Clinical report
Detection and molecular diagnosis of a new case of congenital analbuminaemia
Detección y diagnóstico molecular de un nuevo caso de analbuminemia congénita
M. Josefa Cabrejas Núñez, Cristina Izquierdo Álvarez, Emiliano Gónzalez Vioque, Alejandro Almería Lafuente, Ramona Ángeles Silvestre Mardomingo
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Servicio de Bioquímica Clínica, Hospital Universitario Puerta de Hierro-Majadahonda, Madrid, Majadahonda, Spain
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Josefa Cabrejas Núñez, Cristina Izquierdo Álvarez, Emiliano Gónzalez Vioque, Alejandro Almería Lafuente, Ramona Ángeles Silvestre Mardomingo" "autores" => array:5 [ 0 => array:2 [ "nombre" => "M. Josefa" "apellidos" => "Cabrejas Núñez" ] 1 => array:2 [ "nombre" => "Cristina" "apellidos" => "Izquierdo Álvarez" ] 2 => array:2 [ "nombre" => "Emiliano" "apellidos" => "Gónzalez Vioque" ] 3 => array:2 [ "nombre" => "Alejandro" "apellidos" => "Almería Lafuente" ] 4 => array:4 [ "nombre" => "Ramona Ángeles" "apellidos" => "Silvestre Mardomingo" "email" => array:1 [ 0 => "ramonaangeles.silvestre@salud.madrid.org" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Servicio de Bioquímica Clínica, Hospital Universitario Puerta de Hierro-Majadahonda, Madrid, Majadahonda, Spain" "identificador" => "aff0005" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Detección y diagnóstico molecular de un nuevo caso de analbuminemia congénita" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1637 "Ancho" => 3500 "Tamanyo" => 345611 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0010" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Genetic study. (A) Family tree of the patient. (B) Sanger sequencing with the homozygous variant c.1289 + 1G > A detected in the patient shown by the arrows.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Albumin, protein synthesized in the liver and encoded by the gene <span class="elsevierStyleItalic">ALB</span> (chromosome 4q13.3), constitutes 60–65% of total serum proteins and is abundant in extra vascular and transudate spaces. Its main functions include the maintenance of oncotic pressure and the transport of endogenous and exogenous compounds since it has great affinity for small hydrophobic molecules (fatty acids, certain hormones and drugs), calcium, bilirubin, amino acids, etc.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1,2</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">The most common causes of hypoalbuminemia are: malnutrition, decreased synthesis (mainly associated with liver disease), increased catabolism (inflammatory processes), increased loss/elimination (renal dysfunction, malabsorptive enteropathy, severe burns, etc.) and/or alteration in its distribution between intra- and extra-vascular compartments.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Congenital analbuminaemia (CAA) (MIM # 616000) is an autosomal recessive disease with an estimated prevalence of less than 1/10<span class="elsevierStyleSup">6</span> associated to defects in the <span class="elsevierStyleItalic">ALB</span> gene which imply the absence or significant decrease in albumin levels. The serum total protein test of these patients has a characteristic electrophoretic pattern (absence of the albumin fraction associated with a significant increase in alpha and beta fractions). CAA should be confirmed with a genetic study. Carriers of CAA may have albuminemia at the lower limit of normal because the non-mutated allele is expressed normally.<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4,5</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">Adults with CAA have mild clinical signs (fatigue, low blood pressure, mild oedema and, occasionally, lipodystrophy in the lower limbs). It is rarely associated with systemic oedema, probably due to the compensatory increase in other plasma proteins (lipoproteins, globulins). The most common biochemical sign in these patients is hyperlipidaemia, especially hypercholesterolemia, which requires statin treatment, reflecting the important role of albumin in lipid metabolism and transport.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1,4</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">In contrast to the benign presentation of CAA in adults, high morbidity and/or mortality during foetal and neonatal periods has been described in families with CAA, suggesting that albumin plays an important role in early stages of development.<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">Although CAA can be easily diagnosed, so far only about 70 cases have been registered worldwide (Register of Analbuminaemia Cases: 4).</p><p id="par0035" class="elsevierStylePara elsevierViewall">In this article, we describe a case of CAA detected in our hospital and that, to date, is the first case described in Spain in which the associated molecular defect has been confirmed.