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RESUMEN Introducción: el síndrome de Aicardi (SA; OMIM #304050) es un trastorno genético raro, cuya incidencia es de aproximadamente 1/100.000. Fue descrito en 1965 como una triada consistente en agenesia del cuerpo calloso, lagunas coriorretinianas y espasmos infantiles. Asocia discapacidad intelectual severa y epilepsia de difícil control. Aunque su espectro clínico es variable, tiene por lo general un pronóstico infausto debido a la elevada morbimortalidad asociada. Se considera un trastorno esporádico causado por variantes patogénicas en heterocigosis de un gen ligado al cromosoma X, que causa mortalidad embrionaria en varones hemicigotos. Objetivo: este trabajo pretende llevar a cabo una revisión bibliográfica acerca de la literatura científica disponible del síndrome de Aicardi. De esta manera se hará una actualización sobre esta entidad en cuanto a definiciones, prevalencia e incidencia, etiología, espectro clínico y pronóstico de los pacientes afectos. Materiales y métodos: se lleva a cabo una búsqueda bibliográfica retrospectiva en las principales bases de datos científicas. Para ello, se utilizan las palabras clave “Aicardi”, “agenesia del cuerpo calloso”, “espasmos infantiles” y “encefalopatía epiléptica”. Conclusiones: desde su descripción se ha ido ampliando el espectro de manifestaciones clínicas del síndrome. Actualmente no se conoce la existencia de un biomarcador que posibilite el diagnóstico, por lo que éste continúa siendo eminentemente clínico. Se debe tener un alto nivel de sospecha en espasmos infantiles de debut precoz en mujeres con alteraciones en neuroimagen. ABSTRACT Introduction: Aicardi syndrome (AS; OMIM #304050) is a rare genetic disorder, with an incidence of approximately 1/100,000. It was described in 1965 as a triad consisting of agenesis of the corpus callosum, chorioretinal lacunae, and infantile spasms. It is associated with severe intellectual disability and difficult-to-control epilepsy. Although its clinical spectrum is variable, it generally has a poor prognosis due to the associated morbidity and mortality. It is considered a sporadic disorder caused by heterozygous pathogenic variants of a gene linked to the X chromosome, which causes embryonic mortality in hemizygous males. Objective: this article performs a bibliographic review of the available scientific literature on Aicardi syndrome. In doing so, we hope to update the disorder’s definitions, prevalence and incidence, etiology, clinical spectrum and prognosis of affected patients. Materials and methods: we performed a retrospective bibliographic search in the main scientific databases. For this, we searched for the keywords "Aicardi", "agenesia of the corpus callosum", "infantile spasms" and "epileptic encephalopathy". Conclusions: since it was first described, the spectrum of clinical manifestations of the syndrome has been expanding. Currently, there is no known biomarker that makes diagnosis possible, so it continues to be eminently clinical diagnosis. A high level of suspicion should be present in cases of early-onset infantile spasms in women with neuroimaging abnormalities.

DeSanto-Shinawi syndrome is a rare neurodevelopmental disorder caused by loss-of-function variants of WAC, located on chromosome 10p12.1. This syndrome is characterized by dysmorphic facial features, intellectual disability, and behavioral problems.In this case report, we present a new deletion case and summarize the clinical data of previously reported individuals, comparing the similarities and differences between cases caused by point mutations versus those which are caused by deletions in the 10p region.Some differential features could facilitate the diagnostic suspicion guiding the optimal diagnostic tests that should be requested in each case scenario.

El síndrome de Rubinstein-Taybi (SRT) es una enfermedad de causa genética con baja incidencia. Clínicamente presenta retraso en crecimiento y desarrollo, rasgos dismórficos faciales con sonrisa característica, manos y pies con primeros dedos anchos, así como discapacidad intelectual, entre otras. Se han descrito dos genes en relación con el SRT: el gen CREBBP en el cromosoma 16p13.3 (un 60% de los casos) y el gen EP300 en 22q13 (un 5% de los casos), siendo la causa desconocida en aproximadamente un 35%. La mayoría de los casos son de novo. Identificar mutaciones causantes de enfermedades genéticas permite confirmar el diagnóstico clínico, con su consecuente orientación en pronóstico y tratamiento, así como conocer rutas biológicas y posibles dianas terapéuticas. Las técnicas de secuenciación masiva podrían explicar la causa de este síndrome en los casos sin mutación de los genes descritos. MATERIAL Y MÉTODO: Se analizó la relación entre fenotipo y genotipo de 36 casos diagnosticados clínicamente de SRT, tras el estudio de los genes CREBBP y EP300 y en aquellos con resultado negativo, se buscaron otros genes candidatos con estudio de exoma completo. Se recogió iconografía y un cuestionario exhaustivo de cada caso para describir su fenotipo de forma pormenorizada. La muestra se subdividió en grupos según gen, tipo de mutación y exón afectado. Se describieron y compararon los distintos subgrupos con otras series publicadas. Previo al resultado del estudio genético se clasificó cada caso como SRT o no SRT, basándose en la aproximación clínica-fenotípica. Se trató de establecer un diagnóstico molecular preciso de cada caso. RESULTADOS: 27 casos presentaron mutaciones en el gen CREBBP (9 deleciones y 18 mutaciones puntuales), 3 casos mutaciones puntuales en EP300, en 4 casos se confirmó otro diagnóstico genético distinto de SRT y en 2 casos no se encontró mutación que justificara la sintomatología. Los fenotipos clínicos entre los casos con afectación de CREBBP, con independencia del tipo de mutación o su localización, no mostraron diferencias reseñables. Los casos con mutación en EP300 mostraron un fenotipo menos grave que los CREBBP, aunque con variabilidad entre ellos. Se clasificó adecuadamente previo a estudio genético a todos los pacientes sin SRT y a 23 de los 27 afectos de mutaciones en CREBBP. No se clasificó clínicamente como SRT ninguno de los tres casos con mutaciones en EP300. CONCLUSIONES: No hemos encontrado una relación clara entre el tipo de mutación y el fenotipo clínico, ni por el gen mutado, tipo o localización de la mutación, lo cual concuerda con la literatura revisada. Hemos realizado estudio de exoma en los dos casos en los que no hallamos mutaciones asociadas a SRT, sin encontrar genes candidatos a su fenotipo. Previo al estudio genético, se clasificó acertadamente a los casos sin SRT, pero los casos con mutación en EP300 fueron erróneamente clasificados como no SRT, aun siéndolo. Se estableció un diagnóstico molecular definitivo en todos los casos a excepción de dos, con estudio negativo, incluido secuenciación de exoma.

