Introduction: A trial of melatonin treatment in children with septo-optic dysplasia (SOD) and sleep disruption is accepted clinical practice in many centers. However, no objective measurements of sleep/activity patterns with 24-h melatonin profiles have been published for these individuals, and the pathophysiological basis underlying sleep disorders in SOD remains largely unknown.Methods: We studied six children with rest-activity disturbances and SOD. All wore an Actiwatch-Mini (a noninvasive method of detecting and recording movement intensity) for 2 wk and were admitted to hospital for a 24-h period during which hourly measurements of serum melatonin were taken. Sleep data were analyzed in conjunction with a detailed sleep diary. Ethical approval was obtained for these studies.Results: Two children produced virtually no melatonin throughout the 24-h period of measurement and had fragmented sleep patterns with no evidence of a non-24-h sleep-wake disorder or delayed sleep-phase disorder. One child had a normal melatonin profile despite actigraphy showing an arrhythmic sleep pattern. The remaining three children had fragmented sleep, with two having normal melatonin profiles and one having a modest increase in daytime melatonin concentrations, making the timing of dim-light melatonin onset difficult to discern.Conclusions: There is considerable variation in timing and amount of melatonin secretion in these children. Surprisingly, none of the children had either actigraphic or melatonin profile evidence of a non-24-h sleep-wake disorder or delayed sleep-phase disorder. Understanding the heterogeneous nature of underlying sleep disorders in this group of children is important and has implications for their management. (J Clin Endocrinol Metab 95: E198-E203, 2010)

Introduction: While growth hormone (GH) plays an important role in normal brain development, its effect on brain growth and cognition in GH deficient individuals continues to be debated. We have now investigated a cohort of children with isolated growth hormone deficiency (IGHD) using cognitive and motor skills assessment, volumetric MRI and diffusion tensor imaging (DTI) and compared the findings with those in a cohort of children with idiopathic short stature (ISS). Methods: All children underwent a psychological assessment including the Weschler Intelligence Scale for Children (Fourth edition and the Movement ABC (M-ABC) test. DTI was performed on a Siemens Avanto 1.5 Tesla MRI scanner. Following the acquisition of a T1-weighted volume scan 20 diffusion-sensitised directions were acquired with a b value of 1000 s mm, this protocol was repeated 3 times. Correction for eddy current induced distortions, brain extraction, and calculation of diffusion tensor fractional anisotropy (FA) and mean diffusivity (MD) values was carried out using FSL tools (http://www.fmrib.ox.ac.uk/fsl). Analysis of the cognitive data showed that children with IGHD had significantly lower VIQ and M-ABC scores than controls. Corticospinal tract FA has previously been shown to correlate with motor impairment in individuals with chronic stroke and brain injury, and the basal ganglia have also been shown to play an important role in motor skills performance. We therefore performed corticospinal tract tractography using a probabilistic neighbourhood tractography (NT) approach (1) and acquired volumes for the basal ganglia from the 3-D datasets using the technique of Fischl et al (2). Brain volumes were compared using ANCOVA, controlling for age at scan, total brain volume (TBV) and sex. Partial correlation was used to assess the relationship between neural volumes and FA of the corticospinal tract to FSIQ, PIQ, VIQ and scores on the MABC (controlled for age at scan, sex and TBV). Results: Fifteen children (mean 8.6yrs) with IGHD, and 12 (mean 8.5yrs) with ISS were studied. When compared to controls, children with IGHD had lower VIQ (p<0.02) and M-ABC (p<0.02) scores. VIQ scores correlated significantly with IGF1 and IGFBP-3 standard deviation scores (p<0.03, p<0.02) in children with IGHD. Left thalamic (p<0.01) and accumbens nuclei (p<0.01), and left and right globus pallidum (L p<0.01, R p<0.007) were significantly smaller and left corticospinal tract MD significantly higher (p<0.03) in IGHD (Figure 1). IGF-1 and IGFBP-3 did not correlate significantly with FA or MD. Left corticospinal tract FA in the entire cohort correlated significantly with scores on performance IQ (p<0.007), and the aim (p<0.006), manual dexterity (p<0.02) and total (p<0.007) scores of the Movement-ABC test (Figure 2). In IGHD left corticospinal tract FA correlated significantly with M-ABC (p<0.04) and performance IQ (p<0.04) scores. Conclusions: Our data suggest an effect of IGF1 and IGFBP-3 on VIQ in IGHD. We also report, for the first time to our knowledge, the presence of white matter abnormalities in the corticospinal tract and basal ganglia abnormalities, in association with deficits in cognitive function and motor performance, in children with IGHD. These findings provide evidence that the GHIGF-1 axis plays a significant role in neural development. The neural correlates of cognitive deficits we have identified in patients with IGHD may also offer insights into the pathogenesis of the cognitive decline associated with ageing and the somatopause. Follow-up studies are now required to determine whether GH treatment can rectify some of these abnormalities in brain and cognitive functioning as this would have major implications for clinical practice.

