A novel mutation in the ZNF462 gene c.3306dup; p.(Gln1103Thrfs*10) is associated to Weiss-Kruszka syndrome. A case report.

BACKGROUND: Weiss-Kruszka syndrome (WSKA) is a rare disorder caused by mutations in the ZNF462 gene or deletion of 9p31.2 chromosome region, involving ZNF462. The prevalence of WSKA is unknown as only 24 affected individuals have been described. This syndrome should be suspected in individuals presenting mild global developmental delay and common craniofacial abnormalities. CASE PRESENTATION: We presented a case of an infant, 3 years and 4-month life who presented pondostatural and psychomotor retardation, generalized hypotonia with hypermobility, bilateral palpebral ptosis, epicanthal folds, and poorly expressive facies as the main clinical features. These characteristics lead to the realization of genetics studies that resulted in the identification of a novel mutation c.3306dup; p.(Gln1103Thrfs*10) in ZNF462. CONCLUSIONS: WSKA should be suspected in individuals presenting mild global developmental delay, ptosis, downslanting palpebral fissures, exaggerated Cupid's Bow, arched eyebrows, epicanthal folds and short upturned nose with a bulbous tip. Hypertrophy of the ventricular septum and severe OSA were described in our patient and should be considered in future reviews of the disease. This case is added to the reduced number of publications previously reported regarding WSKA and contributes to understanding the genetic characteristics, clinical features, and diagnosis of this syndrome.Abbreviations: WSKA: Weiss-Kruszka syndrome; CP: craniofacial perimeter; WES: whole-exome sequencing; RSV: respiratory syncytial virus; OSA: obstructive sleep apnoea; ACMG: American College of Medical Genetics and Genomics.

[Early infantile epileptic encephalopathy due to ITPA mutation]. / Encefalopatía epiléptica infantil precoz por mutación en ITPA.

TITLE: Encefalopatía epiléptica infantil precoz por mutación en ITPA.

Acute cerebellitis in paediatric patients: Our experience. / Cerebelitis aguda en Pediatría: nuestra experiencia.

INTRODUCTION: Acute cerebellitis is a rare inflammatory disease with a highly variable clinical course that ranges from benign self-limiting symptoms to a fulminant presentation associated with a high risk of death due to compression of the posterior fossa, acute hydrocephalus, and intracranial hypertension. METHODS: We reviewed clinical, laboratory, and radiological findings from children diagnosed with acute cerebellitis between May 2007 and November 2016. We analysed treatments and clinical and radiological progression. RESULTS: Nine children met the diagnostic criteria for cerebellitis. Headache, vomiting, and drowsiness were the most frequent initial symptoms; ataxia, dysarthria, and dysmetria were the most common cerebellar signs. Cerebellitis was diagnosed with magnetic resonance imaging, which revealed cerebellar involvement (unilateral or bilateral); computerised tomography images either were normal or showed indirect signs such as triventricular hydrocephalus due to extrinsic compression of the aqueduct of Sylvius. Corticosteroids were the most commonly used treatment (6 patients). One patient required surgery due to triventricular hydrocephalus. Eight patients recovered completely, whereas the ninth displayed neurological sequelae. CONCLUSIONS: Cerebellitis is a medical and surgical emergency; diagnosis requires a high level of suspicion and an emergency brain magnetic resonance imaging study. It is a clinical-radiological syndrome characterised by acute or subacute encephalopathy with intracranial hypertension and cerebellar syndrome associated with T2-weighted and FLAIR hyperintensities in the cerebellar cortex (unilaterally or bilaterally) and possible triventricular dilatation. Treatment is based on high-dose corticosteroids and may require external ventricular drain placement and decompressive surgery.

Transition from paediatric care to adult care for patients with mucopolysaccharidosis. / Transición desde la asistencia pediátrica a la adulta en pacientes con mucopolisacaridosis.

Mucopolysaccharidosis are multisystem diseases that require large multidisciplinary teams for their care. Specific recommendations are therefore needed for the transition from childhood to adulthood in this patient group. To overcome the barriers that might arise during the transition, the authors consider it essential to implement a flexible plan with a coordinator for the entire process, systematising the information through a standardised paediatric discharge report and educating the patient and their family about the disease, showing the characteristics of the healthcare system in this new stage. The final objective is that, once the transition to adulthood has been completed, the patient's autonomy and potential development are maximised and that the patient receives appropriate healthcare during this transition.

[A study of the demand for health care in hereditary-metabolic diseases in a Spanish tertiary care hospital]. / Estudio de la demanda asistencial de las enfermedades metabolico-hereditarias en un hospital español de tercer nivel.

