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Our experience with the aetiological diagnosis of global developmental delay and intellectual disability: 2006–2010
Nuestra experiencia en el diagnóstico etiológico del retraso global del desarrollo y discapacidad intelectual: 2006-2010
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"apellidos" => "Peña-Segura" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Unidad de Neuropediatría, Hospital Universitario Miguel Servet, Zaragoza, Instituto Aragonés de Ciencias de la Salud, Zaragoza, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Unidad de Enfermedades Metabólicas, Hospital Universitario Miguel Servet, Instituto Aragonés de Ciencias de la Salud, Zaragoza, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Nuestra experiencia en el diagnóstico etiológico del retraso global del desarrollo y discapacidad intelectual: 2006-2010" ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Global psychomotor delay (GDD) and intellectual disability (ID) are frequent reasons for visiting a paediatric neurologist. Estimated prevalence of psychomotor and mental retardation oscillates between 1% and 10%.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> There is no established aetiological diagnosis in 50% to 80% of all cases.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> Yield of diagnostic evaluation for children with GDD/ID varies greatly (10%–81%), which reflects many factors including differences between study populations and durations. This situation makes systematic reviews more complicated to perform.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> Consequently, there is no consensus regarding which studies should be performed on children with GDD/ID.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1–11</span></a> Studies should also be updated and adapted to dynamic social, technical and scientific developments. This article provides a retrospective review of the experience with aetiological diagnosis of GDD/ID cases in our hospital's paediatric neurology unit over the 5-year period between 2006 and 2010.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Material and methods</span><p id="par0010" class="elsevierStylePara elsevierViewall">The paediatric neurology unit at our tertiary hospital was established in May 1990 and its database contains all the cases evaluated by the unit since that date. This database is updated with all new events related to symptoms, progression, treatment, or complementary studies.<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">12–14</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">In 2008, we expanded our diagnostic protocol for different paediatric neurological diseases, such as prenatal encephalopathies or GDD/ID, with a view to identifying genetic alterations and inborn errors of metabolism (IEM). We applied this diagnostic protocol to new cases as well as to older cases without an aetiological diagnosis. Extensive urine and blood biochemistry studies, neuroimaging studies (mostly brain MRI scans), karyotyping and fragile-X syndrome testing, and other specific genetic studies had been completed for most of the children included in our review. Those studies are listed in the ‘Results’ section. We established a diagnosis of GDD for those patients younger than 5 years who presented altered neurodevelopment in 2 or more categories of the Denver Developmental Screening Test or Haizea-Llevant scale. A diagnosis of ID was established for patients older than 5 years who presented an intelligence quotient of <85 or needed special education or significant curriculum adaptation.</p><p id="par0020" class="elsevierStylePara elsevierViewall">We provide a retrospective review of our experience with aetiological diagnosis of GDD/ID cases during the 5-year period between 2006 and 2010.</p><p id="par0025" class="elsevierStylePara elsevierViewall">Our study analyses case incidence during this period and the prevalence of those previously diagnosed cases that were followed up during the study period. We included both children with isolated GDD/ID and those with GDD/ID associated with other concomitant diseases such as childhood cerebral palsy (CCP), autism spectrum disorders (ASD), or epilepsy; cases of regression are also included. ASD cases displaying normal intelligence (high-functioning autism) were excluded. We reviewed the diagnosis and the studies performed for patients with no established aetiological diagnosis.</p><p id="par0030" class="elsevierStylePara elsevierViewall">Pearson's chi-square test with one degree of freedom was used to establish the statistical relationship between different concomitant disorders and having GDD/ID or not.</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Results</span><p id="par0035" class="elsevierStylePara elsevierViewall">Between 1 January 2006 and 31 December 2010, 6108 children were added to the database. A total of 995 (16.5%) presented GDD/ID.</p><p id="par0040" class="elsevierStylePara elsevierViewall">Despite completion of multiple studies, no aetiological diagnoses were assigned in 686 cases (69%). Aetiological diagnoses were provided in 309 cases (31%) (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0045" class="elsevierStylePara elsevierViewall">Among cases in which an aetiological diagnosis was established, 142 (46%) had a genetic cause: 118 genetic encephalopathies and 24 IEM. In 126 cases, diagnosis was based on medical history (102 perinatal encephalopathies, 20 post-natal encephalopathies, and 4 brain tumours). Cases diagnosed using the medical history were excluded from the analytical study. As a result, a total of 869 GDD/ID cases were analysed (686 without an established diagnosis and 183 diagnosed).</p><p id="par0050" class="elsevierStylePara elsevierViewall">We have analysed the relationship between obtaining an aetiological diagnosis and the association with specific diseases such as CCP, epilepsy, infantile spasms/West syndrome, microcephaly, macrocephaly, neonatal seizures, ASD, visual impairment, or hypoacusia in all cases with GDD/ID. We excluded cases (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>126) diagnosed based on clinical history. Our data show a statistically significant association between obtaining an aetiological diagnosis and presence of CCP, epilepsy, infantile spasms/West syndrome, or visual impairment. There is no statistically significant association between ASD and presenting an aetiological diagnosis (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>).</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0055" class="elsevierStylePara elsevierViewall">The following complementary tests were performed for the GDD/ID group without an established diagnosis.