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Methods</span><p id="par0040" class="elsevierStylePara elsevierViewall">Albuminemia was determined by colorimetry (bromocresol green, Advia<span class="elsevierStyleItalic">®</span> 2400 Chemical, Siemens Healthineers) and by nephelometry (Dimension Vista<span class="elsevierStyleItalic">®</span> 1500, Siemens Healthineers). Electrophoretic protein analysis was performed by capillary electrophoresis (Capillarys, Sebia) and agarose gel electrophoresis (HYDRASYS<span class="elsevierStyleItalic">®</span>, Sebia). The rest of the biochemical parameters were determined following the usual techniques of our laboratory (Advia<span class="elsevierStyleItalic">®</span> 2400, Immulite, Advia Centauro, Siemens Healthineers).</p><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Molecular analysis of the <span class="elsevierStyleItalic">ALB</span> gene</span><p id="par0045" class="elsevierStylePara elsevierViewall">The DNA was extracted from a sample of anticoagulated whole blood (K3EDTA) using the Maxwell®-16 System (Maxwell®-16 Blood DNA Purification Kit). The amplification of the 14 coding exons plus adjacent intronic regions of the ALB gene (NM_000477.6) was done by PCR according to Watkins et al.<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> Sanger sequencing was performed by a fluorescent dideoxy chain-termination method on the ABI3130 sequencer (BigDye® Terminator Cycle Sequencing kit, Applied Biosystems).</p><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Ethical aspects</span><p id="par0050" class="elsevierStylePara elsevierViewall">The patient signed the informed consent and the provisions of the Helsinki declaration were met.</p></span></span></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Patient and results</span><p id="par0055" class="elsevierStylePara elsevierViewall">A 42-year-old woman who went to an internal medicine office for an angiomyolipoma in the right kidney. In preoperative study hypoproteinaemia and hypoalbuminemia of unknown aetiology were observed. The patient had a good general condition, asthenia and slight oedema in lower limbs.</p><p id="par0060" class="elsevierStylePara elsevierViewall">Regarding laboratory data, the following stand out: hypoproteinaemia (4.7 g/dl; RV: 6–8 g/dl), hypoalbuminemia (1.6 g/dl; RV: 3.5–5.6 g/dl) and hypercholesterolemia despite being treated with statins: total cholesterol 272 mg/dl (RV: 150–200 mg/dl) and LDL cholesterol (calculated) 175 mg/dl (RV: 70–160 mg/dl); normal values of HDL cholesterol 72 mg/dl (RV: 45–90 mg/dl) and triglycerides 125 mg/dl (RV: 30–200 mg/dl); normal liver profile: ALT 30 U/l (RV: 6–40 U/l); AST 30 U/l (RV: 6–40 U/l), GGT 27 U/l (RV: 6–36 U/l). Normal thyroid function: TSH 3.23 μIU/ml (RV: 0.35–5.0 μIU/ml), free T4 1.04 ng/dl (RV: 0.70–1.98 ng/dl). Normal levels of immunoglobulins: IgG 1300 mg/dl RV: 700–1609 mg/dl; IgM 111 mg/dl (RV: 40–230 mg/dl) and IgA 201 mg/dl (RV: 70–400 mg/dl). Preserved renal function: creatinine 0.66 mg/dl (RV: 0.50–0.90 mg/dl), glomerular filtration rate (MDRD-IDMS) > 60 and negative urine protein test.</p><p id="par0065" class="elsevierStylePara elsevierViewall">In the differential diagnosis of hypoalbuminemia, protein loss was ruled out because there was no proteinuria, dermal lesions or digestive problems. Lever and kidney functions were preserved. On the other hand, lab prealbumin values of 62 mg/dl (RV: 20–40 mg/dl) ruled out possible malnutrition. However, all parameters were confirmed in a new lab test in order to assess the possible haemodilution of the sample.</p><p id="par0070" class="elsevierStylePara elsevierViewall">Before confirming all the parameters, the laboratory recommended a serum total protein test (capillary electrophoresis [<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>A]) where the decrease in albumin peak was evidenced: 11.6% (RV: 55.8–66%) associated with the compensatory increase of the other protein fractions: alpha 1: 12.3% (RV: 2.9–4.9%); alpha 2: 25.5% (RV: 7.1–11.8%); beta 1: 14.1% (RV: 4.7–7.2%); beta 2: 10.3% (RV: 3.2–6.5%); gamma: 25.9% (RV: 11.1–18.8%). The normal distribution of proteins in capillary electrophoresis is shown in <a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>B. Analbuminaemia was also confirmed by agarose gel electrophoresis (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>C and D). In this case, the albumin fraction was lower than that observed in capillary electrophoresis (2.1%; 0.1 g/dl). This serum albumin concentration was confirmed by determining albuminemia by nephelometry: 0.121 g/dl (RV: 3.5–5.2 g/dl).</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0075" class="elsevierStylePara elsevierViewall">Upon suspicion of CAA, the patient was referred for a genetic study. A new clinical examination showed perimalleolar oedema, lipodystrophy, and a BMI of 29.5. Personal history: born in Brazil of non-consanguineous parents. The family tree of the proband showed one abortion and one live birth, while her mother had 5 abortions of a total of 10 pregnancies (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>A).