Motor performance after treatment of pilocytic astrocytoma in the posterior fossa in childhood.

BACKGROUND: Pilocytic astrocytoma is the most common brain tumour type in childhood located in the posterior fossa, and treated mainly with surgery. These tumours have low mortality, but knowledge concerning its long-term outcome is sparse. AIMS: The aim was to investigate if patients treated for pilocytic astrocytoma in the posterior fossa had motor complications, including balance, motor and process skills. METHODS AND RESULTS: This descriptive single-centre study includes eight children and 12 adults, treated for pilocytic astrocytoma as children. Motor performance was investigated with Bruininks-Oseretsky Test of Motor Proficiency, Second Edition, and dynamic balance with the mini-balance evaluation systems test. Physiological cost index, six-minute walk test, hand grip strength and assessment of motor and process skills were also evaluated. Ten patients reported motor difficulties, mainly from the upper limbs. The motor performance test showed results within normal limits except for manual dexterity, which was significantly below mean (p = .008). In the dynamic balance test patients had significantly lower results compared with controls (p = .036). Physiological cost index, six-minute walk tests and hand grip strength showed results within normal limits. In the Assessment of Motor and Process Skills, patients over 16 years had significantly lower results compared with test norms for motor activities of daily living (ADL) and 30% of all patients scored below the cut-off level for difficulties with motor skills. CONCLUSIONS: Motor performance for patients treated for pilocytic astrocytoma in the posterior fossa in childhood is satisfactory but some patients display difficulties with balance, manual dexterity and ADL motor skills. Thus, it is important to identify those in need of motor follow-up and training.

Cognitive, language, and school performance in children and young adults treated for low-grade astrocytoma in the posterior fossa in childhood.

BACKGROUND: Pilocytic astrocytoma is the most common brain tumour type in childhood located in the posterior fossa, and treated mainly with surgery. These tumours have low mortality, but knowledge concerning its long-term outcome is sparse. AIM: The aim of this study was to investigate whether children treated for pilocytic astrocytoma in the posterior fossa had late complications affecting cognition, language and learning. METHODS: This descriptive single-centre study includes eight children and 12 adults treated as children for pilocytic astrocytoma in the posterior fossa, with a mean follow-up time of 12.4 (range 5-19) years. Well-established tests of intelligence, executive, language and academic function were used. RESULTS: Intelligence tests showed average results compared with norms. Five patients scored <-1 SD (70-84) and 3 low average (85-92) on full scale IQ. The patients scored average on subtests regarding executive function, except for significantly lower results in inhibition/switching (p = .004). In Rey complex figure test half of the patients scored below -1 SD. Language tests were normal except for significantly lower results in naming ability (p = .049) and in inference (p = .046). In academic tests, results were average, except for significantly lower results in reading speed (p = .024). Patients with learning difficulties performed worse in the tests. CONCLUSIONS: The patients' functional outcome was favourable but, a not-negligible part of the patients displayed neurocognitive difficulties as revealed by extensive neuro-cognitive and academic testing. Thus, it is important to identify those in need of more thorough cognitive and pedagogic follow-up programmes, including school interventions.

Somatostatin receptor expression and mTOR pathway activation in glioneuronal tumours of childhood.

PURPOSE: To investigate the expression of somatostatin receptors (SSTRs) and markers of mTOR pathway in paediatric glioneuronal tumours and correlate these findings with tumour type, BRAFV600E mutational status and clinical characteristics such as tumour location, seizure frequency and duration, and age. METHOD: 37 children and adolescents with a neuropathological diagnosis of glioneuronal tumour were identified over a 22-year period. Immunohistochemical analyses for SSTRs type 1, 2A, 3, 5 and ezrin-radixin-moesin (ERM) and phosphorylated S6 (pS6), which are indicators of mTOR pathway activation, were performed in tumour specimens from 33 patients and evaluated using the immunoreactive score (IRS). The IRS were compared to tumour type, BRAFV600E status and clinical characteristics. RESULTS: Ganglioglioma (GG) was the most frequently encountered subgroup (n = 27), followed by dysembryoplastic neuroepithelial tumour (DNET; n = 4). GGs expressed SSTR2A and SSTR3 to a high extent, 56 % and 44 % respectively. Expression of SSTR2A was also found in DNETs. Signs of mTOR pathway activation were abundant in GGs, but only present in one DNET. No correlations with BRAFV600E presence or clinical characteristics were found. CONCLUSIONS: Expression of SSTRs and activation of mTOR pathway in paediatric glioneuronal tumour suggest that somatostatin analogues and mTOR inhibitors may have potential therapeutic implications in a subset of inoperable childhood glioneuronal tumours causing medically refractory epilepsy and/or tumour growth. Further clinical studies are warranted to validate these findings.