ObjectiveTo investigate whether publication of the results of the ORACLE Children's Study, a 7-year follow-up of the ORACLE trial, changed practice with regard to the routine prescription of antibiotics to women with preterm rupture of membranes or spontaneous preterm labour (intact membranes).DesignA comparative questionnaire survey of clinical practice in November 2007 (before publication) and March 2009 (after publication).PopulationLead obstetricians for labour wards of all maternity units in the UK.MethodsSelf-administered questionnaires requested information about the routine prescription of antibiotics to women with either preterm rupture of membranes or spontaneous preterm labour (intact membranes).Main outcome measuresChange in practice for prescription of antibiotics.ResultsThe response rate was 166/214 (78%) in 2007 and 158/209 (76%) in 2009. In total, 120 maternity units responded on both occasions. For women with preterm rupture of membranes, 162/214 (98%) in 2007 and 151/158 (96%) in 2009 maternity units reported that they prescribed antibiotics, with the majority using erythromycin (98%). For women with spontaneous preterm labour (intact membranes), 35/166 (21%) in 2007 and 25/158 (16%) in 2009 maternity units reported that they routinely prescribed antibiotics. The findings from units who responded on both occasions are similar.ConclusionsThere has been little change in the reported prescription of antibiotics to women with either preterm rupture of membranes or spontaneous preterm labour following publication of the ORACLE Children's Study. This suggests that current practice may require updated guidance.

Background The ORACLE II trial compared the use of erythromycin and/or amoxicillin-clavulanate (co-amoxiclav) with that of placebo for women in spontaneous preterm labour and intact membranes, without overt signs of clinical infection, by use of a factorial randomised design. The aim of the present study-the ORACLE Children Study II-was to determine the long-term effects on children after exposure to antibiotics in this clinical situation.Methods We assessed children at age 7 years born to the 4221 women who had completed the ORACLE 11 study and who were eligible for follow-up with a structured parental questionnaire to assess the child's health status. Functional impairment was defined as the presence of any level of functional impairment (severe, moderate, or mild) derived from the mark III Multi-Attribute Health Status classification system. Educational outcomes were assessed with national curriculum test results for children resident in England.Findings Outcome was determined for 3196 (71%) eligible children. Overall, a greater proportion of children whose mothers had been prescribed erythromycin, with or without co-amoxiclav, had any functional impairment than did those whose mothers had received no erythromycin (658 [42.3%] of 1554 children vs 574 [38.3%] of 1498; odds ratio 1.18, 95% CI 1.02-1.37). Co-amoxiclav (with or without erythromycin) had no effect on the proportion of children with any functional impairment, compared with receipt of no co-amoxiclav (624 [40.7%] of 1523 vs 608 [40.0%] of 1520; 1.03, 0.89-1.19). No effects were seen with either antibiotic on the number of deaths, other medical conditions, behavioural patterns, or educational attainment. However, more children whose mothers had received erythromycin or co-amoxiclav developed cerebral palsy than did those born to mothers who received no erythromycin or no co-amoxiclav, respectively (erythromycin: 53 [3.3%] of 1611 vs 27 [1.7%] of 1562, 1.93, 1.21-3.09; co-amoxiclav: 50 [3.2%] of 1587 vs 30 [1.9%] of 1586, 1.69, 1.07-2.67). The number needed to harm with erythromycin was 64 (95% CI 37-209) and with co-amoxiclav 79 (42-591).Interpretation The prescription of erythromycin for women in spontaneous preterm labour with intact membranes was associated with an increase in functional impairment among their children at 7 years of age. The risk of cerebral palsy was increased by either antibiotic, although the overall risk of this condition was low.Funding UK Medical Research Council.