Background Rubinstein-Taybi syndrome (RSTS) is a rare autosomal dominant neurodevelopmental disorder characterized by broad thumbs and halluces. RSTS is caused by mutations in CREBBP and in EP300 genes in 50–60% and 8%, respectively. Up to now, 76 RSTS-EP300 patients have been described. We present the clinical and molecular characterization of a cohort of RSTS patients carrying EP300 mutations. Methods Patients were selected from a cohort of 72 individuals suspected of RSTS after being negative in CREBBP study. MLPA and panel-based NGS EP300 were performed. Results Eight patients were found to carry EP300 mutations. Phenotypic characteristics included: intellectual disability (generally mild), postnatal growth retardation, infant feeding problems, psychomotor and language delay and typical facial dysmorphisms (microcephaly, downslanting palpebral fissures, columella below the alae nasi, and prominent nose). Broad thumbs and/or halluces were common, but angulated thumbs were only found in two patients. We identified across the gene novel mutations, including large deletion, frameshift mutations, nonsense, missense and splicing alterations, confirming de novo origin in all but one (the mother, possibly underdiagnosed, has short and broad thumbs and had learning difficulties). Conclusions The clinical evaluation of our patients corroborates that clinical features in EP300 are less marked than in CREBBP patients although it is difficult to establish a genotype-phenotype correlation although. It is remarkable that these findings are observed in a RSTS-diagnosed cohort; some patients harbouring EP300 mutations could present a different phenotype. Broadening the knowledge about EP300-RSTS phenotype may contribute to improve the management of patients and the counselling to the families.

Background Rubinstein‐Taybi syndrome (RSTS) is a rare congenital disorder characterized by broad thumbs and halluces, intellectual disability, distinctive facial features, and growth retardation. Clinical manifestations of RSTS are varied and overlap with other syndromes’ phenotype, which makes clinical diagnosis challenging. CREBBP is the major causative gene (55%–60% of the cases), whereas pathogenic variants found in EP300 represent the molecular cause in 8% of RSTS patients. A wide range of CREBBP pathogenic variants have been reported so far, including point mutations (30%–50%) and large deletions (10%). Methods The aim of this study was to characterize the CREBBP genetic variant spectrum in 39 RSTS patients using Multiplex Ligation‐dependent Probe Amplification and DNA sequencing techniques (Sanger and Trio‐based whole‐exome sequencing). Results We identified 15 intragenic deletions/duplications, ranging from one exon to the entire gene. As a whole, 25 de novo point variants were detected: 4 missense, 12 nonsense, 5 frameshift, and 4 splicing pathogenic variants. Three of them were classified as of uncertain significance and one of the patients carried two different variants. Conclusion Seventeen of the 40 genetic variants detected were reported for the first time in this work contributing, thus, to expand the molecular knowledge of this complex disorder.

BACKGROUND: Rubinstein-Taybi syndrome (RSTS) is a rare congenital disorder characterized by broad thumbs and halluces, intellectual disability, distinctive facial features, and growth retardation. Clinical manifestations of RSTS are varied and overlap with other syndromes' phenotype, which makes clinical diagnosis challenging. CREBBP is the major causative gene (55%-60% of the cases), whereas pathogenic variants found in EP300 represent the molecular cause in 8% of RSTS patients. A wide range of CREBBP pathogenic variants have been reported so far, including point mutations (30%-50%) and large deletions (10%). METHODS: The aim of this study was to characterize the CREBBP genetic variant spectrum in 39 RSTS patients using Multiplex Ligation-dependent Probe Amplification and DNA sequencing techniques (Sanger and Trio-based whole-exome sequencing). RESULTS: We identified 15 intragenic deletions/duplications, ranging from one exon to the entire gene. As a whole, 25 de novo point variants were detected: 4 missense, 12 nonsense, 5 frameshift, and 4 splicing pathogenic variants. Three of them were classified as of uncertain significance and one of the patients carried two different variants. CONCLUSION: Seventeen of the 40 genetic variants detected were reported for the first time in this work contributing, thus, to expand the molecular knowledge of this complex disorder.

