Neurologic disorders in long-term survivors of neuroblastoma - a population-based cohort study within the Adult Life after Childhood Cancer in Scandinavia (ALiCCS) research program.

Background: Neuroblastoma is the commonest extracranial solid tumor of childhood, yet rare, and with poor survival before 1990, especially for high-risk disease; thus, information on late effects is sparse. With great advances in cancer treatment, survival has reached 80% in the Nordic countries. The aim of the study was to investigate the risk of developing neurologic disorders after neuroblastoma.Material and methods: Through population-based cancer registries of four Nordic countries we identified 654 5-year survivors of neuroblastoma (diagnosed 1959-2008) and 133,668 matched population comparisons. We grouped neurologic diagnoses from national hospital registries into 11 main diagnostic categories and 56 disease-specific sub-categories and calculated relative risks (RRs), absolute excess risks (AERs), cumulative incidence and mean cumulative count (MCC). Information on cancer treatment was available for 49% of survivors.Results: A hospital contact for a neurologic disorder was observed in 181 survivors 5 years or more from cancer diagnosis with 59 expected, yielding a RR of 3.1 (95% CI 2.7-3.6) and an AER of 16 per 1,000 person-years (95% CI 12-19). The most frequent disorders included epilepsy, paralytic syndromes, diseases of the eyes and ears and hearing loss. The cumulative incidence of any neurologic disorder was 31% in survivors 20 years after cancer diagnosis with a MCC of 0.5 unique diagnoses. All risks were highest in survivors of high-risk neuroblastoma.Conclusion: Neuroblastoma survivors represent a population with a high risk of developing neurologic disorders. Our results should contribute to improving health care planning and underscores the need for systematic follow-up care of this vulnerable group of survivors.

Neurologic disorders in 4858 survivors of central nervous system tumors in childhood-an Adult Life after Childhood Cancer in Scandinavia (ALiCCS) study.

Background: A comprehensive overview of neurologic complications among survivors of central nervous system (CNS) tumors in childhood is lacking. We aimed to investigate the risk for these disorders in a large, population-based study with outcome measures from nationwide hospital registries. Methods: We identified 4858 five-year survivors with diagnoses of CNS tumor in childhood in Denmark, Iceland, Finland, and Sweden in 1943-2007, and 166658 matched population comparison subjects. Inpatient discharge diagnoses of neurologic disorders were used to calculate relative risks (RRs) and absolute excess risks (AERs). Results: A neurologic disorder was verified in 1309 survivors, while 92.4 were expected, yielding an overall RR of 14.2 (95% confidence interval [CI]: 13.3-15.1) and an AER of 20 hospitalizations per 1000 persons per year. The risks remained increased more than 20 years after diagnosis (RR: 6.3, 95% CI: 5.6-7.2; AER: 11, 9-12). The most frequent diagnoses were epilepsy (affecting 14.1% of all survivors) followed by hydrocephalus (9.5%) and paralytic syndromes (4.2%), with RRs of 28.7 (95% CI: 26.0-31.6), 243 (95% CI: 190-311), and 40.3 (95% CI: 33.1-49.2), respectively. Of these outcomes, 30%-40% were diagnosed prior to or synchronously with the CNS tumor. The survivors had highly increased RRs for infectious diseases of the CNS, disorders of cranial nerves, and degenerative diseases of the nervous system. Conclusions: Survivors of childhood CNS tumors are at markedly increased risk for neurologic disorders throughout their lives. Health care professionals must be aware of survivors who might benefit from preventive interventions and intensive follow-up.

Development of hypomelanotic macules is associated with constitutive activated mTORC1 in tuberous sclerosis complex.

TSC1 and TSC2 are genes mutated in the syndrome TSC (tuberous sclerosis complex). We describe a 3-generation family with 17 affected members, all presenting classic TSC features except renal manifestations. The disease segregates with a silent substitution in TSC2, c.4149C>T, p.(Ser1383Ser), which leads to the formation of an active donor splice site, resulting in three shorter alternatively spliced transcripts with premature stop codons. However a small amount of normal spliced transcript is apparently produced from the mutated allele, which might explain the milder phenotype. The gene products of TSC1/2 form a complex which at energy limiting states, down-regulates the activity of the regulator of protein synthesis, the mammalian target of rapamycin complex1 (mTORC1). As expected, in contrast to cultured control fibroblasts, starvation of cultured patient fibroblasts obtained from a hypomelanotic macule did not lead to repression of mTORC1, whereas partial repression was observed in patient fibroblasts obtained from non-lesional skin. The findings indicate that the development of hypomelanotic macules is associated with constitutive activated mTORC1, whereas mild deregulation of mTORC1 allows the maintenance of normal skin. Furthermore, the finding establishes the pathogenic effect of the "silent" c.4149C>T substitution and emphasizes the need for awareness when interpreting silent substitutions in general.

Is maternal smoking during pregnancy a risk factor for hyperkinetic disorder?--Findings from a sibling design.