</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0080" class="elsevierStylePara elsevierViewall">Sanger sequencing of 14 exons plus adjacent intron regions of the <span class="elsevierStyleItalic">ALB</span> gene was carried out (NM_000477.6) in the molecular study conducted in our laboratory. The homozygous variant c.1289 + 1G > A was detected (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>B).</p><p id="par0085" class="elsevierStylePara elsevierViewall">It was recommended to report the finding to the son, parents and siblings of the proband, in order to offer genetic counselling. The study could not be extended due to geographical impossibility.</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Discussion</span><p id="par0090" class="elsevierStylePara elsevierViewall">The case of a woman with hypoalbuminemia is reported in which the most common causes of this disease are ruled out, demonstrating analbuminaemia by electrophoresis and nephelometry. When the CAA is suspected, the molecular study of the <span class="elsevierStyleItalic">ALB</span> gene was carried out, confirming this diagnosis.</p><p id="par0095" class="elsevierStylePara elsevierViewall">The genetic study demonstrated the presence of the homozygous variant c.1289 + 1G > A. This variant, previously described and called the Guimarães variant, affects the canonical sequence of <span class="elsevierStyleItalic">splicing</span> 5′(GT), causing its inactivation. The deletion of said sequence results in the complete deletion of exon 10 from the <span class="elsevierStyleItalic">ALB</span> gene during <span class="elsevierStyleItalic">splicing.</span> This produces a change in the <span class="elsevierStyleItalic">frameshift</span> which implies the generation of a truncated protein (p.Phe398Alafs*33).<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> It is a pathogenic mutation that, when homozygous, would explain the analbuminaemia observed in the patient.</p><p id="par0100" class="elsevierStylePara elsevierViewall">So far this is the first confirmed case of CAA characterized in Spain. Previously, only the case of a 17-year-old male with 0.55 g/dl albuminemia and hypercholesterolemia (454 mg/dl) had been published, but without a confirmatory genetic study.<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">Currently, approximately 70 cases of CAA have been described, with the Kayseri variant being the most common molecular defect. It is a 2-base deletion c.228_229delAT found in 13 probands. Until now, the Guimarães variant has only been described in 4 cases in the world.<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4,8,9</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">Albumin levels are usually measured by colorimetry due to their high affinity for organic anions and complex dye molecules. In our laboratory, bromocresol green (recommended by the American Association for Clinical Chemistry) is used, which has a high affinity for albumin and does not suffer interference due to high bilirubin or haemoglobin levels. The literature review on CAA shows great variability of the described albuminemia (values <0.01–1 g/dl) in subjects affected by CAA.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> This may be due to the lower accuracy of colorimetric assays at low albumin levels that would lead to overestimation of their serum levels. The presence of aberrant molecular forms of albumin with different affinity for the dye could also explain these differences, although to date, circulating truncated molecular forms have not been described in these patients.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> In our case, albuminemia measured colorimetrically (1.6 g/dl) is greater than that determined by nephelometry (0.121 g/dl) and that the estimated value in the serum total protein test (0.1 g/dl; calculated as a percentage of total proteinemia).</p><p id="par0115" class="elsevierStylePara elsevierViewall">Finally, regarding the serum total protein test, it should be noted that, in the development of capillary electrophoresis, the technical conditions were modified so that alpha and beta-lipoproteins migrate alongside albumin. This avoids the occurrence of lipoprotein bands that can induce suspicion of the presence of monoclonal proteins in the alpha and beta fractions. The consequent overestimation of the albumin fraction in subjects with normal albuminemia would not be significant. However, in patients with CAA (severe decrease in albuminemia and increased lipoproteinemia) such overestimation may be relevant.</p><p id="par0120" class="elsevierStylePara elsevierViewall">Regarding the clinical stage of the patient, it should be noted that her health status is good despite hypercholesterolemia (in treatment since the age of 18) and lower limb lipodystrophy. This confirms that CAA in adults is associated with a non-serious phenotype.