Clinical characteristics, long-term complications and health-related quality of life (HRQoL) in children and young adults treated for low-grade astrocytoma in the posterior fossa in childhood.

INTRODUCTION: Pilocytic astrocytoma is the most common brain tumour in childhood but knowledge concerning its long-term outcome is sparse. The aim of the study was to investigate if children treated for low-grade pilocytic astrocytoma in the posterior fossa had complications affecting physical and psychological health, cognitive functions, learning difficulties and HRQoL. METHODS: A descriptive single-centre study, where 22 children and young adults out of 27 eligible patients (81%) treated for pilocytic astrocytoma, with a mean follow-up time of 12.4 years (5-19 years) participated (14 adults, two by telephone interviews and eight children). The study included a review of medical records, an interview, neurological investigation, screening tools for psychiatric symptoms (Beck Depression and Anxiety Inventories and Beck Youth Inventory Scales) and HRQoL measures (RAND-36). RESULTS: Motor complications were most common, reported in 12 patients and mainly affecting fine-motor skills. Seven patients reported cognitive difficulties affecting performance in school. Educational support was given in the period immediately after treatment but not after primary school. None had elevated levels of psychiatric symptoms and the level of HRQoL as well as their psychosocial and educational situation was in correspondence with Swedish norms. The HRQoL score for vitality (VT) almost reached statistical significance. CONCLUSIONS: The long-term functional outcome for children treated for low-grade astrocytoma is favourable. However, some patients report neurological complications and learning difficulties, which are unmet in school. Therefore, there is a need to identify those who need more thorough medical and cognitive follow-up programmes including interventions in school.

Cognition, health-related quality of life, and mood in children and young adults diagnosed with a glioneuronal tumor in childhood.

AIMS: The aim of this study was to investigate long-term cognitive outcome, health-related quality of life (HRQoL), and psychiatric symptoms in children and young adults diagnosed with a glioneuronal tumor in childhood. METHODS: Twenty-eight children and adolescents (0-17.99years) with a minimum postoperative follow-up time of five years were eligible for the study; four persons declined participation. A cross-sectional long-term follow-up evaluation was performed using the following study measures: Wechsler Intelligence Scale for Children (WISC-IV) or Wechsler Adult Intelligence Scale (WAIS-IV), Reys Complex Figure Test (RCFT), Short Form 36 version 2 (SF-36v2), Short Form 10 (SF-10), Quality of Life in Epilepsy 31 (QOLIE-31), Hospital Anxiety Depression Scale (HADS) or Beck Youth Inventory Scales (BYI), and Rosenberg Self-Esteem Scale. Historical WISC-III and RCFT data were used to compare cognitive longitudinal data. RESULTS: Mean follow-up time after surgery was 12.1years. Sixty-three percent (15/24) were seizure-free. Despite a successive postoperative gain in cognitive function, a significant reduction relative to norms was seen in the seizure-free group with respect to perceptual reasoning index (PRI), working memory index (WMI), and full-scale intelligence quotient (FSIQ). Seizure freedom resulted in acceptable HRQoL. Thirty-two percent and 16% exceeded the threshold level of possible anxiety and depression, respectively, despite seizure freedom. CONCLUSION: Although lower than in corresponding reference groups, cognitive outcome and HRQoL are good provided that seizure freedom or at least a low seizure severity can be achieved. There is a risk of elevated levels of psychiatric symptoms. Long-term clinical follow-up is advisable.

Cerebral Palsy in Extremely Preterm Infants.