BACKGROUND: Rubinstein-Taybi syndrome (RSTS) is a rare autosomal dominant neurodevelopmental disorder characterized by broad thumbs and halluces. RSTS is caused by mutations in CREBBP and in EP300 genes in 50-60% and 8%, respectively. Up to now, 76 RSTS-EP300 patients have been described. We present the clinical and molecular characterization of a cohort of RSTS patients carrying EP300 mutations. METHODS: Patients were selected from a cohort of 72 individuals suspected of RSTS after being negative in CREBBP study. MLPA and panel-based NGS EP300 were performed. RESULTS: Eight patients were found to carry EP300 mutations. Phenotypic characteristics included: intellectual disability (generally mild), postnatal growth retardation, infant feeding problems, psychomotor and language delay and typical facial dysmorphisms (microcephaly, downslanting palpebral fissures, columella below the alae nasi, and prominent nose). Broad thumbs and/or halluces were common, but angulated thumbs were only found in two patients. We identified across the gene novel mutations, including large deletion, frameshift mutations, nonsense, missense and splicing alterations, confirming de novo origin in all but one (the mother, possibly underdiagnosed, has short and broad thumbs and had learning difficulties). CONCLUSIONS: The clinical evaluation of our patients corroborates that clinical features in EP300 are less marked than in CREBBP patients although it is difficult to establish a genotype-phenotype correlation although. It is remarkable that these findings are observed in a RSTS-diagnosed cohort; some patients harbouring EP300 mutations could present a different phenotype. Broadening the knowledge about EP300-RSTS phenotype may contribute to improve the management of patients and the counselling to the families.

Resumen: Introducción: 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. Material y método: 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. Resultados: 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. Discusión: 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. Abstract: Introduction: 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. Material and method: 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. Results: 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. Discussion: 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. Palabras clave: Retraso psicomotor global, Discapacidad intelectual, Diagnóstico etiológico, Microarray comparative genomic hybridisation, Keywords: Global developmental delay, Intellectual disability, Microarray comparative genomic hybridisation

Introduction: 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. Material and method: 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. Results: 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. Discussion: 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. Resumen: Introducción: 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. Material y método: 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. Resultados: 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. Discusión: 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. Keywords: Global developmental delay, Intellectual disability, Microarray comparative genomic hybridisation, Palabras clave: Retraso psicomotor global, Discapacidad intelectual, Diagnóstico etiológico, Microarray comparative genomic hybridisation

Resumen: Presentamos el caso de un varón de 13 años diagnosticado de displasia fibromuscular (DFM) por estudio angiográfico, con imagen “arrosariada” de la carótida interna, tras presentar 2 ictus isquémicos en 9 días. Se decidió tratamiento conservador con ácido acetilsalicílico en dosis antiagregantes. Veinte meses después, la evolución clínica es favorable, sin que haya presentado nuevos episodios.La DFM es una causa muy poco frecuente de ictus en la infancia. Se conoce poco acerca de su etiología. A pesar de tratarse de una entidad habitualmente asintomática, debemos pensar en su existencia ante ictus repetidos o no explicables por otra causa. Su pronóstico y tratamiento son controvertidos debido al escaso número de pacientes en edad pediátrica con esta enfermedad. Abstract: We present the case of a 13 year-old patient diagnosed with fibromuscular dysplasia (FMD) by angiographic study, with “string of beads” image of internal carotid, after undergoing two ischemic strokes in nine days. Conservative treatment with acetylsalicylic acid at antiaggregant doses was decided. Twenty months later the clinical progress is favorable without presenting any new episodes. FMD is a very uncommon cause of stroke in childhood. Little is known about its etiology. In spite of it usually being an asymptomatic disease, it must be considered in cases of repeated or inexplicable strokes. Its prognosis and treatment is controversial, due to the limited number of pediatric patients with this pathology.

Introducción: La malformación de Chiari tipo I consiste en el descenso de las amígdalas cerebelosas a través del foramen magno. Con frecuencia es asintomática, pero puede presentar clínica por afectación de cerebelo, troncoencéfalo, porción superior de la médula cervical y pares craneales bajos. Objetivo: Se presenta nuestra experiencia de 16 años con 16 casos de malformación de Chiari tipo I; sólo en 2 existen síntomas atribuibles a la anomalía de Chiari tipo I, y en una de ellas la primera manifestación clínica consistió en un trastorno respiratorio durante el sueño. Caso clínico: Niña de 15 años con tos crónica diaria, agravada con el ejercicio, de 5 años de duración. La madre observaba desde hacía 1 año que al dormir la niña roncaba y realizaba repetidamente pausas de apnea. Tenía cefaleas ocasionales e hipersomnolencia diurna. Las exploraciones física y neurológica fueron normales, salvo ausencia de reflejo nauseoso bilateral. El estudio polisomnográfico nocturno evidenció un patrón seudoperiódico con alternancia de pausas de apnea con ciclos de respiraciones profundas, con graves repercusiones gasométricas y sobre la frecuencia cardíaca. La resonancia magnética mostró anomalía de Chiari tipo I. La ventilación mecánica no invasiva supuso una mejoría clínica y gasométrica en la paciente. Discusión: La descompresión quirúrgica es discutida. Está indicada de forma precoz, antes de que aparezca daño neurológico irreversible. Se asocia con una reducción significativa en el número de apneas centrales y microdespertamientos. Se recomienda en casos sintomáticos o en casos con progression radiológica de la anomalía de Chiari o de la siringomielia asociada. : Introduction: Type I Chiari malformation consists on the caudal displacement of cerebellar tonsils through the foramen magnum. It is often asymptomatic, although it may display symptoms as a result of cerebellum, brainstem, high cervical spinal cord or the lower cranial nerve, involvement. Objective: We report our experience over the last 16 years. We have identified 16 patients with type I Chiari malformation. Only 2 cases showed common type I Chiari symptoms and just one had respiratory disorder as the first clinical sign. Clinical case: A 15 year old girl presented with a 5 years history of chronic daily cough aggravated by the exercise. Snoring and sleep apnea had been noted by her mother for 1 year. The girl eventually suffered from migraine and diurnal hypersomnolence. The physical and neurological examination was normal with the only exception being the absence of bilateral nauseous reflex. A nocturnal polysomnography study demonstrated a pseudoperiodic pattern with apnea pauses associated to cycles of deep breathing, resulting in severe gasometric repercussion and bradycardia. Magnetic resonance imaging of the brain showed Chiari I malformation. Non-invasive mechanical ventilation treatment significantly improved the clinical symptoms and gasometric analysis. Discussion: Surgical posterior fossa decompression is discussed. Early decompression before appearance of irreversible neurological damage is recommended. It is associated with a significant reduction in the number of central apneas and sleep arousals. Surgical intervention is recommended in symptomatic patients and in cases of radiographic Chiari malformation or syrinx progression.