AIM: To determine the characteristics of the demand for health care in hereditary-metabolic diseases in a Spanish tertiary care hospital. PATIENTS AND METHODS: We conducted a retrospective descriptive study involving a review of the epidemiological data, reasons for visiting, diagnoses and complementary studies of the patients treated by a metabolic disease unit over a period of 6 years and 11 months. RESULTS: Altogether 1012 patients were evaluated. There was a predominance of males (52%) and of patients under the age of 1 year (42.09%). 71.44% of them were under 6 years old. Approximately half of the patients (50.3%) came from hospitals (wards, outpatients, neonatology, emergency department, neuropaediatrics and intensive care), followed by the neonatal screening programme (20.36%) and primary care (14.82%). The most frequent reasons for visiting and diagnoses can be seen in their respective tables. CONCLUSIONS: The study of the demand for health care in hereditary-metabolic diseases is useful as a means to detect needs in their field and to try to adapt care to meet them. Medical, scientific and social progress makes it necessary to have an expert in metabolism present in reference clinical units. As members of multidisciplinary teams alongside other specialists, they will contribute towards accomplishing a suitable presumptive diagnosis, diagnosis, management and follow-up. It is necessary to keep them constantly up-to-date and ensure adequate training of new experts in metabolism, since this is the best way to deliver optimal care for those with metabolic illnesses, which are usually rare diseases.

TITLE: Estudio de la demanda asistencial de las enfermedades metabolico-hereditarias en un hospital español de tercer nivel.Objetivo. Conocer las caracteristicas de la demanda asistencial de las enfermedades metabolico-hereditarias en un hospital español de tercer nivel. Pacientes y metodos. Estudio descriptivo retrospectivo en el que se revisan los datos epidemiologicos, los motivos de consulta, los diagnosticos y los estudios complementarios de los pacientes atendidos por la unidad de enfermedades metabolicas durante un periodo de 6 años y 11 meses. Resultados. Se valoraron un total de 1.012 pacientes. Hay un predominio de varones (52%) y de pacientes menores de 1 año (42,09%). El 71,44% son menores de 6 años. Los pacientes provienen en un 50,3% del ambito hospitalario (planta, consultas externas, neonatologia, urgencias, neuropediatria y cuidados intensivos), seguido del programa de cribado neonatal (20,36%) y de atencion primaria (14,82%). Conclusiones. El estudio de la demanda asistencial de las enfermedades metabolico-hereditarias es util para detectar necesidades en su campo y tratar de adecuar la asistencia a estas. Los avances medicos, cientificos y sociales hacen necesaria la existencia del experto en metabolismo en unidades clinicas de referencia, integrado en equipos multidisciplinares con otros especialistas, para una adecuada sospecha, diagnostico, manejo y seguimiento. Debe estar en continua actualizacion y garantizar la adecuada formacion de nuevos expertos en metabolismo, la mejor via para una optima atencion de los pacientes afectados de enfermedades metabolicas, habitualmente enfermedades raras.

Descriptive study of symptomatic epilepsy by age of onset in patients with a 3-year follow-up at the Neuropaediatric Department of a reference centre. / Estudio descriptivo de las epilepsias sintomáticas según edad de inicio controladas durante 3 años en una Unidad de Neuropediatría de referencia regional.

OBJECTIVE: We conducted a descriptive study of symptomatic epilepsy by age at onset in a cohort of patients who were followed up at a neuropaediatric department of a reference hospital over a 3-year period PATIENTS AND METHODS: We included all children with epilepsy who were followed up from January 1, 2008 to December 31, 2010 RESULTS: Of the 4595 children seen during the study period, 605 (13.17%) were diagnosed with epilepsy; 277 (45.79%) of these had symptomatic epilepsy. Symptomatic epilepsy accounted for 67.72% and 61.39% of all epilepsies starting before one year of age, or between the ages of one and 3, respectively. The aetiologies of symptomatic epilepsy in our sample were: prenatal encephalopathies (24.46% of all epileptic patients), perinatal encephalopathies (9.26%), post-natal encephalopathies (3.14%), metabolic and degenerative encephalopathies (1.98%), mesial temporal sclerosis (1.32%), neurocutaneous syndromes (2.64%), vascular malformations (0.17%), cavernomas (0.17%), and intracranial tumours (2.48%). In some aetiologies, seizures begin before the age of one; these include Down syndrome, genetic lissencephaly, congenital cytomegalovirus infection, hypoxic-ischaemic encephalopathy, metabolic encephalopathies, and tuberous sclerosis. CONCLUSIONS: The lack of a universally accepted classification of epileptic syndromes makes it difficult to compare series from different studies. We suggest that all epilepsies are symptomatic because they have a cause, whether genetic or acquired. The age of onset may point to specific aetiologies. Classifying epilepsy by aetiology might be a useful approach. We could establish 2 groups: a large group including epileptic syndromes with known aetiologies or associated with genetic syndromes which are very likely to cause epilepsy, and another group including epileptic syndromes with no known cause. Thanks to the advances in neuroimaging and genetics, the latter group is expected to become increasingly smaller.