</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Conclusions</span><p id="par0125" class="elsevierStylePara elsevierViewall">So far, this is the first case confirmed by molecular study of CAA in Spain. The patient has the Guimarães variant described in only 4 other patients in the world.</p><p id="par0130" class="elsevierStylePara elsevierViewall">It is important that clinicians keep in mind that in patients with AAC, albuminemia may be overestimated with the usual colorimetric techniques and, in these cases, a more specific method for the determination of albumin should be considered. Additionally, in the case of suspicion of CAA, agarose gel electrophoresis is recommended as capillary electrophoresis overestimates the albumin fraction.</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Conflict of interests</span><p id="par0135" class="elsevierStylePara elsevierViewall">The authors declare no conflict of interest.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:12 [ 0 => array:3 [ "identificador" => "xres1324847" "titulo" => "Abstract" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Introduction and objectives" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Materials and methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1221419" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "xpalclavsec1221418" "titulo" => "Abbreviations" ] 3 => array:3 [ "identificador" => "xres1324846" "titulo" => "Resumen" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Introducción y objetivos" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Material y métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusiones" ] ] ] 4 => array:2 [ "identificador" => "xpalclavsec1221417" "titulo" => "Palabras clave" ] 5 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 6 => array:3 [ "identificador" => "sec0010" "titulo" => "Methods" "secciones" => array:1 [ 0 => array:3 [ "identificador" => "sec0015" "titulo" => "Molecular analysis of the ALB gene" "secciones" => array:1 [ 0 => array:2 [ "identificador" => "sec0020" "titulo" => "Ethical aspects" ] ] ] ] ] 7 => array:2 [ "identificador" => "sec0025" "titulo" => "Patient and results" ] 8 => array:2 [ "identificador" => "sec0030" "titulo" => "Discussion" ] 9 => array:2 [ "identificador" => "sec0035" "titulo" => "Conclusions" ] 10 => array:2 [ "identificador" => "sec0040" "titulo" => "Conflict of interests" ] 11 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2019-06-05" "fechaAceptado" => "2019-10-03" "PalabrasClave" => array:2 [ "en" => array:2 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1221419" "palabras" => array:4 [ 0 => "Albumin" 1 => "<span class="elsevierStyleItalic">ALB</span> gene (4q13.3 chromosome)" 2 => "Congenital analbuminaemia" 3 => "Guimarães variant" ] ] 1 => array:4 [ "clase" => "abr" "titulo" => "Abbreviations" "identificador" => "xpalclavsec1221418" "palabras" => array:2 [ 0 => "CCA" 1 => "VR" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1221417" "palabras" => array:4 [ 0 => "Albúmina" 1 => "gen <span class="elsevierStyleItalic">ALB</span> (cromosoma 4q13.3)" 2 => "Analbuminemia congénita (MIM #616000)" 3 => "Variante Guimarães" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Introduction and objectives</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Congenital analbuminaemia (CCA) (MIM #616000) is an autosomal recessive disorder (prevalence < 1/10<span class="elsevierStyleSup">6</span>) caused by defects in the <span class="elsevierStyleItalic">ALB</span> gene leading to absence or severe reduction of albuminaemia. This paper describes a case of CCA detected and diagnosed in our hospital.</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Materials and methods</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">A 42-year old woman showing hypoproteinaemia and hypoalbuminaemia of unknown aetiology. Biochemical study was performed according to routine quality controlled analytical procedures: albuminaemia (colorimetric and nephelometric methods). Protein electrophoresis (capillary and agarose gel). Molecular study of the <span class="elsevierStyleItalic">ALB</span> gene: DNA extraction, PCR amplification of the 14 coding exons plus adjacent intron regions and Sanger sequencing.</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">After discarding the most common causes of hypoalbuminaemia, the analbuminaemia was confirmed by nephelometry and protein electrophoresis. The proband was found to be homozygous for molecular defect in the <span class="elsevierStyleItalic">ALB</span> gene: variant c.1289 + 1G > A previously reported as Guimarães variant.</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">This is the first case of CCA confirmed by molecular study in Spain. The proband shows the Guimarães variant previously described in 4 patients worldwide.