</p><p id="par0060" class="elsevierStylePara elsevierViewall">Normal biochemistry tests: 550 ammonia tests, 518 amino acids tests, 525 lactic acid tests, 497 CK tests, 448 thyroid hormone tests, 340 long chain fatty acid analyses, 282 o-tolidine tests, 298 homocysteine tests, 288 ceruloplasmin tests, 281 copper tests, 250 organic acid tests, 179 CDT tests (detection of congenital disorder of glycosylation [CDG]) and 13 neurotransmitter studies in cerebrospinal fluid.</p><p id="par0065" class="elsevierStylePara elsevierViewall">Normal genetic tests: 457 karyotyping studies, 399 fragile-X screenings, 59 subtelomeric deletion studies, 50 CGH arrays, 46 Angelman syndrome tests, 27 Prader–Willi syndrome tests, 18 myotonic dystrophy tests, and mutation tests (12 for <span class="elsevierStyleItalic">MECP2</span>, 7 for <span class="elsevierStyleItalic">CDKL5</span>, 16 for <span class="elsevierStyleItalic">SCN1A</span> and <span class="elsevierStyleItalic">GABRG2</span>). We performed a retrospective analysis for cytomegalovirus DNA in dried blood spots from newborn screening tests in 9 cases.</p><p id="par0070" class="elsevierStylePara elsevierViewall">Results from 284 brain MRI scans, 141 head CT scans, and 69 MR spectroscopy scans were also normal.</p><p id="par0075" class="elsevierStylePara elsevierViewall">Some neuroimaging studies yielded abnormal results but were not sufficient to establish an aetiological diagnosis: 107 MRI scans and 77 head CT scans.</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Discussion</span><p id="par0080" class="elsevierStylePara elsevierViewall">Our series seems to indicate that assigning an aetiological diagnosis is easier when GDD/ID is associated with CCP, infantile spasms/West syndrome or visual impairment, but more difficult in cases of ASD (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>).</p><p id="par0085" class="elsevierStylePara elsevierViewall">Obviously, some entities are easy to diagnose based on clinical signs, such as Down syndrome, tuberous sclerosis, or neurofibromatosis type 1; this increases the genetic yield of complementary studies, especially genetic tests.</p><p id="par0090" class="elsevierStylePara elsevierViewall">We did not analyse the presence of dysmorphic features or skin anomalies, factors which increase the probability of delivering aetiological diagnoses.</p><p id="par0095" class="elsevierStylePara elsevierViewall">While it was not possible to link the degree of ID to the likelihood of determining an aetiological diagnosis, such a diagnosis is more difficult to assign in cases of mild disability.</p><p id="par0100" class="elsevierStylePara elsevierViewall">IEM screening in children with GDD/ID has a diagnostic yield of between 0.2% and 4.6%, depending on the presence of clinical indicators and the range of the studies performed. CDT testing (percentage of carbohydrate-deficient transferrin) to diagnose CDG syndromes has a diagnostic yield of up to 1.4%, and tests for creatine synthesis and transport defects has a yield of up to 2.8%.<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> In our series, we did not perform urine studies for creatine synthesis and transport defects; although these defects can also be detected by MR spectroscopy, routine testing should screen for them given that these conditions are treatable.</p><p id="par0105" class="elsevierStylePara elsevierViewall">Non-specific biochemistry studies have a very low diagnostic yield and they are not very useful in children older than 2–3 years with isolated GDD/ID.</p><p id="par0110" class="elsevierStylePara elsevierViewall">Genetic encephalopathies, congenital infections, peroxisomal or mitochondrial or lysosomal disorders, CDG syndromes, and other IEMs can display indistinguishable clinical signs in their early stages. IEMs are a rare cause of GDD/ID (approximately 1%), especially if there are no signs or symptoms indicating a metabolic problem. However, identifying an IEM can be crucial to the patient's outcome. It is possible that studying relatively rare IEMs would have a greater impact on families and the society than studying genetic syndromes, considering that the former can affect treatment and outcome. The possibility of starting effective treatment should have a more significant effect on clinical practice than the figures for diagnostic yield.<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3,8</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">There is no general consensus on performing neuroimaging studies when evaluating a child with GDD/ID. Recommendations vary from performing neuroimaging studies on all patients to limiting their use to cases in which scans are clinically indicated.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> Except in some emergency situations, the current test of choice for studying encephalopathies of all types is MRI. Neuroimaging can establish the aetiological diagnosis, as in the 2 cases of Joubert syndrome we present and in some cases of tuberous sclerosis. Although it does not determine the diagnosis in some patients, it can help identify causes in specific cases, just as a dysmorphology examination can orient doctors towards a clinical diagnosis.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> MRI scans guided the aetiological diagnostic process in our cases of lissencephaly, CRASH syndrome, syntelencephaly, congenital cytomegalovirus infection, and leukodystrophy.</p><p id="par0120" class="elsevierStylePara elsevierViewall">The diagnostic yield of genetic studies is increasing and these studies are becoming the first step in the diagnostic process. In children with GDD/ID, the CGH array is diagnostic in 7.8% of all cases, reaching 10.6% in cases with syndromic features. High resolution karyotyping result is abnormal in at least 4.6% of cases and in 18.6% of cases with syndromic features. Results from FMR1 for fragile-X screening are positive in at least 2% of patients with mild or moderate GDD/ID. <span class="elsevierStyleItalic">MECP2</span> gene analysis provides a diagnosis in 1.5% of girls with moderate or severe GDD/ID, compared to less than 0.5% of boys with GDD/ID.<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall">CHG array is the genetic test with the highest diagnostic yield in children with GDD/ID with no established cause.<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> It provided the diagnosis in 29.5% of the cases in our series (21 out of 71).</p><p id="par0130" class="elsevierStylePara elsevierViewall">Next-generation (massive) sequencing panels will certainly change diagnostic approaches to determining the aetiologies of ID.