BACKGROUND AND OBJECTIVES: The risk of cerebral palsy (CP) is high in preterm infants and is often accompanied by additional neurodevelopmental comorbidities. The present study describes lifetime prevalence of CP in a population-based prospective cohort of children born extremely preterm, including the type and severity of CP and other comorbidities (ie, developmental delay and/or cognitive impairment, neurobehavioral morbidity, epilepsy, vision and hearing impairments), and overall severity of disability. In this study, we also evaluate whether age at assessment, overall severity of disability, and available sources of information influence outcome results. METHODS: All Swedish children born before 27 weeks' gestation from 2004 to 2007 were included (the Extremely Preterm Infants in Sweden Study). The combination of neonatal information, information from clinical examinations and neuropsychological assessments at 2.5 and 6.5 years of age, original medical chart reviews, and extended chart reviews was used. RESULTS: The outcome was identified in 467 (94.5%) of eligible children alive at 1 year of age. Forty-nine (10.5%) children had a lifetime diagnosis of CP, and 37 (76%) were ambulatory. Fourteen (29%) had CP diagnosed after 2.5 years of age, 37 (76%) had at least 1 additional comorbidity, and 27 (55%) had severe disability. The probability for an incomplete evaluation was higher in children with CP compared with children without CP. CONCLUSIONS: Children born extremely preterm with CP have various comorbidities and often overall severe disability. The importance of long-term follow-up and of obtaining comprehensive outcome information from several sources in children with disabilities is shown.

The Structured Observation of Motor Performance in Infants can detect cerebral palsy early in neonatal intensive care recipients.

BACKGROUND: The detection of motor problems in infancy requires a detailed assessment method that measures both the infants' level of motor development and movement quality. AIMS: To evaluate the ability of the Structured Observation of Motor Performance in Infants (SOMP-I) to detect cerebral palsy (CP) in neonatal intensive care recipients. STUDY DESIGN: Prospective cohort study analyzed retrospectively. SUBJECTS: 212 (girls: 96) neonatal intensive care recipients (mean gestational age 34weeks, range: 23-43). Twenty infants were diagnosed with CP. OUTCOME MEASURES: The infants were assessed using SOMP-I at 2, 4, 6 and 10months' corrected age. Accuracy measures were calculated for level of motor development, quality of motor performance and a combination of the two to detect CP at single and repeated assessments. RESULTS: At 2months, 17 of 20 infants with CP were detected, giving a sensitivity of 85% (95% CI 62-97%) and a specificity of 48% (95% CI 40-55%), while the negative likelihood ratio was 0.3 (95% CI 0.1-0.9) and the positive likelihood ratio was 1.6 (95% CI 1.3-2.0). At 6months all infants with CP were detected using SOMP-I, and all infants had repeatedly been assessed outside the cut-offs. Specificity was generally lower for all assessment ages, however, for repeated assessments sensitivity reached 90% (95% CI 68-99%) and specificity 85% (95% CI 79-90%). CONCLUSIONS: SOMP-I is sensitive for detecting CP early, but using the chosen cut-off can lead to false positives for CP. Assessing level and quality in combination and at repeated assessments improved predictive ability.

Glioneuronal tumors in childhood - Before and after surgery. A long-term follow-up study.

AIM: To give a detailed description of the long-term outcome of a cohort of children with glioneuronal tumors regarding pre- and postsurgical factors, including "dual" and "double" pathology, seizure freedom, and psychosocial outcome. METHODS: During a fifteen-year period (1995-2009), all patients (age 0-17.99years) with a glioneuronal brain tumor diagnosed and treated at Uppsala University Children's Hospital were identified from the National Brain Tumor Registry and the National Epilepsy Surgery Registry. Hospital medical records were reviewed and neuroradiological and neuropathological findings were re-evaluated. A cross-sectional long-term follow-up prospective evaluation, including an interview, neurologic examination, and electroencephalogram, was accomplished in patients accepting participants in the study. RESULTS: A total of 25 out of 28 (89%) eligible patients were included. The M:F ratio was 1.5:1. Mean follow-up time after surgery was 12.1years (range 5.0-19.3). Twenty patients were adults (>18years) at follow-up. Seizure freedom was achieved in 64%. Gross total resection (GTR) was the only preoperative factor significantly correlating to seizure freedom (p=0.027). Thirty-eight percent were at some time postoperatively admitted for a psychiatric evaluation. There was a trend towards both higher educational level and employment status in adults who became seizure free. CONCLUSION: Long-term outcome is good regarding seizure freedom if GTR can be achieved, but late seizure recurrence can occur. "Dual" and "double" pathology is uncommon and does not influence seizure outcome. Obtaining seizure freedom seems to be important for psychosocial outcome, but there is a risk for psychiatric comorbidities and long-term follow-up by a multi-professional team is advisable.