Background The ORACLE I trial compared the use of erythromycin and/or amoxicillin-clavulanate (co-amoxiclav) with that of placebo for women with preterm rupture of the membranes without overt signs of clinical infection, by use of a factorial randomised design. The aim of the present study-the ORACLE Children Study I-was to determine the long-term effects on children of these interventions.Methods We assessed children at age 7 years born to the 4148 women who had completed the ORACLE I trial and who were eligible for follow-up with a structured parental questionnaire to assess the child's health status. Functional impairment was defined as the presence of any level of functional impairment (severe, moderate, or mild) derived from the mark III Multi-Attribute Health Status classification system. Educational outcomes were assessed with national curriculum test results for children resident in England.Findings Outcome was determined for 3298 (75%) eligible children. There was no difference in the proportion of children with any functional impairment after prescription of erythromycin, with or without co-amoxiclav, compared with those born to mothers who received no erythromycin (594 [38.3%] of 1551 children vs 655 [40.4%] of 1620; odds ratio 0.91, 95% CI 0.79-1.05) or after prescription of co-amoxiclav, with or without erythromycin, compared with those born to mothers who received no co-amoxiclav (645 [40.6%] of 1587 vs 604 [38.1%] of 1584; 1.11, 0.96-1.28). Neither antibiotic had a significant effect on the overall level of behavioural difficulties experienced, on specific medical conditions, or on the proportions of children achieving each level in reading, writing, or mathematics at key stage one.Interpretation The prescription of antibiotics for women with preterm rupture of the membranes seems to have little effect on the health of children at 7 years of age.Funding UK Medical Research Council.

Background: Developmental eye anomalies, which include anophthalmia (absent eye) or microphthalmia (small eye) are an important cause of severe visual impairment in infants and young children. Heterozygous mutations in SOX2, a SOX1B-HMG box transcription factor, have been found in up to 10% of individuals with severe microphthalmia or anophthalmia and such mutations could also be associated with a range of non-ocular abnormalities. Methods: We performed mutation analysis on a new cohort of 120 patients with congenital eye abnormalities, mainly anophthalmia, microphthalmia and coloboma. Multiplex ligation-dependent probe amplification (MLPA) and fluorescence in situ hybridisation (FISH) were used to detect whole gene deletion. Results: We identified four novel intragenic SOX2 mutations (one single base deletion, one single base duplication and two point mutations generating premature translational termination codons) and two further cases with the previously reported c.70del20 mutation. Of 52 patients with severe microphthalmia or anophthalmia analysed by MLPA, 5 were found to be deleted for the whole SOX2 gene and 1 had a partial deletion. In two of these, FISH studies identified sub-microscopic deletions involving a minimum of 328 Kb and 550 Kb. The SOX2 phenotypes include a patient with anophthalmia, oesophageal abnormalities and horseshoe kidney, and a patient with a retinal dystrophy implicating SOX2 in retinal development. Conclusion: Our results provide further evidence that SOX2 haploinsufficiency is a common cause of severe developmental ocular malformations and that background genetic variation determines the varying phenotypes. Given the high incidence of whole gene deletion we recommend that all patients with severe microphthalmia or anophthalmia, including unilateral cases be screened by MLPA and FISH for SOX2 deletions.