Phenotype in patients with intellectual disability and pathological results in array CGH. / Fenotipo en pacientes con discapacidad intelectual y array-CGH patológico.

INTRODUCTION: Global developmental delay (GDD) and intellectual disability (ID) are frequent reasons for consultation in paediatric neurology departments. Nowadays, array comparative genomic hybridisation (array-CGH) is one of the most widely used techniques for diagnosing these disorders. Our purpose was to determine the phenotypic features associated with pathological results in this genetic test. METHODS: We conducted a blind study of the epidemiological, clinical, anthropometric, and morphological features of 80 patients with unexplained ID to determine which features were associated with pathological results in array-CGH. RESULTS: Pathological results were found in 27.5% of the patients. Factors associated with pathological results in array-CGH were a family history of GDD/ID (OR = 12.1), congenital malformations (OR = 5.33), having more than 3 facial dysmorphic features (OR = 20.9), and hypotonia (OR = 3.25). CONCLUSIONS: Our findings are consistent with those reported by other published series. We therefore conclude that the probability of having pathological results in array-CGH increases with the presence of any of the features mentioned above in patients with ID/GDD.

Our experience with the aetiological diagnosis of global developmental delay and intellectual disability: 2006-2010.

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.

[Epidemiological study of the metabolic diseases with homocystinuria in Spain]. / Estudio epidemiológico de las enfermedades metabólicas con homocistinuria en España.

OBJECTIVES: To determine the prevalence of homocystinuria in Spain and to establish the measures and mechanisms to ensure its prevention, diagnosis and treatment. MATERIAL AND METHODS: A national cross-sectional survey was conducted by means of a questionnaire sent to 35 hospitals in which children and adult patients are treated. RESULTS: Using the questionnaires submitted by 25 physicians from 16 centres, 75 patients were identified: 41 transsulphuration defects (one deceased), 27 remethylation (six deaths) and 7 without a syndromic diagnosis. The age at diagnosis varied widely, and 18 cases had more than one sibling affected. The more severe clinical manifestations involved the patients with remethylation defects. There was a high percentage of cognitive impairment, followed by lens diseases. Almost half of the patients had neurological disorders. There was increased vascular involvement in CBS-deficient adults. The therapeutic options most used were, folic acid, hydroxycobalamin and betaine. CONCLUSIONS: In view of these results and especially the small number of CBS deficiencies detected, we conclude that there is a need to introduce newborn screening for classical homocystinuria and ensure implementation of an appropriate diagnostic workup in all patients at risk.

Prenatal encephalopathies of unknown origin. Our 19-years experience. To what extent must genetic and biochemical studies be carried out?

INTRODUCTION: We examine those prenatal encephalopathies with clinical or neuroimaging data of encephalopathy before the birth. They affect a significant number of children seen by paediatric neurologists. They can be of disruptive origin (due to vascular problems, drugs, toxins or congenital infections), and genetically determined. We include cases of autism spectrum disorder and mental retardation with no history of perinatal of postnatal damages. MATERIAL AND METHODS: We analysed our 19 year neuro-paediatric data base in search of prenatal encephalopathies and their diagnostic origin. We also analyse the studies made in the cases with a diagnosis of unknown origin. RESULTS: The 19 year period of study in the data base included 11,910 children, and 1596 (13.5%) were considered as prenatal encephalopathies; 1307 children (81.4%) had a diagnosis of unknown origin, despite many investigations being done in a large number of them. DISCUSSION: Most of the children included in this study suffer a rare disease, and whether they are identified or not, they increasingly require an early diagnosis. Peroxisomal, mitochondrial, lysosomal diseases, carbohydrate glycosylation deficiency syndrome and other inborn error of metabolism, congenital infections and genetic encephalopathies, can be clinically indistinguishable in early life and require specific studies to identify them. Early diagnosis requires strategies using step-wise systematic studies, giving priority to those diseases that could be treated, and in many cases using an individualised approach. We believe that the potential benefits of early diagnosis, including savings on further studies, genetic counselling and prenatal diagnosis, overcome the financial costs.