Creatine transporter (CT) deficiency is an X-linked disorder caused by mutations in the SLC6A8 gene. We describe a clinical, biochemical and molecular examination of a child with X-linked cerebral creatine deficiency. Increased urinary creatine/creatinine ratio, abnormal brain proton magnetic resonance spectroscopy and reduced creatine transport confirmed the clinical diagnosis. SLC6A8 analysis revealed a novel mutation that was hemizygous in the child and not detected in his mother. CT deficiency should be considered in children, especially males, with mental retardation.

Gorlin syndrome (GS) is a disorder transmitted by dominant autosomal inheritance associated to mutations in PTCH1, the main characteristic of which is the appearance of basal cell carcinomas, together with skeletal abnormalities, odontogenic keratocysts and intracranial tumours.A girl aged 3 years and 10 months, who was admitted due to acute ataxia. Some of the more striking features in the patient's personal history include psychomotor retardation and a family history of suspected GS in the mother as a result of a maxillary cyst. An examination revealed macrocephaly with a prominent forehead and hypertelorism, as well as nevus. A genetic study for GS was requested, in which mutation c.930delC was detected in exon 6 of the PTCH1 gene in heterozygosis.In GS there is an increase in the likelihood of developing basal cell carcinomas and strict dermatological monitoring is necessary. A clinical neurological follow-up and also magnetic resonance imaging scans are needed for an early diagnosis of intracranial tumours, especially in the case of medulloblastomas. Odontogenic keratocysts, other skin disorders, and cardiac and ovarian fibromas are characteristic, as are skeletal abnormalities, which require regular clinical and neuroimaging controls and treatment if needed, but radiation must be avoided. GS is a rare disorder, but it must be suspected in the presence of characteristic alterations. It requires a multidisciplinary follow-up, and it is also necessary to establish a protocol on how to act so as to allow early diagnosis and treatment of the potentially severe complications deriving from this disease.Sindrome de Gorlin en la edad pediatrica.Introduccion. El sindrome de Gorlin (SG) es un trastorno de herencia autosomica dominante asociado a mutaciones en el gen PTCH1, cuya principal caracteristica es la aparicion de carcinomas basocelulares, unido a anomalias esqueleticas, queratoquistes odontogenicos y tumores intracraneales. Caso clinico. Niña de 3 años y 10 meses, ingresada por ataxia aguda. Destacan como antecedentes personales retraso psicomotor y como antecedentes familiares la sospecha de SG en la madre por quiste maxilar. En la exploracion, se aprecia macrocefalia con frente prominente e hipertelorismo, asi como nevo. Se solicita estudio genetico de SG, en el que se detecta la mutacion c.930delC en el exon 6 del gen PTCH1 en heterocigosis. Conclusiones. En el SG hay un aumento de la susceptibilidad al desarrollo de carcinomas basocelulares y es preciso un estrecho control dermatologico. Es necesario un seguimiento neurologico clinico y de imagen, mediante resonancia magnetica, para el diagnostico precoz de tumores intracraneales, fundamentalmente el meduloblastoma. Tambien son caracteristicos los queratoquistes odontogenicos, otras alteraciones cutaneas, fibromas cardiacos y ovaricos, asi como anomalias esqueleticas, que precisan controles clinicos y de imagen periodicos, y tratamiento en caso de ser necesarios, pero debe evitarse la radiacion. El SG es un trastorno poco frecuente, que se debe sospechar ante la presencia de alteraciones caracteristicas. Es necesario un seguimiento multidisciplinar, asi como establecer un protocolo de actuacion, para un temprano diagnostico y tratamiento de las complicaciones potencialmente graves derivadas de esta enfermedad.