Background Congenital visual impairment has serious consequences for early development, particularly in those with the most profound impairment. Although there is individual variation, developmental delays and risks, including 'developmental setback', are widespread. There is no scientifically robust developmental framework grounded in contemporary theory and scientific knowledge to guide early intervention which may prevent or minimize the risk factors and developmental difficulties. The UK governmental initiative, Early Support, gave the impetus for developing a new developmental framework for babies and young children with visual impairment.Methods This paper reports on the scientific literature that underpins the new framework and the limitations of existing intervention materials. The case for focusing on particular vulnerable areas and developing a new developmental framework, the Early Support Developmental Journal for babies and children with severe visual impairment, is presented.Conclusions The future direction for service delivery and evaluation is briefly described.

Marked differences are seen in neurological and health status, intellectual functioning, school performance and behaviour between children born prematurely and those born at term. Assessment in later childhood has identified more subtle problems than the severe disability or sensory deficits readily identifiable at two years. These problems include learning disabilities, specific neuropsychological deficits in executive function, difficulties in visual-motor integration and perception, selective language impairment, motor coordination disorders, behaviour problems, attention deficit hyperactivity disorder (ADHD), and reduced educational achievement. Follow-up to school entry and beyond is thus required to determine the true prevalence and nature of the neurodevelopmental problems arising from preterm birth. Consensus about the assessment used, definitions of disability and health status, age of assessment and who undertakes it are necessary and should allow comparison across populations; this may help to maximise outcomes for children clearly at biological risk. Assessment of outcome for children born preterm beyond two years is required for counselling parents, planning health and education provision, for evaluation of services and to facilitate understanding of the longer term effects of preterm birth on brain development.

AIMS:1. To determine the survival and morbidity of infants at discharge with a birthweight of less than 1500 g in the geographically defined population of East Anglia. 2. To demonstrate a cost-effective method of regional data collection. 3. To determine whether there were any changes in the demand for neonatal care. STUDY DESIGN AND SUBJECTS:A prospective cohort analysis using a single database to collect data on 1244 very low birthweight infants from eight neonatal units in one Region from 1993 to 1997. RESULTS:Estimated ascertainment of VLBW infants to the study was 96%. Over the 5 years survival rates were stable (75-79%). 52% of deaths in infants admitted for neonatal care occurred on day 1, with just 15% of deaths occurring after 28 days of life. Mortality risk significantly decreased with increasing gestational age at birth. Compared to 22-25-week old infants, the mortality risk decreased by 65% for 26-27-week old infants (OR 0.35 95% CI (0.21, 0.59)) and by 92% for 32-39-week old infants (OR 0.08 95% CI (0.03, 0.21)) with intermediate odds ratios of 0.22 (0.12, 0.42) and 0.13 (0.06, 0.28) for the 28-29 and 30-39 weeks gestation, respectively. Higher birthweight, after adjusting for gestation also decreased the mortality risk (OR 0.78 per 100 g difference, 95% CI (0.71, 0.86)). No change was seen in the number of extremely preterm infants admitted for intensive care or resource utilisation, although a significant increase was seen in the number of infants dying in delivery rooms. There was a reduction in the reported incidence of pulmonary interstitial emphysema (10-4%) but no change in the number of ventilation days or the rate of chronic lung disease. The mean maternal age increased from 27.7 years to 28.9 years during the study. Maternal steroid administration increased (30% to 59%) and was associated with a decreased risk of mortality (OR 0.44, 95% CI: 0.31-0.62). CONCLUSIONS:It is possible to collect useful data from the neonatal period at a reasonable cost from a geographically defined population. This information was used for informing clinicians, counselling parents and in the era of managed clinical networks will be useful in guiding the provision of effective health care resources.