Neurodevelopmental Outcomes Among Extremely Preterm Infants 6.5 Years After Active Perinatal Care in Sweden.

IMPORTANCE: Active perinatal care increases the rate of survival of extremely preterm infants, but there are concerns that improved survival might increase the rate of disabled survivors. OBJECTIVE: To determine the neurodevelopmental outcomes of a national cohort of children 6.5 years of age who had been born extremely preterm (<27 weeks' gestational age) in Sweden. DESIGN, SETTING, AND PARTICIPANTS: Population-based prospective cohort study of consecutively born extremely preterm infants. All of these infants were born in Sweden during the period from April 1, 2004, to March 31, 2007. Of 707 live-born extremely preterm infants, 486 (68.7%) survived to 6.5 years of age. These children were assessed and compared with matched controls who had been born at term. Comparison estimates were adjusted for demographic differences. Assessments ended in February 2014, and analysis started thereafter. MAIN OUTCOMES AND MEASURES: Cognitive ability was measured with the fourth edition of the Wechsler Intelligence Scale for Children (WISC-IV), and the mean (SD) scores of the children who had been born extremely preterm were compared with those of the controls. Clinical examinations and parental questionnaires were used for diagnosis of cerebral palsy, hearing and vision impairments, and cognition for the children who were not assessed with the WISC-IV. RESULTS: Of 486 eligible infants who were born extremely preterm, 441 (90.7%) were assessed at 6.5 years of age (59 by medical record review only) alongside 371 controls. The adjusted mean (SD) full-scale WISC-IV score was 14.2 (95% CI, 12.1-16.3) points lower for children who had been born extremely preterm than for controls. Cognitive disability was moderate for 18.8% of extremely preterm children and 2.2% of controls (P < .001), and it was severe for 11.1% of extremely preterm children and 0.3% of controls (P < .001). Cerebral palsy was observed in 9.5% of extremely preterm children and 0.0% of controls (P < .001), blindness was observed in 2.0% of extremely preterm children and 0.0% of controls (P < .001), and hearing impairment was observed in 2.1% of extremely preterm children and 0.5% of controls (P = .07). Overall, 36.1% (95% CI, 31.7%-40.6%) of extremely preterm children had no disability, 30.4% (95% CI 26.3%-34.8%) had mild disability, 20.2% (95% CI, 16.6%-24.2%) had moderate disability, and 13.4% (95% CI, 10.5%-16.9%) had severe disability. For extremely preterm children, moderate or severe overall disability decreased with gestational age at birth (adjusted odds ratio per week, 0.65 [95% CI, 0.54-0.79]; P < .001) and increased from 26.6% to 33.5% (P = .01) for children assessed both at 2.5 and 6.5 years. CONCLUSIONS AND RELEVANCE: Of the 441 extremely preterm infants who had received active perinatal care, 293 (66.4%) had no or mild disability at 6.5 years; of the 371 controls, 11 (3.0%) had moderate or severe disability. Disability rates at 6.5 years increased relative to the rates at 2.5 years. Results are relevant for health care professionals and planners, and for clinicians counseling families facing extremely preterm births.

Clinical characteristics and late effects in CNS tumours of childhood: Do not forget long term follow-up of the low grade tumours.

AIM: To investigate clinical characteristics and late effects of CNS tumours in childhood with a special focus on low-grade tumours, especially low-grade astrocytoma and glioneuronal tumours. METHODS: A retrospective population based study was performed at Uppsala University Children's Hospital, a tertiary referral centre for children with CNS tumours. Patients were identified from the National Brain Tumour Registry and the National Epilepsy Surgery Registry. Hospital medical records were analysed for patients with a follow up of ≥5 years after diagnosis. A re-evaluation of the neuro-pathological diagnosis was performed. RESULTS: A total of 193 patients (age 0-17.99 years) during a twelve-year period (1995-2006) were included; 149 survived ≥5 years. Three larger subgroups could be identified: astrocytic, embryonal and glioneuronal tumours. A supratentorial location was found in 52%. Medical late effects were mainly neurological and endocrinological, affecting 81% and 26% of surviving patients. Cognitive late effects were a frequent finding in the whole group but also in low-grade astrocytoma and glioneuronal tumours (53% and 67%). Thirty per cent had some kind of pedagogic support in school. CONCLUSION: Late effects are common in long-term survivors of CNS tumours in childhood. Low-grade astrocytoma and glioneuronal tumours are no exception, and the findings support the need for long-term follow up.

