca Filippi-Arriagab, Irene Hernández Hernándeza, Stephanie Solange Tasayco Hamanc, Andreea Ciudina,d,
Corresponding author
a Endocrinology and Nutrition Department, Hospital Universitari Vall d’Hebron, Barcelona, Spain
b Clinical Pharmacology Department, Hospital Universitari Vall d’Hebron, Barcelona, Spain
c Gastroenterology Department, Hospital Universitari Vall d’Hebron, Barcelona, Spain
d Universitat Autònoma de Barcelona, Spain
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"cabecera" => "<span class="elsevierStyleTextfn">Scientific letter</span>" "titulo" => "Wolfram syndrome: Phenotypic heterogeneity and novel genetic variants in the <span class="elsevierStyleItalic">WFS1</span> gene" "tienePdf" => "en" "tieneTextoCompleto" => "en" "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "153" "paginaFinal" => "154" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Síndrome de Wolfram: heterogeneidad fenotípica y nuevas variantes genéticas en el gen WFS1" ] ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Joana Lima Ferreira, Vanessa Carvalho, Filipa Espada, João Massano, Ana Paula Marques, Rosa Maria Príncipe" "autores" => array:6 [ 0 => array:2 [ "nombre" => "Joana" "apellidos" => "Lima Ferreira" ] 1 => array:2 [ "nombre" => "Vanessa" "apellidos" => "Carvalho" ] 2 => array:2 [ "nombre" => "Filipa" "apellidos" => "Espada" ] 3 => 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Haman, Andreea Ciudin" "autores" => array:5 [ 0 => array:3 [ "nombre" => "Efrain" "apellidos" => "Cordero-Vázquez" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 1 => array:3 [ "nombre" => "Francesca" "apellidos" => "Filippi-Arriaga" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 2 => array:3 [ "nombre" => "Irene Hernández" "apellidos" => "Hernández" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 3 => array:3 [ "nombre" => "Stephanie Solange Tasayco" "apellidos" => "Haman" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] ] ] 4 => array:4 [ "nombre" => "Andreea" "apellidos" => "Ciudin" "email" => array:1 [ 0 => "aciudin@vhebron.net" ] "referencia" => array:3 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">d</span>" "identificador" => "aff0020" ] 2 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] ] "afiliaciones" => array:4 [ 0 => array:3 [ "entidad" => "Endocrinology and Nutrition Department, Hospital Universitari Vall d’Hebron, Barcelona, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Clinical Pharmacology Department, Hospital Universitari Vall d’Hebron, Barcelona, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Gastroenterology Department, Hospital Universitari Vall d’Hebron, Barcelona, Spain" "etiqueta" => "c" "identificador" => "aff0015" ] 3 => array:3 [ "entidad" => "Universitat Autònoma de Barcelona, Spain" "etiqueta" => "d" "identificador" => "aff0020" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Un nuevo caso de diabetes MODY1 y pancreatitis crónica hereditaria: coexistencia de dos mutaciones genéticas poco frecuentes" ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Maturity-onset diabetes of the young (MODY), is group of an uncommon genetic disorders characterised by autosomal dominant inheritance of a single nucleotide mutation, absence of pancreatic autoimmunity biomarkers and of clinical signs of insulin resistance. It represents between 1 and 5% of cases of diabetes mellitus (DM) and includes up to 15 subtypes, that differ from each other according to the mutated gene. The MODY1 subtype is secondary to a mutation in the hepatocyte nuclear factor 4 alpha (HNF4A) gene (accounts for 5–10% of the MODY).<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">1</span></a> Chronic pancreatitis (CP) can be secondary to environmental factors (alcohol consumption, smoking or hypertriglyceridemia); and/or hereditary genetic alterations (genes PRSS1, CFTR, SPINK1, CTRC). Among the genetic causes of CP, mutations in the chymotrypsin gene C (CTRC) is the less frequent.<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">2</span></a> Furthermore, several mutations in HNF4A and CTRC genes with uncertain meaning were described separately.<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">3</span></a> Nevertheless little is known about the interactions between these mutations in the same individual. We report for the first time the clinical features of the coexistence of two mutations of uncertain meaning in the genes HNF4A and CTRC, respectively. Informed consent was obtained from the patient. All the data included in the report comes from the medical history. No data presented in the paper was previously shared or ceded.