Raquel Perez Delgadoa, Ana Soria Marzob, Inmaculada Garcia Jimenezc, Carmen Campos Callejac, Juan Ramon Garcia Matad, Miguel Lafuente Hidalgob, Alberto Garcia Oguizae, Javier Lopez Pisonf, Jose Luis Pena Segurae y Antonio Baldellou Vazquezb aUnidad de Neuropediatria. Unidad de Urgencias. Hospital Universitario Miguel Servet. Zaragoza. Espana. bUnidad de Metabolismo. Hospital Universitario Miguel Servet. Zaragoza. Espana. cUnidad de Metabolismo. Grupo de Calidad de Urgencias Pediatricas. Unidad de Urgencias. Hospital Universitario Miguel Servet. Zaragoza. Espana. dUnidad de Calidad Asistencial (UCA). Hospital Universitario Miguel Servet. Zaragoza. Espana. eUnidad de Neuropediatria. Hospital Universitario Miguel Servet. Zaragoza. Espana. fUnidad de Neuropediatria. Grupo de Calidad de Urgencias Pediatricas. Hospital Universitario Miguel Servet. Zaragoza. Espana.

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.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.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.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.

We present the case of a 13 year-old patient diagnosed with fibromuscular dysplasia (FMD) by angiographic study, with "string of beads" image of internal carotid, after undergoing two ischemic strokes in nine days. Conservative treatment with acetylsalicylic acid at antiaggregant doses was decided. Twenty months later the clinical progress is favorable without presenting any new episodes. FMD is a very uncommon cause of stroke in childhood. Little is known about its etiology. In spite of it usually being an asymptomatic disease, it must be considered in cases of repeated or inexplicable strokes. Its prognosis and treatment is controversial, due to the limited number of pediatric patients with this pathology.

The prognosis of epilepsy is essentially determined by its aetiology and a poorer prognosis is generally associated with an early onset of the seizures.In this study we review our experience in epilepsies in children born after 1st January 1997 and who had their first acute non-symptomatic seizure before 31st March 2007 and between the ages of 3 and 12 months. Special attention is given to the analysis of cases of remote non-symptomatic epilepsies.Of the children born in that period, 267 were diagnosed with epilepsy, and the first seizure occurred between 3 and 12 months of age in 69 cases: 39 of which were symptomatic and 30 were cryptogenic and idiopathic epilepsies. West's syndrome/childhood spasms were observed in 20 cases (17 of the symptomatic cases and three of the cryptogenic and idiopathic patients). The cryptogenic and idiopathic cases were divided into three groups depending on their electroencephalogram pattern: nine generalised, 18 with no generalised alterations and three hypsarrhythmias. In addition, the three groups were analysed taking into account three degrees of psychomotor development: normal, slight retardation and moderate/severe retardation. None of the non-generalised cases presented severe psychomotor retardation, whereas 78% of the generalised and 33% of those with West's syndrome developed an important degree of retardation in their course.Our experience is compatible with the existence of epilepsies that have their onset in the early months of life and a good prognosis, which is important when it comes to the information and therapeutic approaches in cases of remote non-symptomatic epilepsy.

In neuropaediatrics, the aetiological diagnosis rarely allows a causal treatment to be established. In many cases, all we can offer is referral to early intervention (EI) and botulinum toxin type A (BTA). The only requirement before starting both interventions is a functional or syndromic diagnosis.Here we analyse the experience gained from an EI programme carried out in the region of Aragon since February 2003 and with the BTA service in the Neuropaediatric Unit of the Hospital Universitario Miguel Servet since November 2003.By the end of 2007, 2629 requests had been made for admission to the EI programme and in the year 2007 a total of 702 children were treated. In four years and four months 122 children with infantile cerebral palsy (ICP) were infiltrated with BTA, with positive results in 70% of cases and mild, transient side effects in 13.1%.The children, parents and professionals involved all view EI and BTA with satisfaction. Neuropaediatrics is one of the medical specialties that are best suited to child development and early intervention centres (CDIAT). The neuropaediatrician participates in all the stages of the EI: detection, diagnosis, information and intervention. He or she may act as the coordinating and homogenising element in EI, that is to say, as a link between CDIAT and health care services. Neuropaediatricians are also essential in EI training and education, in family training, information and awareness campaigns, primary care, social services and nurseries. Treatment with BTA cannot be viewed as an isolated technique, but instead as part of a programme in which physiotherapy, orthosis and sometimes surgery play a fundamental role. Coordination among the different professionals involved in treating the child with ICP is absolutely crucial.

The quality of the health care in a major part of neuropaediatrics benefits from appropriate communication and strategies that have been agreed with primary care (PC) paediatricians.We analyse the children who were assessed in the Neuropaediatric service at the Hospital Universitario Miguel Servet in Saragossa over a period of eight years and we also discuss the most important courses of action followed in the most prevalent problems.Eight reasons for visiting accounted for 86% of the total number: paroxysmal disorders (33%), headache (27%), psychomotor retardation (11.5%), alterations affecting the shape or size of the head (5.6%), problems at school and/or attention deficit (4.5%), behavioural disorders (4.25%), gait disorders (3.5%) and perinatal distress (3.4%). The most frequent diagnoses are headaches/migraines (26%), non-epileptic paroxysmal disorders (16.5%), prenatal encephalopathy (10.5%), epilepsy (8%), mental retardation (7.5%), infantile cerebral palsy (4.6%), cryptogenic attention deficit hyperactivity disorder (ADHD) (3.8%) and cryptogenic autism (3.6%).The PC paediatrician working in close relation with the children and their families in all cases is the person mainly responsible for conducting a follow-up on some of the most prevalent problems, such as headaches, many non-epileptic paroxysmal disorders and ADHD. The processes must be established, clearly specified, based on the best evidence, with the participation and within reach of all the professionals involved, in order to favour homogeneity and keep variability in the interventions to a minimum. Channels of communication, including the information and communications technologies, need to be set up to allow health professionals to be permanently up-to-date and capable of controlling their patients in the best possible way.