Neurodevelopmental outcome in extremely preterm infants at 2.5 years after active perinatal care in Sweden.

IMPORTANCE: Active perinatal care increases survival of extremely preterm infants; however, improved survival might be associated with increased disability among survivors. OBJECTIVE: To determine neurodevelopmental outcome in extremely preterm children at 2.5 years (corrected age). DESIGN, SETTING, AND PARTICIPANTS: Population-based prospective cohort of consecutive extremely preterm infants born before 27 weeks of gestation in Sweden between 2004 and 2007. Of 707 live-born infants, 491 (69%) survived to 2.5 years. Survivors were assessed and compared with singleton control infants who were born at term and matched by sex, ethnicity, and municipality. Assessments ended in February 2010 and comparison estimates were adjusted for demographic differences. MAIN OUTCOMES AND MEASURES: Cognitive, language, and motor development was assessed with Bayley Scales of Infant and Toddler Development (3rd edition; Bayley-lll), which are standardized to mean (SD) scores of 100 (15). Clinical examination and parental questionnaires were used for diagnosis of cerebral palsy and visual and hearing impairments. Assessments were made by week of gestational age. RESULTS: At a median age of 30.5 months (corrected), 456 of 491 (94%) extremely preterm children were evaluated (41 by chart review only). For controls, 701 had information on health status and 366 had Bayley-lll assessments. Mean (SD) composite Bayley-III scores (cognition, 94 [12.3]; language, 98 [16.5]; motor, 94 [15.9]) were lower than the corresponding mean scores for controls (cognition, 104 [10.6]; P < .001; adjusted difference in mean scores, 9.2 [99% CI, 6.9-11.5]; language, 109 [12.3]; P < .001; adjusted difference in mean scores, 9.3 [99% Cl, 6.4-12.3]; and motor, 107 [13.7]; P < .001; adjusted difference in mean scores, 12.6 [99% Cl, 9.5-15.6]). Cognitive disability was moderate in 5% of the extremely preterm group vs 0.3% in controls (P < .001) and it was severe in 6.3% of the extremely preterm group vs 0.3% in controls (P < .001). Language disability was moderate in 9.4% of the extremely preterm group vs 2.5% in controls (P < .001) and severe in 6.6% of the extremely preterm group vs 0% in controls (P < .001). Other comparisons between the extremely preterm group vs controls were for cerebral palsy (7.0% vs 0.1%; P < .001), for blindness (0.9% vs 0%; P = .02), and for hearing impairment (moderate and severe, 0.9% vs 0%; P = .02, respectively). Overall, 42% (99% CI, 36%-48%) of extremely preterm children had no disability, 31% (99% CI, 25%-36%) had mild disability, 16% (99% CI, 12%-21%) had moderate disability, and 11% (99% CI, 7.2%-15%) had severe disability. Moderate or severe overall disability decreased with gestational age at birth (22 weeks, 60%; 23 weeks, 51%; 24 weeks, 34%; 25 weeks, 27%; and 26 weeks, 17%; P for trend < .001). CONCLUSIONS AND RELEVANCE: Of children born extremely preterm and receiving active perinatal care, 73% had mild or no disability and neurodevelopmental outcome improved with each week of gestational age. These results are relevant for clinicians counseling families facing extremely preterm birth.

Prenatal characteristics of infants with a neuronal migration disorder: a national-based study.