BACKGROUND: Studies have consistently shown that pregnancy smoking is associated with twice the risk of hyperactivity/inattention problems in the offspring. An association of this magnitude may indicate behavioural difficulties as one of the most important health effects related to smoking during pregnancy. However, social and genetic confounders may fully or partially account for these findings. METHODS: A cohort including all singletons born in Finland from 1 January 1987 through 31 December 2001 was followed until 1 January 2006 based on linkage of national registers. Data were available for 97% (N = 868,449) of the population. We followed singleton children of smoking and non-smoking mothers until they had an International Classification of Diseases, 10th revision, diagnosis of hyperkinetic disorder (HKD) or to the end of the observation period. We used sibling-matched Cox regression analyses to control for social and genetic confounding. RESULTS: We found a much smaller association between exposure to maternal smoking during pregnancy and risk of HKD in children using the sibling-matched analysis [hazards ratio (HR) = 1.20, 95% confidence interval (CI) 0.97-1.49] than was observed in the entire cohort (HR 2.01, 95% CI 1.90-2.12). CONCLUSIONS: Our findings suggest that the strong association found in previous studies may be due to time-stable familial factors, such as environmental and genetic factors. If smoking is a causal factor, the effect is small and less important than what the previous studies indicate.

Smoking during pregnancy and hyperactivity-inattention in the offspring--comparing results from three Nordic cohorts.

BACKGROUND: Prenatal exposure to smoking has been associated with Attention Deficit Hyperactivity Disorder (ADHD) in a number of epidemiological studies. However, mothers with the ADHD phenotype may 'treat' their problem by smoking and therefore be more likely to smoke even in a society where smoking is not acceptable. This will cause genetic confounding if ADHD has a heritable component, especially in populations with low prevalence rates of smoking since this reason for smoking is expected to be proportionally more frequent in a population with few 'normal' smokers. We compared the association in cohorts with different smoking frequencies. METHODS: A total of 20 936 women with singleton pregnancies were identified within three population-based pregnancy cohorts in Northern Finland (1985-1986) and in Denmark (1984-1987 and 1989-1991). We collected self-reported data on their pre-pregnancy and pregnancy smoking habits and followed the children to school age where teachers and parents rated hyperactivity and inattention symptoms. RESULTS: Children, whose mothers smoked during pregnancy, had an increased prevalence of a high hyperactivity-inattention score compared with children of nonsmokers in each of the cohorts after adjustment for confounders but we found no statistical significant difference between the associations across the cohorts. CONCLUSION: The estimated association was not strongest in the population with the fewest smokers which does not support the hypothesis that the association is entirely due to genetic confounding.

Smoking during pregnancy and the risk for hyperkinetic disorder in offspring.

OBJECTIVE: Maternal smoking during pregnancy may increase the risk for behavioral disorders. The aim of this study was to investigate the association between smoking during pregnancy and hyperkinetic and attention-deficit/hyperactivity disorder in the offspring in a large population-based study. METHODS: This study was designed as a nested case-control study. Data were obtained from Danish longitudinal registers and included 170 children with hyperkinetic disorder and 3765 population-based control subjects, who were matched by age, gender, and date of birth. Potential confounders, including newborn characteristics, socioeconomic status, and family history of psychiatric illnesses, were evaluated by conditional logistic regression analyses. RESULTS: Women who smoked during pregnancy had a 3-fold increased risk for having offspring with hyperkinetic disorder compared with nonsmokers. Socioeconomic factors and history of mental disorder in the parents or siblings seemed to confound the result to some extent (adjusted relative risk: 1.9; 95% confidence interval: 1.3-2.8). Adjustment for parental age or exclusion of children with low birth weight (<2500 g), preterm delivery (<37 weeks completed gestation), and Apgar scores <7 at 5 minutes revealed no changes in the results. Also, excluding children with conduct disorders or comorbid disorders revealed no change in the results. CONCLUSIONS: Our results showed an increased risk for hyperkinetic disorder in children of mothers who smoked during pregnancy. This could not be explained by newborn characteristics, parental socioeconomic status, family history of psychiatric hospitalizations or contact as outpatients, conduct disorders, or comorbidity.

Maternal lifestyle factors in pregnancy risk of attention deficit hyperactivity disorder and associated behaviors: review of the current evidence.

OBJECTIVE: The purpose of this review was to examine the literature assessing the relationship between prenatal exposure to nicotine, alcohol, caffeine, and psychosocial stress during pregnancy to the risk of developing behavioral problems related to attention deficit hyperactivity disorder (ADHD) in childhood. METHOD: PubMed, MEDLINE, EMBASE, and PsycINFO were searched systematically. Studies using DSM diagnostic criteria and other validated diagnostic or screening instruments for ADHD and those examining ADHD symptoms were included. A narrative approach was used because the studies differed too much in methods and data sources to permit a quantitative meta-analysis. RESULTS: Twenty-four studies on nicotine (tobacco smoking), nine on alcohol, one on caffeine, and five on psychosocial stress were identified. All were published between 1973 and 2002. In spite of inconsistencies, the studies on nicotine indicated a greater risk of ADHD-related disorders among children whose mothers smoked during pregnancy. Contradictory findings were reported in the alcohol studies, and no conclusion could be reached on the basis of the caffeine study. Results from studies on psychological stress during pregnancy were inconsistent but indicated a possible modest contribution to ADHD symptoms in the offspring. Many studies suffered from methodological shortcomings, such as recall bias, crude or inaccurate exposure assessments, low statistical power, and lack of or insufficient control of confounders. A general lack of information on familial psychopathology also limited the interpretations. CONCLUSIONS: Exposure to tobacco smoke in utero is suspected to be associated with ADHD and ADHD symptoms in children. Other maternal lifestyle factors during pregnancy may also be associated with these disorders. Further studies are needed to reach conclusions.