</p></span>" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Introduction and objectives" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Materials and methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] "es" => array:3 [ "titulo" => "Resumen" "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Introducción y objetivos</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">La analbuminemia congénita (AAC) (MIM #616000) es una enfermedad autosómica recesiva (prevalencia < 1/10<span class="elsevierStyleSup">6</span>) causada por defectos en el gen <span class="elsevierStyleItalic">ALB</span> que implican la ausencia o marcada disminución de la albuminemia. En este artículo, describimos un caso de AAC detectado en nuestro hospital.</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Material y métodos</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Mujer de 42 años con hipoproteinemia e hipoalbuminemia de causa no filiada. El estudio bioquímico se realizó siguiendo las técnicas y los controles de calidad habituales de nuestro laboratorio: albuminemia (colorimetría y nefelometría); electroforesis de proteínas (capilar y gel de agarosa) y análisis molecular del gen <span class="elsevierStyleItalic">ALB</span> (extracción de ADN y amplificación PCR de los 14 exones codificantes más regiones intrónicas adyacentes y secuenciación Sanger).</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Descartadas las causas más frecuentes de hipoalbuminemia, se confirmó la analbuminemia por electroforesis y nefelometría. El estudio molecular del gen <span class="elsevierStyleItalic">ALB</span> evidenció la presencia de la variante c.1289 + 1G > A (variante Guimarães) en homozigosis.</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusiones</span><p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Este es el primer caso confirmado mediante estudio molecular de AAC en España. La paciente presenta la variante Guimarães descrita previamente en otros 4 pacientes en el mundo.</p></span>" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Introducción y objetivos" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Material y métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusiones" ] ] ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Cabrejas Núñez MJ, Izquierdo Álvarez C, González Vioque E, Almería Lafuente A, Silvestre Mardomingo RÁ. Detección y diagnóstico molecular de un nuevo caso dea nalbuminemia congénita. Med Clin (Barc). 2020;154:275–278.</p>" ] ] "multimedia" => array:2 [ 0 => array:8 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2935 "Ancho" => 3167 "Tamanyo" => 542413 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0005" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Electrophoretic profiles. In each case the blue arrow indicates the albumin fraction. Capillary electrophoresis (A and B): (A) Capillary electrophoresis of the patient’s serum showing a significant decrease in the albumin fraction (blue boxed values) and a compensatory increase in the alpha and beta fractions. (B) Normal protein distribution in capillary electrophoresis. Note: The scale of the graphs is adjusted to the highest protein fraction. Gel electrophoresis (B and C). (C) Electrophoretic profile of the patient’s serum on an agarose gel that shows the drastic reduction of the albumin fraction (blue boxed values) associated with a compensatory increase in the alpha and beta fractions. (D) Agarose gel (the fractions in which the serum proteins are separated are identified to the right of the image). The migration on the left corresponds to the sample of the patient (marked with a black arrow); the rest of the migrations correspond to samples of four subjects with normal albuminemia.</p>" ] ] 1 => array:8 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1637 "Ancho" => 3500 "Tamanyo" => 345611 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0010" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Genetic study. (A) Family tree of the patient. (B) Sanger sequencing with the homozygous variant c.1289 + 1G > A detected in the patient shown by the arrows.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:10 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Human serum albumin from bench to bedside" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "G. Fanali" 1 => "A. di Masi" 2 => "V. Trezza" 3 => "M. Marino" 4 => "M. Fasano" 5 => "P. Ascenzi" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Mol Aspect Med" "fecha" => "2011" "volumen" => "33" "paginaInicial" => "209" "paginaFinal" => "290" ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0010" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Molecular structure of the human albumin gene is revealed by nucleotide sequence within q11-22 of chromosome 4" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "P.P. Minghetti" 1 => "D.E. Ruffner" 2 => "W.J. Kuang" 3 => "O.E. Dennison" 4 => "J.W. Hawkins" 5 => "W.G. Beattie" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ "tituloSerie" => "J Biol Chem" "fecha" => "1986" "paginaInicial" => "6747" "paginaFinal" => "6757" ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0015" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Causes and mechanism of