The development of the central nervous system is complex and includes dorsal and ventral induction, neuronal proliferation, and neuronal migration, organization, and myelination. Migration occurs in humans in early fetal life. Pathogenesis of malformations of the central nervous system includes both genetic and environmental factors. Few epidemiological studies have addressed the impact of prenatal exposures. All infants born alive and included in the Swedish Medical Birth Register 1980-1999 were included in the study. By linkage to the Patient Register, 820 children with a diagnosis related to a neuronal migration abnormality were identified. Through copies of referrals for computer tomography or magnetic resonance imaging of the brain, the diagnosis was confirmed in 17 children. Median age of the mothers was 29 years. At the start of pregnancy, four out of 17 women smoked. Almost half of the women had a body mass index that is low or in the lower range of average. All infants were born at term with normal birth weights. Thirteen infants had one or more concomitant diseases or malformations. Two infants were born with rubella syndrome. The impact of low maternal body mass index and congenital infections on neuronal migration disorders in infants should be addressed in future studies.

Novel amplifications in pediatric medulloblastoma identified by genome-wide copy number profiling.

Medulloblastoma (MB) is a WHO grade IV, invasive embryonal CNS tumor that mainly affects children. The aggressiveness and response to therapy can vary considerably between cases, and despite treatment, ~30% of patients die within 2 years from diagnosis. Furthermore, the majority of survivors suffer long-term side-effects due to severe management modalities. Several distinct morphological features have been associated with differences in biological behavior, but improved molecular-based criteria that better reflect the underlying tumor biology are in great demand. In this study, we profiled a series of 25 MB with a 32K BAC array covering 99% of the current assembly of the human genome for the identification of genetic copy number alterations possibly important in MB. Previously known aberrations as well as several novel focally amplified loci could be identified. As expected, the most frequently observed alteration was the combination of 17p loss and 17q gain, which was detected in both high- and standard-risk patients. We also defined minimal overlapping regions of aberrations, including 16 regions of gain and 18 regions of loss in various chromosomes. A few noteworthy narrow amplified loci were identified on autosomes 1 (38.89-41.97 and 84.89-90.76 Mb), 3 (27.64-28.20 and 35.80-43.50 Mb), and 8 (119.66-139.79 Mb), aberrations that were verified with an alternative platform (Illumina 610Q chips). Gene expression levels were also established for these samples using Affymetrix U133Plus2.0 arrays. Several interesting genes encompassed within the amplified regions and presenting with transcript upregulation were identified. These data contribute to the characterization of this malignant childhood brain tumor and confirm its genetic heterogeneity.

Development of smooth pursuit eye movements in very preterm infants: 1. General aspects.

AIM: To investigate early oculo-motor development in a population-based cohort of very preterm infants. METHODS: Early oculo-motor development was prospectively studied by measuring smooth pursuit eye movements at 2 and 4 months corrected age in a population of very preterm infants born in Uppsala County 2004-2007. Eighty-one preterm infants were studied, and 32 healthy term infants constituted the control group. RESULTS: The study group consisted of infants with a mean gestational age of 28 + 5 weeks. At 2 and 4 months corrected age, infants born very preterm showed lower gain (p < 0.001) and proportion of smooth pursuit eye movements (p < 0.001) compared to the control group. The boys showed higher gain of smooth pursuit eye movements at both 2 and 4 months corrected age, compared to girls. CONCLUSIONS: Oculo-motor development measured by smooth pursuit eye movements is delayed in very preterm infants at 2 and 4 months corrected age. This might be a risk factor or early indicator of later perceptual and behavioural impairment.

Prenatal exposure to medicines and the risk of childhood brain tumor.

BACKGROUND: Childhood brain tumors are associated with high mortality and morbidity but little is known about its causes. About half of women use medicines when pregnant and some of the medicines commonly used might be carcinogenic. OBJECTIVE: The aim with this population-based case-control study was to analyze associations between specific groups of medicines taken during pregnancy and the risk of brain tumor in the offspring. METHODS: All children, up to 15 years of age, born in Sweden between 1975 and 1984 were eligible for the study. Cases (N=512) were children diagnosed with brain tumor and controls (N=525) were randomly selected from the Medical Birth Register. Exposure data on medicines was extracted blindly from antenatal medical records and grouped according to Anatomical Therapeutic Chemical (ATC) code. Information on maternal reproductive history was received from the Medical Birth Register. We used logistic regression to estimate associations between fetal exposure to medicines and childhood brain tumor. RESULTS: No significant changes in risk were noted after exposure to iron supplementation, antiemetics, analgesics, antibiotics or any other main ATC group. A tendency of protective effect was seen for prenatal exposure to folic acid (adjusted OR 0.6, 95% CI 0.3-1.1). Ten children with a diagnosis of brain tumor had been exposed to beta-blocking agents in fetal life as compared to two children without brain tumor (adjusted OR 5.3, 95% CI 1.2-24.8). CONCLUSIONS: In this case-control study, an increased risk of brain tumor was seen in children exposed to beta-blocking agents during fetal life. However, due to the low number of exposed the interpretation of this finding should be made with caution.