The aetiology and clinical features of peroxisomal diseases vary widely. An altered very-long-chain fatty acid (VLCFA) profile is commonly found in many of these diseases, and this makes it easier to point the diagnosis in the right direction.We review our experience in the diagnosis of cases of peroxisomal diseases with an altered VLCFA pattern; these were determined in serum only when there was a strong clinical suspicion up to the end of 1998, when their quantification by chromatography was introduced into our laboratory.The neuropaediatric database included 10,239 cases between May 1990 and 1st October 2007. Ten cases of peroxisomal disease with an altered VLCFA pattern were identified, all of them males. There were two cases of Zellweger syndrome spectrum, one unclassified peroxisomal oxidation defect and seven X-linked adrenoleukodystrophies (four with neurological compromise and three with no neurological damage; two were identified in siblings of patients and the other due to the presence of Addison's syndrome).In our 10 cases, the diagnosis was guided by the clinical or familial features that led to the determination of VLCFA. Being able to determine VLCFA makes early systematic diagnosis of patients possible. At present, VLCFA determination is performed when there is a clinical suspicion of Zellweger spectrum, suspected X-linked adrenoleukodystrophy/adrenomyeloneuropathy of unclear causation, Addison's disease, both in males and females, and above all in cases of chronic encephalopathy of unknown causation, with or without prenatal onset.

We review retrospectively the clinical histories of patients who were immediately switched from carbamazepine (CBZ) to oxcarbazepine (OXC), being administered a minimum of 1.3 times the CBZ dosis in 2 daily dosis of OXC.The immediate switching was carried out in 22 paediatric cases. 17 patients were taking CBZ in monotherapy and 5 in politherapy. The change was made in 20 cases to lower the number of seizures (and to avoid side effects in 4 of them), and in 2 only to reduce drowsiness and fatigue. The average change was from 18.62 mg/kg of CBZ to 28.89 mg/kg of OXC. The medium change rate was 1.6:1 (maximum: 2:1).In 19 cases there were no side effects. With one boy, the essential tremor worsened and two girls became more tired and drowsy. Three experienced less drowsiness and one less weight increase. Twelve cases showed no seizure changes. Five cases became immediately seizure-free, three of them for a prolongated time. There was a reduction in seizure frequency in 2 cases, with posterior disappearance in one of them. Three cases experienced a reduction in seizure intensity. In two cases OXC was stopped after 24 seizure-free months. Fourteen patients were still taking OXC, 8 in monotherapy, with a mean follow-up of 31.5 months.Given the potential benefits, ease and good tolerability, we advise trying with immediate switching to OXC, before adding another antiepileptic drug to CBZ.

As result of our aim to improve the quality standard of our emergency system, work has been carried out in relation to the development and monitorization of effective clinical protocols in the department of paediatric practice.An evidence based review approach was taken to design a clinical protocol about Bell's palsy condition for the paediatric emergency department. Previous protocol approved in March 2003 was reviewed accordingly with the new designed protocol's quality standards. The Bell's palsy cases reported since March 2003 until June 2006 to paediatric emergency department were analyzed.A total of 27 patients affected by Bell's palsy were reported to the hospital's emergency department. Facial expression was described in 85.19% of the cases. Cranial nerves normal function was reported in 77.78%. Fundoscopic examination was described in 77.78% and otoscopic findings in 44.44%; the absence of herpes vesicles was analyzed only in 11.11%. All patients received steroid therapy (prednisone) and the treatment resulted in the complete recovery. The mean time to resolution was 58.6 days.In order to improve hospital's quality standards, clinical protocols should be designed and verified regularly to ensure the proper performance. Medical auditing also contributes to improve effectiveness in health attendance.

Introduccion. El sindrome de Gorlin (SG) es un trastorno de herencia autosomica dominante asociado a mutaciones en el gen PTCH1, cuya principal caracteristica es la aparicion de carcinomas basocelulares, unido a anomalias esqueleticas, queratoquistes odontogenicos y tumores intracraneales. Caso clinico. Nina de 3 anos y 10 meses, ingresada por ataxia aguda. Destacan como antecedentes personales retraso psicomotor y como antecedentes familiares la sospecha de SG en la madre por quiste maxilar. En la exploracion, se aprecia macrocefalia con frente prominente e hipertelorismo, asi como nevo. Se solicita estudio genetico de SG, en el que se detecta la mutacion c.930delC en el exon 6 del gen PTCH1 en heterocigosis. Conclusiones. En el SG hay un aumento de la susceptibilidad al desarrollo de carcinomas basocelulares y es preciso un estrecho control dermatologico. Es necesario un seguimiento neurologico clinico y de imagen, mediante resonancia magnetica, para el diagnostico precoz de tumores intracraneales, fundamentalmente el meduloblastoma. Tambien son caracteristicos los queratoquistes odontogenicos, otras alteraciones cutaneas, fibromas cardiacos y ovaricos, asi como anomalias esqueleticas, que precisan controles clinicos y de imagen periodicos, y tratamiento en caso de ser necesarios, pero debe evitarse la radiacion. El SG es un trastorno poco frecuente, que se debe sospechar ante la presencia de alteraciones caracteristicas. Es necesario un seguimiento multidisciplinar, asi como establecer un protocolo de actuacion, para un temprano diagnostico y tratamiento de las complicaciones potencialmente graves derivadas de esta enfermedad.