hypoalbuminaemia" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "P.E. Ballmer" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1054/clnu.2001.0439" "Revista" => array:6 [ "tituloSerie" => "Clin Nutr" "fecha" => "2001" "volumen" => "20" "paginaInicial" => "271" "paginaFinal" => "273" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11407876" "web" => "Medline" ] ] ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib0020" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:1 [ "referenciaCompleta" => "The albumin website [accessed 7 May 2019]. Available from: <a target="_blank" href="http://www.albumin.org">http://www.albumin.org</a>." ] ] ] 4 => array:3 [ "identificador" => "bib0025" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Diagnosis, phenotype and molecular genetics of congenital analbuminemia" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "L. Minchioti" 1 => "G. Caridi" 2 => "M. Campagnoli" 3 => "F. Lugani" 4 => "M. Galliano" 5 => "U. Kragh-Hansen" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.3389/fgene.2019.00336" "Revista" => array:5 [ "tituloSerie" => "Front Genet" "fecha" => "2019" "volumen" => "10" "paginaInicial" => "336" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/31057599" "web" => "Medline" ] ] ] ] ] ] ] ] 5 => array:3 [ "identificador" => "bib0030" "etiqueta" => "6" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Perinatal and childhood morbidity and mortality in congenital analbuminemia" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "J.M. Toye" 1 => "E.G. Lemire" 2 => "K.L. Baerg" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Paediatr Child Health" "fecha" => "2012" "volumen" => "17" "paginaInicial" => "20" "paginaFinal" => "23" ] ] ] ] ] ] 6 => array:3 [ "identificador" => "bib0035" "etiqueta" => "7" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "A nucleotide insertion and frameshift cause analbuminemia in an italian family" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "S. Watkins" 1 => "J. Madison" 2 => "M. Galliano" 3 => "L. Minchiotti" 4 => "F.W. Putman" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1073/pnas.91.6.2275" "Revista" => array:6 [ "tituloSerie" => "Proc Natl Acad Sci U S A" "fecha" => "1994" "volumen" => "91" "paginaInicial" => "2275" "paginaFinal" => "2279" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8134387" "web" => "Medline" ] ] ] ] ] ] ] ] 7 => array:3 [ "identificador" => "bib0040" "etiqueta" => "8" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "A novel splicing mutation causes analbuminemia in a Portuguese boy" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "G. Caridi" 1 => "M. Dagnino" 2 => "M. Di Duca" 3 => "H. Pinto" 4 => "C. Espinheira Mdo" 5 => "A. Guerra" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.ymgme.2011.12.009" "Revista" => array:7 [ "tituloSerie" => "Mol Genet Metab" "fecha" => "2012" "volumen" => "105" "paginaInicial" => "479" "paginaFinal" => "483" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22227324" "web" => "Medline" ] ] "itemHostRev" => array:3 [ "pii" => "S1542356515011131" "estado" => "S300" "issn" => "15423565" ] ] ] ] ] ] ] 8 => array:3 [ "identificador" => "bib0045" "etiqueta" => "9" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Congenital analbuminemia in unrelated Algerian and Turkish families is caused by the same molecular defect in the albumin gene" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "G. Caridi" 1 => "M. Abdelbasset" 2 => "A. Reha" 3 => "M. Campagnoli" 4 => "F. Lugani" 5 => "M. El Amine Abada" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Ann Lab" "fecha" => "2018" "volumen" => "38" "paginaInicial" => "185" "paginaFinal" => "188" ] ] ] ] ] ] 9 => array:3 [ "identificador" => "bib0050" "etiqueta" => "10" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Influence of methodology on the detection and diagnosis of congenital analbuminemia" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "A.W. Lyon" 1 => "P. Meinert" 2 => "G.A. Bruce" 3 => "V.A. Laxdal" 4 => "M.L. Salkie" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:7 [ "tituloSerie" => "Clin Chem" "fecha" => "1998" "volumen" => "44" "paginaInicial" => "2365" "paginaFinal" => "2367" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9799768" "web" => "Medline" ] ] "itemHostRev" => array:3 [ "pii" => "S1542356510007809" "estado" => "S300" "issn" => "15423565" ] ] ] ] ] ] ] ] ] ] ] ] "idiomaDefecto" => "en" "url" => "/23870206/0000015400000007/v1_202004071208/S2387020620300644/v1_202004071208/en/main.assets" "Apartado" => array:4 [ "identificador" => "43315" "tipo" => "SECCION" "en" => array:2 [ "titulo" => "Clinical report" "idiomaDefecto" => true ] "idiomaDefecto" => "en" ] "PDF" => "https://static.elsevier.es/multimedia/23870206/0000015400000007/v1_202004071208/S2387020620300644/v1_202004071208/en/main.pdf?idApp=UINPBA00004N&text.app=https://www.elsevier.es/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2387020620300644?idApp=UINPBA00004N" ]
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