</p><p id="par0010" class="elsevierStylePara elsevierViewall">A 62 years old male patient has been controlled for diabetes in our hospital since 2012. The patient, native of Morocco, has lived in Spain in the last 30 years. No relevant medical family history, except for his mother diagnosed with orally treated type 2 diabetes when 60 years old was referred. He was diagnosed with diabetes mellitus (DM) with 41 years and normoweighted, in form of simple hyperglycemia in a routine analysis. DM was initially classified as type 2, receiving oral treatment and maintaining HbA1c levels between 6.4 and 7.2% (DCCT 4.7–6.4%). Autoimmune tests were negative (anti-GAD65<span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>5<span class="elsevierStyleHsp" style=""></span>U/ml (0–5<span class="elsevierStyleHsp" style=""></span>U/ml) and anti-IA2<span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>7.5<span class="elsevierStyleHsp" style=""></span>U/ml (0–7.5<span class="elsevierStyleHsp" style=""></span>U/ml)). The patient presented progressive deterioration of HbA1c requiring insulin treatment, but with detectable C peptide (0.93<span class="elsevierStyleHsp" style=""></span>ng/ml). He has not developed any microangiopathic or macroangiopathic complications. Patient suffered also of hypertryglyceridemia under treatment with fibrates. It should be noted that the cholesterol lipidic profile always showed levels of total cholesterol<span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>150<span class="elsevierStyleHsp" style=""></span>mg/dl, HDL-cholesterol<span class="elsevierStyleHsp" style=""></span>>50<span class="elsevierStyleHsp" style=""></span>mg/dl and LDL-cholesterol<span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>100<span class="elsevierStyleHsp" style=""></span>mg/dl. During clinical follow up, he presented an episode of abdominal pain. A CT scan was performed, showing gross calcifications and atrophy of the body and tail of the pancreas, suggestive of chronic pancreatitis. He had former alcohol consumption of 1–2<span class="elsevierStyleHsp" style=""></span>units/week, but he was abstinent in the last 10 years. At the last visit he was overweight (weight 83<span class="elsevierStyleHsp" style=""></span>kg, height 175<span class="elsevierStyleHsp" style=""></span>cm, BMI 27.1<span class="elsevierStyleHsp" style=""></span>kg/m<span class="elsevierStyleSup">2</span>) and presented with no clinical signs of CP or steatorheea. Laboratory tests: AST: 32<span class="elsevierStyleHsp" style=""></span>IU/L (12–50<span class="elsevierStyleHsp" style=""></span>IU/L), ALT: 26<span class="elsevierStyleHsp" style=""></span>IU/L (8–50<span class="elsevierStyleHsp" style=""></span>IU/L), Alkaline Phosphatase: 60<span class="elsevierStyleHsp" style=""></span>IU/L (30 – 120<span class="elsevierStyleHsp" style=""></span>IU/L), Gamma GT: 24<span class="elsevierStyleHsp" style=""></span>IU/L (9–55<span class="elsevierStyleHsp" style=""></span>IU/L), Amylase 21<span class="elsevierStyleHsp" style=""></span>U/L (8–53<span class="elsevierStyleHsp" style=""></span>U/L), Lipase 46<span class="elsevierStyleHsp" style=""></span>U/L (21–67<span class="elsevierStyleHsp" style=""></span>U/L), faecal elastase<span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>200<span class="elsevierStyleHsp" style=""></span>μg/g in 2 determinations (normal value<span class="elsevierStyleHsp" style=""></span>>200<span class="elsevierStyleHsp" style=""></span>μg/g). The genetic study of hereditary pancreatitis (HP) showed a mutation of CTRC gene on p.Glu225Ala at position 674 (c. 674A>C) of exon 7. The mutation 674A>6 (p.Glu225Ala) of CTRC is considered rare with an overall allele frequency of 0.04% on general population and has an uncertain meaning.<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">3</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">In this context and with a clinical evolution not entirely compatible neither with Type 2 or Type 1 diabetes, a genetic study of MODY was performed showing mutation in heterozygosis c.1321A>G; p.(Ile441Val) in the HNF4A. The clinical phenotype was suggestive of MODY1 (progressive insulin deficiency, hypertriglyceridemia). Nevertheless, the significance of this mutation was catalogued as uncertain. Interestingly, the patient had hypertriglyceridemia, while mutations in HNF4A were associated with low levels.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">4</span></a> Nevertheless, it seems that higher HDL-cholesterol is a more sensitive factor associated with MODY-1 than triglycerides and the case presented during whole follow-up HDL-cholesterol levels<span class="elsevierStyleHsp" style=""></span>>50<span class="elsevierStyleHsp" style=""></span>mg/dl, above the expected value for gender and type2 DM.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">4</span></a> Mutations of CTRC alone are not likely to be a clinical cause of hereditary pancreatitis; however they do confer an increase of it through interaction with environmental factors or other genetic mutations, such as mutations in HNF4A, as in the case of our patient.