<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a></p><p id="par0135" class="elsevierStylePara elsevierViewall">Cost-effectiveness of complementary studies is apparently low in absence of clinical suspicion. The problem here is determining whether we perform too many studies, although identifying major problems, such as fragile-X syndrome, is necessary. Fifteen cases were identified among the 468 cases studied here. Early identification of vertically transmitted disorders, such as myotonic dystrophy or Duchenne muscular dystrophy, is very important from the diagnostic point of view.</p><p id="par0140" class="elsevierStylePara elsevierViewall">Absence of anomalies (negative findings) should also be considered in the diagnostic process.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a></p><p id="par0145" class="elsevierStylePara elsevierViewall">This is a retrospective study of the diagnostic strategy we followed until only recently. We believe that it is important to analyse our practices and share our experience. While this population is heterogeneous and includes cases of easy diagnosis and regression, we did intend to avoid a selection bias.</p><p id="par0150" class="elsevierStylePara elsevierViewall">GDD/ID with no established cause is observed in most genetically determined cases, and its social, family and economic impact is considerable. As a result, there is a high demand for early diagnosis. Most cases of GDD/ID are due to rare diseases and the European Union recommends that its member states implement national plans for rare diseases.<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> The second strategic line of Spain's National Plan is early prevention and detection.<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a></p><p id="par0155" class="elsevierStylePara elsevierViewall">After this review, we have decided to modify our evaluation strategy and emphasise the fact that in determining diagnoses, follow-up studies and personalised approaches are needed in addition to diagnostic protocols.</p><p id="par0160" class="elsevierStylePara elsevierViewall">For children older than 2 to 3 years with isolated GDD/ID, with or without ASD and in the absence of progressive changes, we have decided to perform only one basic blood test (including muscle enzymes in boys to identify cases of Duchenne muscular dystrophy), homocysteine test, CDT, and thyroid hormone test. In children younger than 2 to 3 years in whom progressive changes can be expected, we will continue to run a comprehensive neurometabolic study with the aim of identifying IEM cases early on.</p><p id="par0165" class="elsevierStylePara elsevierViewall">Genetic studies, including high-resolution karyotyping and fragile-X screening, will be performed on every GDD/ID case lacking a diagnosis. Exceptions would be fragile-X screening for girls with obvious macrocephaly or multiple malformations. We will perform CGH array in presence of certain factors such as family history of ID, miscarriages, intrauterine growth restriction, micro- or macrocephaly, microsomy or macrosomy, dysmorphic features, or any other associated malformations of the heart, kidneys, or eyes.</p><p id="par0170" class="elsevierStylePara elsevierViewall">Brain MRI scans will be performed in cases of epilepsy, focal neurological signs, hypoacusia, visual impairment or ophthalmological alterations, macrocephaly/accelerated head growth and microcephaly, or decelerated head growth.</p><p id="par0175" class="elsevierStylePara elsevierViewall">To conclude, we would like to highlight the importance of being able to diagnose rare diseases that are treatable. However, even when treatment is not possible, providing an aetiological diagnosis is always important for purposes of calculating risk of recurrence, providing genetic counselling, and assigning potential prenatal diagnoses. It can also be instrumental in resolving questions from families and professionals and also in limiting the number of diagnostic tests.</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Conflicts of interest</span><p id="par0180" class="elsevierStylePara elsevierViewall">The authors have no conflicts of interest to declare.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:10 [ 0 => array:2 [ "identificador" => "xres370400" "titulo" => array:5 [ 0 => "Abstract" 1 => "Introduction" 2 => "Material and method" 3 => "Results" 4 => "Discussion" ] ] 1 => array:2 [ "identificador" => "xpalclavsec349639" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "xres370401" "titulo" => array:5 [ 0 => "Resumen" 1 => "Introducción" 2 => "Material y método" 3 => "Resultados" 4 => "Discusión" ] ] 3 => array:2 [ "identificador" => "xpalclavsec349638" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Material and methods" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Results" ] 7 => array:2 [ "identificador" => "sec0020" "titulo" => "Discussion" ] 8 => array:2 [ "identificador" => "sec0025" "titulo" => "Conflicts of interest" ] 9 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2013-06-03" "fechaAceptado" => "2013-10-20" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec349639" "palabras" => array:3 [ 0 => "Global developmental delay" 1 => "Intellectual disability" 2 => "Microarray comparative genomic hybridisation" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec349638" "palabras" => array:4 [ 0 => "Retraso psicomotor global" 1 => "Discapacidad intelectual" 2 => "Diagnóstico etiológico" 3 => "Microarray comparative genomic hybridisation" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<span class="elsevierStyleSectionTitle" id="sect0010">Introduction</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Global developmental delay (GDD) and intellectual disability (ID) are common reasons for consultation in paediatric neurology. Results from aetiological evaluations of children with GDD/ID vary greatly, and consequently, there is no universal consensus regarding which studies should be performed.</p> <span class="elsevierStyleSectionTitle" id="sect0015">Material and method</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">We review our experience with determining aetiological diagnoses for children with GDD/ID who were monitored by the paediatric neurology unit over the 5-year period between 2006 and 2010.</p> <span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">During the study period, 995 children with GDD/ID were monitored. An aetiological diagnosis was established for 309 patients (31%), but not in 686 (69%), despite completing numerous tests. A genetic cause was identified in 142 cases (46% of the total aetiologies established), broken down as 118 cases of genetic encephalopathy and 24 of metabolic hereditary diseases. Our data seem to indicate that diagnosis is easier when GDD/ID is associated with cerebral palsy, epilepsy, infantile spasms/West syndrome, or visual deficit, but more difficult in cases of autism spectrum disorders. Genetic studies provide an increasing number of aetiological diagnoses, and they are also becoming the first step in diagnostic studies. Array CGH (microarray-based comparative genomic hybridisation) is the genetic test with the highest diagnostic yield in children with unexplained GDD/ID.