Classification, incidence and survival analyses of children with CNS tumours diagnosed in Sweden 1984-2005.

AIM: Primary tumours in the central nervous system (CNS) are the second most common malignancy in childhood after leukaemia. Sweden has a high incidence and a high-survival rate in international comparative studies. This has raised the question about the type of tumours included in the Swedish Cancer registry. We therefore compared international data to the Swedish Childhood Cancer registry. METHODS: Central nervous system tumours registered in the Swedish Childhood Cancer Registry were reclassified according to ICCC-3. Incidence and survival analyses were performed in the study population. RESULTS: There were 1479 children (<15 years) in Sweden diagnosed with CNS tumours 1984-2005. The distribution of diagnoses was similar to that reported in other studies. The annual incidence was 4.2/100,000 children. The survival rates have not improved significantly between the two time periods before/after 1995 (70% vs. 74%; p = 0.10). CONCLUSIONS: The mean annual incidence of children with CNS tumours was 4.2/100,000 and has not increased during the study period. Survival rate for brain tumours at 10 years follow-up was 72%.

A severe form of Noonan syndrome and autosomal dominant café-au-lait spots - evidence for different genetic origins.

AIM: The clinical overlap among Noonan syndrome (NS), cardio-facio-cutaneous (CFC), LEOPARD and Costello syndromes as well as Neurofibromatosis type 1 is extensive, which complicates the process of diagnosis. Further genotype-phenotype correlations are required to facilitate future diagnosis of these patients. Therefore, investigations of the genetic cause of a severe phenotype in a patient with NS and the presence of multiple café-au-lait spots (CAL) spots in the patient and four members of the family were performed. METHODS: Mutation analyses of candidate genes, PTPN11, NF1, SPRED1 and SPRED2, associated with these syndromes, were conducted using DNA sequencing. RESULTS: A previously identified de novo mutation, PTPN11 F285L and an inherited NF1 R1809C substitution in the index patient were found. However, neither PTPN11 F285L, NF1 R1809C, SPRED1 nor SPRED2 segregated with CAL spots in the family. The results indicate that the familial CAL spots trait in this family is caused by a mutation in another gene, distinct from previous genes associated with CAL spots in these syndromes. CONCLUSION: We suggest that the atypical severe symptoms in the index patient may be caused by an additive effect on the F285L mutation in PTPN11 by another mutation, for example the NF1 R1809C or alternatively, the not yet identified gene mutation associated with CAL spots in this family.

Tetrahydrobiopterin in the treatment of children with autistic disorder: a double-blind placebo-controlled crossover study.

Twelve children, all boys, aged 4 to 7 years, with a diagnosis of autistic disorder and low concentrations of spinal 6R-l-erythro-5,6,7,8-tetrahydrobiopterin (tetrahydrobiopterin) were selected to participate in a double-blind, randomized, placebo-controlled, crossover study. The children received a daily dose of 3 mg tetrahydrobiopterin per kilogram during 6 months alternating with placebo. Treatment-induced effects were assessed with the Childhood Autism Rating Scale every third month. The results showed small nonsignificant changes in the total scores of Childhood Autism Rating Scale after 3- and 6-month treatment. Post hoc analysis looking at the 3 core symptoms of autism, that is, social interaction, communication, and stereotyped behaviors, revealed a significant improvement of the social interaction score after 6 months of active treatment. In addition, a high positive correlation was found between response of the social interaction score and IQ. The results indicate a possible effect of tetrahydrobiopterin treatment.

A patient with type 2 Gaucher's disease with respiratory disease.

A 5-month-old boy had respiratory problems and gastroesophageal reflux. Electron microscopy of a tracheal biopsy specimen showed accumulation of lamellar bodies in the columnar cells indicative of lysosomal storage disease. Subsequently, the child had neurologic symptoms and hepatosplenomegaly, and the diagnosis of Gaucher's disease type 2 was made.