Introduccion. El pronostico de la epilepsia viene determinado fundamentalmente por su etiologia y, en general, se asocia un peor pronostico al comienzo precoz de las crisis. Pacientes y metodos. En este trabajo se revisa nuestra experiencia en epilepsias en ninos nacidos tras el 1 de enero de 1997 y que presentaron la primera crisis no sintomatica aguda antes del 31 de marzo de 2007 y entre los 3 y los 12 meses de edad. Se analizan especialmente los casos de epilepsias no sintomaticas remotas. Resultados. De los ninos nacidos en ese periodo, 267 tienen el diagnostico de epilepsia y la primera crisis entre 3 y 12 meses se dio en 69 casos: 39 epilepsias sintomaticas y 30 criptogenicas e idiopaticas. Veinte manifestaron un sindrome de West/espasmos infantiles (17 de las sintomaticas y tres de las criptogenicas e idiopaticas). Se clasifican las criptogenicas e idiopaticas en tres grupos segun su patron electroencefalografico: 9 generalizadas, 18 sin alteraciones generalizadas y 3 hipsarritmias. Asimismo, se han analizado los tres grupos considerando tres opciones de desarrollo psicomotor: normal, retraso leve y retraso moderado/grave. Ningun caso de las no generalizadas presento retraso psicomotor grave, mientras que el 78% de las generalizadas y el 33% de los sindromes de West desarrollaron un retraso importante en su evolucion. Conclusiones. Nuestra experiencia es compatible con la existencia de epilepsias de presentacion en los primeros meses de vida y buen pronostico, lo cual es importante en la informacion y planteamientos terapeuticos de los casos de epilepsia no sintomatica remota.

Introduccion. Las enfermedades peroxisomales tienen una gran heterogeneidad etiologica y clinica. Un perfil alterado de acidos grasos de cadena muy larga (AGCML) es comun a muchas de ellas, lo que facilita su orientacion diagnostica. Pacientes y metodos. Se revisa nuestra experiencia diagnostica en los casos de enfermedad peroxisomal con patron alterado de AGCML, que se determinaban en suero solo ante fuerte sospecha clinica hasta finales de 1998, fecha en que se introdujo en nuestro laboratorio su cuantificacion por cromatografia. Resultados. En la base de datos de neuropediatria de mayo de 1990 a 1 de octubre de 2007 figuran 10.239 casos. Se han identificado 10 casos de enfermedad peroxisomal con patron alterado de AGCML, todos varones: dos casos de espectro de sindrome de Zellweger, un defecto de la beta-oxidacion peroxisomal sin tipificar y siete adrenoleucodistrofias ligadas a X (cuatro con afectacion neurologica y tres sin dano neurologico; dos identificados por ser hermanos de enfermos y el otro por presentar un sindrome de Addison). Conclusiones. En nuestros 10 casos, el diagnostico se oriento por el cuadro clinico o familiar que llevo a la determinacion de AGCML. La disponibilidad de la determinacion de AGCML permite el diagnostico sistematico de pacientes de forma precoz. Actualmente, la realizamos ante sospecha clinica del espectro Zellweger, sospecha de adrenoleucodistrofia/adrenomieloneuropatia ligada a X, leucoencefalopatias de causa no aclarada, enfermedad de Addison, tanto en varones como mujeres, y ante toda encefalopatia cronica de causa no aclarada de inicio prenatal o no.

Introduccion. La calidad asistencial de gran parte de la neuropediatria se beneficia de una adecuada comunicacion y de estrategias consensuadas con los pediatras de atencion primaria (AP). Pacientes y metodos. Se analizan los ninos valorados en la consulta de neuropediatria del Hospital Universitario Miguel Servet de Zaragoza en ocho anos y se exponen las lineas mas importantes de actuacion en los problemas mas prevalentes. Resultados. El 86% de las primeras visitas se reparte entre ocho motivos de consulta: trastornos paroxisticos (33%), cefalea (27%), retraso psicomotor (11,5%), alteraciones de la forma o tamano de la cabeza (5,6%), problemas escolares y/o atencion deficiente (4,5%), alteraciones del comportamiento (4,25%), trastornos de la marcha (3,5%) y sufrimiento perinatal (3,4%). Los diagnosticos mas frecuentes son cefaleas/migranas (26%), trastornos paroxisticos no epilepticos (16,5%), encefalopatia prenatal (10,5%), epilepsia (8%), retardo mental (7,5%), paralisis cerebral infantil (4,6%), trastorno por deficit de atencion con hiperactividad (TDAH) criptogenico (3,8%) y autismo criptogenico (3,6%). Conclusiones. El pediatra de AP cercano a los ninos y sus familias en todos los casos es el principal responsable del seguimiento de algunos de los problemas mas prevalentes, como cefaleas, muchos trastornos paroxisticos no epilepticos y TDAH. Los procesos deben estar establecidos, claramente explicitados, basados en las mejores evidencias, con la participacion y al alcance de todos los profesionales involucrados, en beneficio de la homogeneidad y reducida variabilidad de las actuaciones. Es necesario establecer vias de comunicacion, incluidas las tecnologias de la informacion y comunicacion para una continua actualizacion y el mejor control de los pacientes.