</p> <span class="elsevierStyleSectionTitle" id="sect0025">Discussion</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">The cost-effectiveness of complementary studies seems to be low if there are no clinically suspected entities. However, even in the absence of treatment, aetiological diagnosis is always important in order to provide genetic counselling and possible prenatal diagnosis, resolve family (and doctors’) queries, and halt further diagnostic studies.</p>" ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "<span class="elsevierStyleSectionTitle" id="sect0035">Introducción</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">El retraso global del desarrollo (RGD) y la discapacidad intelectual (DI) son motivos de consulta frecuentes en la práctica neuropediátrica. El rendimiento de los estudios diagnósticos en niños con RGD/DI varía ampliamente y, en consecuencia, no hay acuerdo universal respecto a los estudios que se deben realizar.</p> <span class="elsevierStyleSectionTitle" id="sect0040">Material y método</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Revisamos nuestra experiencia en el diagnóstico etiológico de los niños con RGD/DI valorados en la consulta de Neuropediatría durante un periodo de 5 años: 2006-2010.</p> <span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Durante el periodo de estudio fueron valorados 995 niños con RGD/DI. El diagnóstico etiológico fue establecido en 309 (31%) y no en 686 (69%), a pesar de múltiples estudios realizados. En 142 niños, el 46% de los casos con diagnóstico etiológico establecido, la causa es genética: 118 encefalopatías genéticas y 24 enfermedades metabólicas hereditarias. Nuestros datos indican que establecer un diagnóstico etiológico es más fácil cuando el RGD/DI está asociado a parálisis cerebral infantil, epilepsia, espasmos infantiles/síndrome de West o déficit visual, pero más difícil en casos de trastorno del espectro autista. Los estudios genéticos están incrementando los diagnósticos etiológicos y constituyéndose en el primer escalón de estudio. El microarray comparative genomic hybridisation es la prueba con mayor rentabilidad diagnóstica en el estudio de RGD/DI.</p> <span class="elsevierStyleSectionTitle" id="sect0050">Discusión</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">El coste-efectividad de los exámenes complementarios es aparentemente bajo en ausencia de orientación clínica. Incluso en ausencia de tratamiento, el diagnóstico etiológico es importante para establecer un consejo genético y posible diagnóstico prenatal, resolver cuestiones a padres y profesionales, y cesar la realización de más pruebas complementarias.</p>" ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0040">Please cite this article as: López-Pisón J, García-Jiménez MC, Monge-Galindo L, Lafuente-Hidalgo M, Pérez-Delgado R, García-Oguiza A, et al. Nuestra experiencia en el diagnóstico etiológico del retraso global del desarrollo y discapacidad intellectual: 2006-2010. Neurología. 2014;29:402–407.</p>" ] ] "multimedia" => array:2 [ 0 => array:7 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:3 [ "leyenda" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">CGH array: microarray-based comparative genomic hybridisation; CMV: cytomegalovirus; FAS: fetal alcohol syndrome; X-ALD: X-linked adrenoleukodystrophy.</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"><td 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" style="border-bottom: 2px solid black">Diseases \t\t\t\t\t\t\n \t\t\t\t</td><td 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" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">N</span> \t\t\t\t\t\t\n \t\t\t\t</td></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">Prenatal encephalopathies of disruptive origin \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">41 (13%) \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">Congenital infections (13 CMV, 3 toxoplasmosis) \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">19 \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">Teratogen-related encephalopathies (16 FAS) \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">18 \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">Encephalopathy related to vascular disruptive syndrome of monozygotic twins \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">4 \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">Genetic encephalopathies \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">118 (38%) \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">Down syndrome \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">12 \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">Fragile-X syndrome \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">7 \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">Subtelomeric deletions \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">7 \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">Patau syndrome \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">1 \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">Other chromosomal defects diagnosed by CGH array<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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">21 \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">Tuberous sclerosis \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">11 \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">Congenital myotonic dystrophy \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">4 \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">Rett syndrome (4 <span class="elsevierStyleItalic">MECP2</span> and 2 <span class="elsevierStyleItalic">CDKL5</span> mutations) \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">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 " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Dravet spectrum disorder with <span class="elsevierStyleItalic">SCN1A</span> mutation \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">9 \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">Prader–Willi syndrome \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">5 \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">Angelman syndrome \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">4 \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">Neurofibromatosis type 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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5 \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">Other genetic encephalopathies<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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">16 \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">Inborn errors of metabolism \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">24 (7.8%) \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">Mitochondrial diseases \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">3 \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">Lysosomal diseases<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">c</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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">7 \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">Disorders of intermediary metabolism<a class="elsevierStyleCrossRef" href="#tblfn0020"><span class="elsevierStyleSup">d</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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">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 " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">X-ALD<a class="elsevierStyleCrossRef" href="#tblfn0025"><span class="elsevierStyleSup">e</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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3 \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">Other IEMs<a class="elsevierStyleCrossRef" href="#tblfn0030"><span class="elsevierStyleSup">f</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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5 \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">Perinatal encephalopathies \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">102 (33%) \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">Post-natal encephalopathies<span class="elsevierStyleSup">g</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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">20 (6.55%) \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">Brain tumours \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">4 (1.3%) \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">Hemispheric tumour \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">2 \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">Cerebellar tumour \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">1 \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">Midline tumour \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">1 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab557833.png" ] ] ] "notaPie" => array:6 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Excludes normal variations and abnormalities whose significance is unclear.</p>" ] 1 => array:3 [ "identificador" => "tblfn0010" "etiqueta" => "b" "nota" => "<p class="elsevierStyleNotepara" id="npar0010">Other genetic encephalopathies: 3 cases of lissencephaly with <span class="elsevierStyleItalic">LIS1</span> mutation, 3 cases of dystrophinopathy, 2 with Williams–Beuren syndrome, 2 with Joubert syndrome, 1 with CRASH syndrome and <span class="elsevierStyleItalic">L1CAM</span> mutation, 1 with syntelencephaly and <span class="elsevierStyleItalic">ZIC2</span> deletion, 1 with Proteus syndrome, 1 with Waardenburg syndrome, 1 with Coffin–Siris syndrome, and 1 with Cornelia de Lange syndrome.</p>" ] 2 => array:3 [ "identificador" => "tblfn0015" "etiqueta" => "c" "nota" => "<p class="elsevierStyleNotepara" id="npar0015">Lysosomal diseases: one case each of Hurler syndrome, neuronal ceroid-lipofuscinosis type 2 (NCL2), and Krabbe disease; 4 cases of metachromic leukodystrophy.</p>" ] 3 => array:3 [ "identificador" => "tblfn0020" "etiqueta" => "d" "nota" => "<p class="elsevierStyleNotepara" id="npar0020">Six disorders of intermediary metabolism: 2 siblings with 4-hydroxybutyric aciduria, 1 case each of homocystinuria, nonketotic hyperglycinemia, maple syrup urine disease, and biotinidase deficiency.</p>" ] 4 => array:3 [ "identificador" => "tblfn0025" "etiqueta" => "e" "nota" => "<p class="elsevierStyleNotepara" id="npar0025">Five other IEMs: 1 case each of CDG syndrome, Menkes disease, Cockayne syndrome, hereditary spastic paraplegia and merosin-deficient congenital muscular dystrophy with occipital lobe cortical dysplasia and drug-resistant epilepsy.</p>" ] 5 => array:3 [ "identificador" => "tblfn0030" "etiqueta" => "f" "nota" => "<p class="elsevierStyleNotepara" id="npar0030">Twenty post-natal encephalopathies: 7 cases of meningitis (5 neonatal), 4 cases of brain lesions, 2 cases of encephalitis, 2 cases of shaken baby syndrome and 2 cases of hypoxic-ischaemic encephalopathy and 3 other cases.</p>" ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Patients with an aetiological diagnosis for global developmental delay and intellectual disability (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>309).</p>" ] ] 1 => array:7 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:3 [ "leyenda" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">No., number of cases with a specific condition; GDD/ID, global developmental delay and intellectual disability; <span class="elsevierStyleItalic">P</span>, statistically significant association between presenting a specific condition and the possibility of assigning an aetiological diagnosis; %, percentage of patients displaying a specific condition with and without an aetiological diagnosis.</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"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " colspan="7" align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Aetiological diagnosis</td></tr><tr title="table-row"><td 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" style="border-bottom: 2px solid black">Pathological conditions \t\t\t\t\t\t\n \t\t\t\t</td><td 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" style="border-bottom: 2px solid black">No. \t\t\t\t\t\t\n \t\t\t\t</td><td 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" style="border-bottom: 2px solid black">Yes (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>183) % \t\t\t\t\t\t\n \t\t\t\t</td><td 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" style="border-bottom: 2px solid black">No. \t\t\t\t\t\t\n \t\t\t\t</td><td 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" style="border-bottom: 2px solid black">No (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>686) % \t\t\t\t\t\t\n \t\t\t\t</td><td 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" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">χ</span><span class="elsevierStyleSup">2</span> test<a class="elsevierStyleCrossRef" href="#tblfn0035"><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-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">P</span> \t\t\t\t\t\t\n \t\t\t\t</td></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">Cerebral palsy \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">63 \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">34 \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">137 \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">20 \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"><span class="elsevierStyleItalic">χ</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleInf">1gl</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>17.03 \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"><.1 \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">Epilepsy \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">64 \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">37 \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">157 \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">23 \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"><span class="elsevierStyleItalic">χ</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleInf">1gl</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>11.12 \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"><.01 \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">Infantile spasms/West syndrome \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">16 \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">8.5 \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">10 \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">1.4 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">χ</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleInf">1gl</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>26.41 \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"><.01 \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">Neonatal 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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5 \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">2.7 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">21 \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">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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">χ</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleInf">1gl</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.054 \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">.81 \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">Autism spectrum disorders \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">48 \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">26 \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">248 \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">36 \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"><span class="elsevierStyleItalic">χ</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleInf">1gl</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>6.33 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><.05 \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">Visual impairment \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">14 \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">7.6 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">23 \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">3.3 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">χ</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleInf">1gl</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>6.54 \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"><.05 \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">Hearing impairment \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">9 \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">4.9 \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">26 \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">3.7 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">χ</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleInf">1gl</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.47 \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">.49 \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">Microcephaly \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">38 \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">20 \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">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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">16 \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"><span class="elsevierStyleItalic">χ</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleInf">1gl</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>2.28 \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">.13 \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">Macrocephaly \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">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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3.3 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">13 \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">1.8 \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"><span class="elsevierStyleItalic">χ</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleInf">1gl</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>1.29 \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">.25 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab557832.png" ] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tblfn0035" "etiqueta" => "a" "nota" => "<p class="elsevierStyleNotepara" id="npar0035"><span class="elsevierStyleItalic">χ</span><span class="elsevierStyleSup">2</span>: Pearson's chi-square test with one degree of freedom.</p>" ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Aetiological diagnosis of patients with GDD/ID and other disorders, and the association between identifying the aetiological diagnosis and the disorder in question. Cases due to prenatal and perinatal encephalopathies and brain tumours have been excluded.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:17 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Practice parameter: evaluation of the child with global developmental delay. Report of the Quality Standards Subcommittee of the American Academy of Neurology and The Practice Committee of the Child Neurology Society" "autores" => array:1 [ 0 => array:3 [ "colaboracion" => "Quality Standards Subcommittee of the American Academy of Neurology; Practice Committee of the Child Neurology Society" "etal" => true "autores" => array:6 [ 0 => "M. Shevell" 1 => "S. Ashwal" 2 => "D. Donley" 3 => "J. Flint" 4 => "M. Gingold" 5 => "D. Hirtz" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Neurology" "fecha" => "2003" "volumen" => "60" "paginaInicial" => "367" "paginaFinal" => "380" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12578916" "web" => "Medline" ] ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0010" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Global developmental delay and mental retardation or intellectual