</p><p id="par0020" class="elsevierStylePara elsevierViewall">CTRC mutations increase trypsin activity by losing the property of CTRC to reduce trypsinogen activation, impairing peptide degradation and carboxypeptidase activation necessary for insulin production, inducing a pathological folding in the endoplasmic reticulum. In consequence cell stress, increased nuclear factor kappa B (NF-κB) and apoptosis are seen. Mutations on HNF4A cause mitochondrial dysfunction by selectively inhibiting the generation of ATP, resulting in reducing the insulin mRNA levels, impaired hyperpolarisation of mitochondrial membrane, down-regulation of GLUT-2, aldolase B or L-PK.<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">5</span></a> Additionally, alcohol and fatty acids cause massive intracellular Ca2+ release and intracellular trypsinogen to trypsin activation,<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">6</span></a> making though a pathological synergic effect. First degree relatives underwent genetic study – <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>. Those that presented one mutation had no clinical expression. This finding supports the theory of complex interactions between the genetic predisposition and environmental factors in the development of CP and DM. In this case, two genetic mutations with uncertain clinical significance became significant when they coexisted and interacted with environmental factors (alcohol consumption, dyslipidemia). More studies of the clinical repercussion of these genetic mutations and the consequences of their interactions are needed and are an open field to explore.</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Conflict of interest</span><p id="par0025" class="elsevierStylePara elsevierViewall">All the authors declare no conflict of interest.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Conflict of interest" ] 1 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "multimedia" => array:1 [ 0 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Family member \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">Age (years) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Gender \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">Gene HNF4A \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">Gene CTRC \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">Gene CTRFA \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">DM \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">PC \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">Mother \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">80 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">F \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">No alterations found \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 available \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 available \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">Yes \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">No \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">Father \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">85 \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">M \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">Change on nucleotide c.1321A>G; p. (Ile441Val) in heterozygosis \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 available \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 available \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">No \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">No \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">Patient \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">62 \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">M \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">Change on nucleotide c.1321A>G; p. (Ile441Val) in heterozygosis \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">c.674A>C, p.Glu225Ala of exon 7 \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">No \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">Yes \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">Yes \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">Son \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">30 \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">M \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">Change on nucleotide c.1321A>G; p. (Ile441Val) in heterozygosis \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">c.674A>C, p.Glu225Ala of exon 7 \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">No \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">No \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">No \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">Son \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">33 \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">M \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">Change on nucleotide c.1321A>G; p. (Ile441Val) in heterozygosis \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">No \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">No \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">No \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">No \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2823175.