Introduccion. En neuropediatria, el diagnostico etiologico pocas veces permite un tratamiento causal. En muchas ocasiones solo podemos ofrecer la derivacion a atencion temprana (AT) y la toxina botulinica tipo A (TBA). Ambas intervenciones solo precisan para su inicio el diagnostico funcional o sindromico. Pacientes y metodos. Se analiza la experiencia en el programa de AT para Aragon desde febrero de 2003 y con la consulta de TBA de la Unidad de Neuropediatria del Hospital Universitario Miguel Servet desde noviembre de 2003. Resultados. El numero de solicitudes al programa de AT hasta finales de 2007 ascendia a 2.629, y en 2007 se atendia a 702 ninos. En cuatro anos y cuatro meses se ha infiltrado con TBA a 122 ninos con paralisis cerebral infantil, con resultados positivos del 70%, y efectos adversos leves y transitorios del 13,1%. Conclusiones. La AT y la TBA se perciben con alta satisfaccion por ninos, padres y profesionales implicados. La neuropediatria es una de las especialidades medicas mas adecuadas en los equipos de atencion temprana (CDIAT). El neuropediatra participa en todas las etapas de AT: deteccion, diagnostico, informacion e intervencion. Puede ser el elemento coordinador y homogeneizador de la AT, el enlace entre CDIAT y servicios sanitarios. Es necesario en programas de formacion y docencia de AT, en campanas de sensibilizacion, informacion y formacion de familias, atencion primaria, servicios sociales y guarderias. El tratamiento con TBA no puede entenderse como una tecnica aislada, sino dentro de un programa donde son fundamentales fisioterapia, ortesis y, en ocasiones, cirugia. Es imprescindible la coordinacion con los profesionales implicados en el tratamiento del nino con paralisis cerebral infantil.

Introduccion. En nuestro hospital se esta trabajando en un plan de mejora de calidad de las urgencias pediatricas que incluye, entre otras actuaciones, la protocolizacion de los procedimientos (mediante la revision de la evidencia disponible) y la monitorizacion de su aplicacion. Pacientes y metodos. Se revisa, segun la evidencia disponible, el protocolo de urgencias de la paralisis facial. Se evalua la aplicacion del previo, consensuado en sesion hospitalaria en marzo del 2003, y se aplican de forma retrospectiva los indicadores disenados en la revision de junio de 2006. Se analizan los casos de paralisis facial a frigore valorados en urgencias de Pediatria desde marzo de 2003 hasta junio de 2006. Resultados. En el periodo de estudio fueron evaluados en Urgencias 27 pacientes con paralisis facial. En el 85,19% de los casos se describio la alteracion de la mimica facial en el informe de urgencias. En el 77,78% de los casos constaba la normalidad de los demas pares craneales, y en el 77,78% del fondo de ojo. En el 44,44% se recogio la normalidad de la otoscopia; solo en el 11,11% se especificaba la ausencia de vesiculas herpeticas. Todos recibieron tratamiento con prednisona, fueron seguidos en la consulta de Neuropediatria y se resolvieron completamente, con una media de 58,6 dias. Conclusiones. En el proceso de mejora de calidad es fundamental la elaboracion de protocolos, y la evaluacion de su cumplimiento mediante indicadores de calidad. El audit y sus reevaluaciones facilitan la implantacion del ciclo de aprendizaje y mejora en la atencion sanitaria, vinculados a la excelencia del trabajo.

Introduccion. El torticolis paroxistico benigno (TPB) se caracteriza por episodios recurrentes de flexion lateral del cuello, acompanados en ocasiones de sintomas vegetativos, ataxia o postura anormal del tronco, con tendencia a desaparecer espontaneamente en meses o anos, y sin alteraciones entre los episodios. Objetivo. Analizar las caracteristicas clinicas y evolutivas de los casos valorados por la Seccion de Neuropediatria de nuestro hospital y catalogados como TPB. Pacientes y metodos. Se han revisado las anamnesis de los pacientes que figuran con diagnostico de TPB en la base de datos de la Seccion de Neuropediatria durante un periodo de 15 anos. Se ha contactado telefonicamente con los pacientes que no seguian un control. Resultados. Se han considerado 13 pacientes con TPB con los criterios tipicos, y 4 con TPB posible (p-TPB), por haber presentado un episodio aislado de torticolis. Se realizo neuroimagen a nueve ninos (69,2%) del grupo de TPB: a seis solo ecografia transfontanelar (ECO TF), a un nino ECO TF y tomografia axial computarizada (TAC), a uno solo TAC, y a otro, TAC y resonancia magnetica. A todos los casos de p-TPB se les realizo neuroimagen: a dos TAC, y a los otros dos, ECO TF. Conclusiones. Establecer el diagnostico de TPB con criterios estrictos puede excluir casos atipicos. Al no disponer de marcadores biologicos, el diagnostico debe basarse en la clinica y evolucion y, en algunos casos, deben realizarse examenes complementarios para descartar otras patologias. Se debe tranquilizar a las familias al diagnosticar al nino TPB, y explicarles que es un proceso benigno con tendencia a desaparecer espontaneamente.