[Continuous monitoring of a guideline: Bell's palsy]. / Monitorización continua de un protocolo: parálisis facial a frigore.

INTRODUCTION: The preparation and review of child neurology guidelines can reduce the variability of our medical practice, thus improving health care. We present the continuous monitoring of our Bell's palsy guideline. MATERIAL AND METHODS: Emergency and medical reports of the children seen in Child Neurology surgery from July 2006 to August 2009 (group 2) are reviewed for the purpose of finding out the present level of compliance with guideline quality criteria and compare it with the previously reviewed period (group 1, from March 2003 to June 2006). Scientific evidence on this topic is also updated. RESULTS: Comparing the compliance rate in group 1 with group 2 shows a rise in group 2 from 85.1% to 100% in facial expression description, from 11.1% to 31.6% on whether or not there is evidence of Herpes Zoster vesicles, from 77.7% to 84.2% whether or not there is evidence fundoscopic examination, and from 77.7% to 86.8% as regards cranial nerve function remaining normal. The rate of fact sheet issue, recorded for the first time in group 2, is 21.1%. DISCUSSION: Medical auditing allows us to evaluate our medical practice and set up ways for improvement according to the deficiencies found. We insist on striving to improve the written record of the most relevant data and never overlook the importance of issuing the fact sheets to parents and paediatricians, to ensure continuity of medical care.

[Epilepsy onset between one month and three months of life: our 11 years experience]. / Epilepsia de inicio entre el mes y los tres meses de vida: nuestra experiencia de 11 años.

INTRODUCTION: The prognosis of epilepsy is basically determined by its aetiology. Early onset of seizures is generally associated with poor progress. MATERIAL AND METHODS: We review our experience in epilepsy with children born after 1 January 1997 and who had their first seizure between 1 and 3 months of age before January 2008. RESULTS: Eighteen cases diagnosed with epilepsy and a first seizure between 1 and 3 months of age were included. One case was within the Dravet syndrome spectrum with the c829 T>G c277G heterozygous mutation of the SCN1A gene. Four were cryptogenic epilepsies and thirteen were asymptomatic: 2 were inborn errors of metabolism (biotinidase deficiency with a response to biotin and Leigh's syndrome); 2 were of infectious origin and the remaining nine prenatal encephalopathy. Nine (50%) currently have a severe psychomotor delay and 2 died. The cryptogenic cases had a relatively poor progress. CONCLUSIONS: Our experience corroborates the poor prognosis associated with early onset, between 1 and 3 months, of epileptic seizures. Given the wide aetiological range and the poor prognosis in the absence of specific treatment, an appropriate diagnostic-therapeutic strategy is required to avoid diagnostic uncertainties and can identify potentially treatable cases, such as some inborn errors of metabolism. In this age group, the protocol for convulsions of unknown cause must be the same as that for neonatal convulsions, including treatment with a vitamin cocktail, after collecting biological samples.

[Neuropaediatrics and primary care. Our experience in the 21st century]. / Neuropediatría y atención primaria.Nuestra experiencia en el siglo XXI.

INTRODUCTION: 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. PATIENTS AND METHODS: 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. RESULTS: 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%). CONCLUSIONS: 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.

[Hereditary juvenile cobalamin deficiency due to mutations in GIF gene]. / Déficit de cobalamina hereditario juvenil causado por mutaciones en el gen GIF.

Inborn errors of cobalamin (Cbl) metabolism affect its absorption, transport, as well as its intracellular metabolism. Hereditary juvenile megaloblastic anaemia due to cobalamin deficiency, results from defects in Cbl absorption. There is a lack of vitamin B12 in congenital pernicious anaemia due to intrinsic factor deficiency and megaloblastic anaemia 1 due to selective intestinal malabsorption of vitamin B12 or Imerslund-Gräsbeck syndrome. Differential diagnosis can't be accomplished only by clinical and biochemical findings. We present a patient from Spain with a megaloblastic anaemia due to intrinsic factor deficiency (IFD). The patient is a compound heterozygous in GIF gene for a splice site mutation inherited from his mother and a missense change inherited from his father. The identification of disease-causing mutations in specific genes has improved our ability to diagnose many of these conditions.

[Facial paralysis reported in a paediatric emergency department: actuation protocol reviewed and verified]. / Parálisis facial en urgencias de pediatría: actualización de nuestro protocolo y autoevaluación.

INTRODUCTION: 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. PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.