disability: conceptualization, evaluation and etiology" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "M. Shevell" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Pediatr Clin N Am" "fecha" => "2008" "volumen" => "55" "paginaInicial" => "1071" "paginaFinal" => "1084" ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0015" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:1 [ "host" => array:1 [ 0 => array:1 [ "LibroEditado" => array:3 [ "titulo" => "Intellectual disability: definition, classification, and systems of supports" "edicion" => "11th ed." "serieFecha" => "2010" ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib0020" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Diagnostic evaluation of developmental delay/mental retardation: an overview" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "A. Battaglia" 1 => "J.C. Carey" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Am J Med Genet C: Semin Med Genet" "fecha" => "2003" "volumen" => "117C" "paginaInicial" => "3" "paginaFinal" => "14" ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib0025" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Diagnostic yield of various genetic approaches in patients with unexplained developmental delay or mental retardation" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "A. Rauch" 1 => "J. Hoyer" 2 => "S. Guth" 3 => "C. Zweier" 4 => "C. Kraus" 5 => "C. Becker" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/ajmg.a.31416" "Revista" => array:6 [ "tituloSerie" => "Am J Med Genet A" "fecha" => "2006" "volumen" => "140" "paginaInicial" => "2063" "paginaFinal" => "2074" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16917849" "web" => "Medline" ] ] ] ] ] ] ] ] 5 => array:3 [ "identificador" => "bib0030" "etiqueta" => "6" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Clinical genetic evaluation of the child with mental retardation or developmental delays" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "J.B. Moeschler" 1 => "M. Shevell" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1542/peds.2006-1006" "Revista" => array:5 [ "tituloSerie" => "Pediatrics" "fecha" => "2006" "volumen" => "117" "paginaInicial" => "2304" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16740881" "web" => "Medline" ] ] ] ] ] ] ] ] 6 => array:3 [ "identificador" => "bib0035" "etiqueta" => "7" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "A “global” approach to global developmental delay end intellectual disability?" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "M.I. Shevell" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/j.1469-8749.2010.03826.x" "Revista" => array:7 [ "tituloSerie" => "Dev Med Child Neurol" "fecha" => "2011" "volumen" => "53" "paginaInicial" => "105" "paginaFinal" => "106" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21244410" "web" => "Medline" ] ] "itemHostRev" => array:3 [ "pii" => "S1525861012004495" "estado" => "S300" "issn" => "15258610" ] ] ] ] ] ] ] 7 => array:3 [ "identificador" => "bib0040" "etiqueta" => "8" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Diagnostic investigations in individuals with mental retardation: a systematic literature review of their usefulness" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "C.D. van Karnebeek" 1 => "M.C. Jansweijer" 2 => "A.G. Leenders" 3 => "M. Offringa" 4 => "R.C. Hennekam" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/sj.ejhg.5201279" "Revista" => array:6 [ "tituloSerie" => "Eur J Hum Genet" "fecha" => "2005" "volumen" => "13" "paginaInicial" => "6" "paginaFinal" => "25" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15523501" "web" => "Medline" ] ] ] ] ] ] ] ] 8 => array:3 [ "identificador" => "bib0045" "etiqueta" => "9" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Medical genetics diagnostic evaluation of the child with global developmental delay or intellectual disability" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "J.B. Moeschler" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1097/WCO.0b013e3282f82c2d" "Revista" => array:6 [ "tituloSerie" => "Curr Opin Neurol" "fecha" => "2008" "volumen" => "21" "paginaInicial" => "117" "paginaFinal" => "122" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18317267" "web" => "Medline" ] ] ] ] ] ] ] ] 9 => array:3 [ "identificador" => "bib0050" "etiqueta" => "10" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Improving genetic health care: a Northern New England pilot project addressing the genetic evaluation of the child with developmental delays or intellectual disability" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "J.B. Moeschler" 1 => "R.S. Amato" 2 => "T. Brewster" 3 => "L. Burke" 4 => "M.B. Dinulos" 5 => "R. Smith" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Am J Med Genet C: Semin Med Genet" "fecha" => "2009" "volumen" => "151C" "paginaInicial" => "241" "paginaFinal" => "254" "itemHostRev" => array:3 [ "pii" => "S0140673611603255" "estado" => "S300" "issn" => "01406736" ] ] ] ] ] ] ] 10 => array:3 [ "identificador" => "bib0090" "etiqueta" => "11" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Evidence report: genetic and metabolic testing on children with global developmental delay. Report of the Quality Standards. Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "D.J. Michelson" 1 => "M.I. Shevell" 2 => "E.H. Sherr" 3 => "J.B. Moeschler" 4 => "A.L. Gropman" 5 => "S. Ashwal" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1212/WNL.0b013e3182345896" "Revista" => array:7 [ "tituloSerie" => "Neurology" "fecha" => "2011" "volumen" => "77" "paginaInicial" => "1629" "paginaFinal" => "1635" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21956720" "web" => "Medline" ] ] "itemHostRev" => array:3 [ "pii" => "S0211139X13001121" "estado" => "S300" "issn" => "0211139X" ] ] ] ] ] ] ] 11 => array:3 [ "identificador" => "bib0060" "etiqueta" => "12" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "A study of the demand for neuropediatric services in a general hospital II. Reasons for consultation" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "J. López-Pisón" 1 => "V. Rebage" 2 => "T. Arana" 3 => "A. Baldellou" 4 => "P. Arcauz" 5 => "J.L. Peña-Segura" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Rev Neurol" "fecha" => "1997" "volumen" => "25" "paginaInicial" => "1685" "paginaFinal" => "1688" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9484518" "web" => "Medline" ] ] ] ] ] ] ] ] 12 => array:3 [ "identificador" => "bib0065" "etiqueta" => "13" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Demand for neuropediatric services in a general referral hospital <span class="elsevierStyleSmallCaps">iii</span>. Diagnosis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "J. López-Pisón" 1 => "T. Arana" 2 => "A. Baldellou" 3 => "V. Rebage" 4 => "M.C. García-Jiménez" 