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Genotype and fenotype characteristics of the family members.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:6 [ 0 => array:3 [ "identificador" => "bib0035" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "How recent advances in genomics improve precision diagnosis and personalized care of maturity-onset diabetes of the young" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "M. Vaxillaire" 1 => "P. Froguel" 2 => "A. Bonnefond" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s11892-019-1202-x" "Revista" => array:3 [ "tituloSerie" => "Curr Diab Rep" "fecha" => "2019" "volumen" => "19" ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0040" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "An evaluation of factors associated with pathogenic PRSS1, SPINK1, CTFR, and/or CTRC genetic variants in patients with idiopathic pancreatitis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "N.Y. Jalaly" 1 => "R.A. Moran" 2 => "F. Fargahi" 3 => "M.A. Khashab" 4 => "A. Kamal" 5 => "A.M. Lennon" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/ajg.2017.106" "Revista" => array:6 [ "tituloSerie" => "Am J Gastroenterol" "fecha" => "2017" "volumen" => "112" "paginaInicial" => "1320" "paginaFinal" => "1329" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28440306" "web" => "Medline" ] ] ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0045" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:1 [ "referenciaCompleta" => "National Center for Biotechnology Information ClinVar. [VCV000240766.5] NM_007272.3(CTRC):c.674A>C (p.Glu225Ala) and [VCV000036345.2], NM_175914.4(HNF4A):c.1321A>G (p.Ile441Val). <a target="_blank" href="https://www.ncbi.nlm.nih.gov/clinvar/variation/VCV000240766.5">https://www.ncbi.nlm.nih.gov/clinvar/variation/VCV000240766.5</a> [accessed 24.05.20]" ] ] ] 3 => array:3 [ "identificador" => "bib0050" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Lipoprotein composition in HNF1A-MODY: differentiating between HNF1A-MODY and type 2 diabetes" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "T.J. McDonald" 1 => "J. McEneny" 2 => "E.R. Pearson" 3 => "G. Thanabalasingham" 4 => "M. Szopa" 5 => "B.M. 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Rakonczay" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1097/MPA. 0000000000000421" "Revista" => array:6 [ "tituloSerie" => "Pancreas" "fecha" => "2015" "volumen" => "44" "paginaInicial" => "1211" "paginaFinal" => "1233" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26465950" "web" => "Medline" ] ] ] ] ] ] ] ] ] ] ] ] ] "idiomaDefecto" => "en" "url" => "/25300164/0000006900000002/v2_202202021023/S253001642100077X/v2_202202021023/en/main.assets" "Apartado" => array:4 [ "identificador" => "65400" "tipo" => "SECCION" "en" => array:2 [ "titulo" => "Cartas al Editor" "idiomaDefecto" => true ] "idiomaDefecto" => "en" ] "PDF" => "https://static.elsevier.es/multimedia/25300164/0000006900000002/v2_202202021023/S253001642100077X/v2_202202021023/en/main.pdf?idApp=UINPBA00004N&text.app=https://www.elsevier.es/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S253001642100077X?idApp=UINPBA00004N" ]
| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 4 | 1 | 5 |
| 2024 October | 19 | 13 | 32 |
| 2024 September | 34 | 18 | 52 |
| 2024 August | 23 | 26 | 49 |
| 2024 July | 21 | 20 | 41 |
| 2024 June | 27 | 13 | 40 |
| 2024 May | 22 | 10 | 32 |
| 2024 April | 21 | 6 | 27 |
| 2024 March | 30 | 16 | 46 |
| 2024 February | 23 | 5 | 28 |
| 2024 January | 33 | 2 | 35 |
| 2023 December | 18 | 1 | 19 |
| 2023 November | 24 | 1 | 25 |
| 2023 October | 38 | 3 | 41 |
| 2023 September | 13 | 0 | 13 |
| 2023 August | 26 | 3 | 29 |
| 2023 July | 18 | 3 | 21 |
| 2023 June | 19 | 3 | 22 |
| 2023 May | 24 | 10 | 34 |
| 2023 April | 32 | 6 | 38 |
| 2023 March | 16 | 5 | 21 |
| 2023 February | 20 | 25 | 45 |
| 2023 January | 20 | 18 | 38 |
| 2022 December | 18 | 15 | 33 |
| 2022 November | 49 | 13 | 62 |
| 2022 October | 30 | 16 | 46 |
| 2022 September | 64 | 37 | 101 |
| 2022 August | 16 | 10 | 26 |
| 2022 July | 1 | 0 | 1 |
| 2022 June | 1 | 0 | 1 |
| 2022 March | 1 | 0 | 1 |
| 2022 February | 4 | 4 | 8 |
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