5 => "J.L. Peña-Segura" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Rev Neurol" "fecha" => "1997" "volumen" => "25" "paginaInicial" => "1896" "paginaFinal" => "1905" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9580291" "web" => "Medline" ] ] ] ] ] ] ] ] 13 => array:3 [ "identificador" => "bib0070" "etiqueta" => "14" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Demand for neuropediatric care in a regional general hospital. V. Complementary tests" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "J. López-Pisón" 1 => "T. Arana" 2 => "V. Rebage" 3 => "A. Baldellou" 4 => "M. Alija" 5 => "J.L. Peña-Segura" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Rev Neurol" "fecha" => "1998" "volumen" => "26" "paginaInicial" => "208" "paginaFinal" => "214" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9580442" "web" => "Medline" ] ] ] ] ] ] ] ] 14 => array:3 [ "identificador" => "bib0075" "etiqueta" => "15" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Diagnostic panel testing: is more better?" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "E.W. Klee" 1 => "N.L. Hoppman-Chaney" 2 => "M.J. Ferber" 3 => "D.N.A. Expanding" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1586/erm.11.58" "Revista" => array:6 [ "tituloSerie" => "Expert Rev Mol Diagn" "fecha" => "2011" "volumen" => "11" "paginaInicial" => "703" "paginaFinal" => "709" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21902532" "web" => "Medline" ] ] ] ] ] ] ] ] 15 => array:3 [ "identificador" => "bib0080" "etiqueta" => "16" "referencia" => array:1 [ 0 => array:1 [ "referenciaCompleta" => "Proposal for a Council recommendation on a European action in the field of rare diseases/* COM/2008/0726 final – CNS 2008/0218 */. Available at: http://eur-law.eu/EN/Proposal-Council-recommendation-European-action-field-rare-diseases,501668,d." ] ] ] 16 => array:3 [ "identificador" => "bib0085" "etiqueta" => "17" "referencia" => array:1 [ 0 => array:1 [ "referenciaCompleta" => "Estrategia en Enfermedades Raras del Sistema Nacional de Salud. Estrategia aprobada por el Consejo Interterritorial del Sistema Nacional de Salud el 3 de junio de 2009. Sanidad 2009. Ministerio de Sanidad y Política Social. Available at: <a id="intr0010" class="elsevierStyleInterRef" href="http://www.msc.es/organizacion/sns/planCalidadSNS/docs/enfermedadesRaras.pdf">http://www.msc.es/organizacion/sns/planCalidadSNS/docs/enfermedadesRaras.pdf</a>" ] ] ] ] ] ] ] ] "idiomaDefecto" => "en" "url" => "/21735808/0000002900000007/v1_201409160948/S217358081400100X/v1_201409160948/en/main.assets" "Apartado" => array:4 [ "identificador" => "17109" "tipo" => "SECCION" "en" => array:2 [ "titulo" => "CO1" "idiomaDefecto" => true ] "idiomaDefecto" => "en" ] "PDF" => "https://static.elsevier.es/multimedia/21735808/0000002900000007/v1_201409160948/S217358081400100X/v1_201409160948/en/main.pdf?idApp=UINPBA00004N&text.app=https://www.elsevier.es/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S217358081400100X?idApp=UINPBA00004N" ]
| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 4 | 0 | 4 |
| 2024 October | 22 | 10 | 32 |
| 2024 September | 33 | 5 | 38 |
| 2024 August | 25 | 2 | 27 |
| 2024 July | 19 | 3 | 22 |
| 2024 June | 8 | 7 | 15 |
| 2024 May | 13 | 5 | 18 |
| 2024 April | 12 | 7 | 19 |
| 2024 March | 19 | 5 | 24 |
| 2024 February | 10 | 4 | 14 |
| 2024 January | 12 | 5 | 17 |
| 2023 December | 13 | 2 | 15 |
| 2023 November | 12 | 5 | 17 |
| 2023 October | 38 | 8 | 46 |
| 2023 September | 26 | 0 | 26 |
| 2023 August | 10 | 7 | 17 |
| 2023 July | 6 | 6 | 12 |
| 2023 June | 13 | 2 | 15 |
| 2023 May | 16 | 6 | 22 |
| 2023 April | 16 | 3 | 19 |
| 2023 March | 16 | 5 | 21 |
| 2023 February | 17 | 6 | 23 |
| 2023 January | 20 | 14 | 34 |
| 2022 December | 30 | 10 | 40 |
| 2022 November | 19 | 11 | 30 |
| 2022 October | 13 | 21 | 34 |
| 2022 September | 15 | 26 | 41 |
| 2022 August | 15 | 17 | 32 |
| 2022 July | 11 | 8 | 19 |
| 2022 June | 8 | 10 | 18 |
| 2022 May | 16 | 13 | 29 |
| 2022 April | 21 | 11 | 32 |
| 2022 March | 18 | 14 | 32 |
| 2022 February | 16 | 6 | 22 |
| 2022 January | 48 | 10 | 58 |
| 2021 December | 49 | 16 | 65 |
| 2021 November | 49 | 8 | 57 |
| 2021 October | 35 | 11 | 46 |
| 2021 September | 19 | 15 | 34 |
| 2021 August | 7 | 6 | 13 |
| 2021 July | 15 | 13 | 28 |
| 2021 June | 15 | 9 | 24 |
| 2021 May | 14 | 17 | 31 |
| 2021 April | 65 | 36 | 101 |
| 2021 March | 58 | 15 | 73 |
| 2021 February | 29 | 7 | 36 |
| 2021 January | 28 | 13 | 41 |
| 2020 December | 41 | 17 | 58 |
| 2020 November | 40 | 11 | 51 |
| 2020 October | 13 | 5 | 18 |
| 2020 September | 22 | 13 | 35 |
| 2020 August | 32 | 16 | 48 |
| 2020 July | 10 | 12 | 22 |
| 2020 June | 33 | 5 | 38 |
| 2020 May | 20 | 24 | 44 |
| 2020 April | 29 | 5 | 34 |
| 2020 March | 39 | 4 | 43 |
| 2020 February | 19 | 7 | 26 |
| 2020 January | 21 | 12 | 33 |
| 2019 December | 14 | 10 | 24 |
| 2019 November | 16 | 10 | 26 |
| 2019 October | 28 | 7 | 35 |
| 2019 September | 24 | 8 | 32 |
| 2019 August | 7 | 2 | 9 |
| 2019 July | 15 | 15 | 30 |
| 2019 June | 37 | 50 | 87 |
| 2019 May | 92 | 50 | 142 |
| 2019 April | 38 | 18 | 56 |
| 2019 March | 13 | 11 | 24 |
| 2019 February | 15 | 12 | 27 |
| 2019 January | 24 | 8 | 32 |
| 2018 December | 15 | 17 | 32 |
| 2018 November | 13 | 10 | 23 |
| 2018 October | 20 | 29 | 49 |
| 2018 September | 11 | 0 | 11 |
| 2018 August | 7 | 5 | 12 |
| 2018 July | 10 | 1 | 11 |
| 2018 June | 8 | 4 | 12 |
| 2018 May | 4 | 9 | 13 |
| 2018 April | 5 | 5 | 10 |
| 2018 March | 11 | 4 | 15 |
| 2018 February | 12 | 4 | 16 |
| 2018 January | 9 | 5 | 14 |
| 2017 December | 11 | 5 | 16 |
| 2017 November | 11 | 6 | 17 |
| 2017 October | 19 | 7 | 26 |
| 2017 September | 6 | 6 | 12 |
| 2017 August | 19 | 9 | 28 |
| 2017 July | 7 | 2 | 9 |
| 2017 June | 14 | 9 | 23 |
| 2017 May | 6 | 18 | 24 |
| 2017 April | 10 | 5 | 15 |
| 2017 March | 6 | 17 | 23 |
| 2017 February | 12 | 11 | 23 |
| 2017 January | 19 | 5 | 24 |
| 2016 December | 15 | 9 | 24 |
| 2016 November | 13 | 6 | 19 |
| 2016 October | 30 | 13 | 43 |
| 2016 September | 10 | 25 | 35 |
| 2016 August | 19 | 9 | 28 |
| 2016 July | 13 | 3 | 16 |
| 2016 June | 16 | 10 | 26 |
| 2016 May | 13 | 15 | 28 |
| 2016 April | 21 | 34 | 55 |
| 2016 March | 15 | 23 | 38 |
| 2016 February | 24 | 18 | 42 |
| 2016 January | 16 | 14 | 30 |
| 2015 December | 11 | 15 | 26 |
| 2015 November | 21 | 15 | 36 |
| 2015 October | 28 | 14 | 42 |
| 2015 September | 27 | 15 | 42 |
| 2015 August | 10 | 11 | 21 |
| 2015 July | 15 | 14 | 29 |
| 2015 June | 13 | 6 | 19 |
| 2015 May | 26 | 21 | 47 |
| 2015 April | 24 | 16 | 40 |
| 2015 March | 23 | 17 | 40 |
| 2015 February | 31 | 10 | 41 |
| 2015 January | 36 | 7 | 43 |
| 2014 December | 31 | 16 | 47 |
| 2014 November | 30 | 18 | 48 |
| 2014 October | 35 | 18 | 53 |
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