Aim: To determine the type and rate of disability at 2 years of age in infants born in the geographically defined population of East Anglia with a birthweight less than 1500 g and to assess the risk factors for disability.Study design: A prospective cohort analysis from all eight neonatal units in East Anglia from 1993-1997 using a single database.Methods: Local paediatricians assessed children at 2 years using the Health Status Questionnaire and data collection was centrally coordinated.Results: Outcomes for 947 children, 99% of survivors, were available, 74 (7.8%) had severe disability and this was significantly associated with gestational age (p < 0.0005), birthweight (p < 0.0005) and sex (p=0.046). Major congenital abnormality contributed 27% of all severe disability. The overall cerebral palsy rate was 6.2%, nine children were blind and five had sensorineural hearing loss requiring aids. These children had a high level of use of community services with 19% of the cohort being referred to one or more community service. ELBW infants or those born < 30 weeks gestation were 1.5 times and twice as likely to have moderate or severe disability and 2.3 and 5.4 times as likely to have cerebral palsy as those weighing 1000 to 1500 g or > 30 weeks gestation. Boys were at higher risk of adverse outcome.Conclusions: The study was able to define the increased risk associated with being born at lower gestational age or lower birthweight and demonstrates successful ascertainment of outcomes for large local populations at a reasonable cost. (c) 2005 Elsevier Ireland Ltd. All rights reserved.

Major malformations of the human eye, including microphthalmia and anophthalmia, are examples of phenotypes that recur in families yet often show no clear Mendelian inheritance pattern. Defining loci by mapping is therefore rarely feasible. Using a candidate-gene approach, we have identified heterozygous coding-region changes in the homeobox gene OTX2 in eight families with ocular malformations. The expression pattern of OTX2 in human embryos is consistent with the eye phenotypes observed in the patients, which range from bilateral anophthalmia to retinal defects resembling Leber congenital amaurosis and pigmentary retinopathy. Magnetic resonance imaging scans revealed defects of the optic nerve, optic chiasm, and, in some cases, brain. In two families, the mutations appear to have occurred de novo in severely affected offspring, and, in two other families, the mutations have been inherited from a gonosomal mosaic parent. Data from these four families support a simple model in which OTX2 heterozygous loss-of-function mutations cause ocular malformations. Four additional families display complex inheritance patterns, suggesting that OTX2 mutations alone may not lead to consistent phenotypes. The high incidence of mosaicism and the reduced penetrance have implications for genetic counseling.

Objective To determine the association between congenital toxoplasmosis and preterm birth, low birthweight and small for gestational age birth.Design Multicentre prospective cohort study.Setting Ten European centres offering prenatal screening for toxoplasmosis.Population Deliveries after 23 weeks of gestation in 386 women with singleton pregnancies who seroconverted to toxoplasma infection before 20 weeks of gestation. Deliveries after 36 weeks in 234 women who seroconverted at 20 weeks or later, and tested positive before 37 weeks.Methods Comparison of infected and uninfected births, adjusted for parity and country of birth.Main outcome measures Differences in gestational age at birth, birthweight and birthweight centile.Results Infected babies were born or delivered earlier than uninfected babies: the mean difference for seroconverters before 20 weeks was - 5.4 days (95% CI: - 1.4, - 9.4), and at 20 weeks or more, - 2.6 days ( 95% CI: - 0.5, - 4.7). Congenital infection was associated with an increased risk of preterm delivery when seroconversion occurred before 20 weeks ( OR 4.71; 95% CI: 2.03, 10.9). No significant differences were detected for birthweight or birthweight centile.Conclusion Babies with congenital toxoplasmosis were born earlier than uninfected babies but the mechanism leading to shorter length of gestation is unknown. Congenital infection could precipitate early delivery or prompt caesarean section or induction of delivery. We found no evidence for a significant association between congenital toxoplasmosis and reduced birthweight or small for gestational age birth.

Background We aimed to determine how response to a parent-completed postal questionnaire measuring development, behaviour, impairment, and parental concerns and anxiety, varies in different European centres. Methods Prospective cohort study of 3 year old children, with and without congenital toxoplasmosis, who were identified by prenatal or neonatal screening for toxoplasmosis in 11 centres in 7 countries. Parents were mailed a questionnaire that comprised all or part of existing validated tools. We determined the effect of characteristics of the centre and child on response, age at questionnaire completion, and response to child drawing tasks. Results The questionnaire took 21 minutes to complete on average. 67% (714/1058) of parents responded. Few parents (60/1058) refused to participate. The strongest determinants of response were the score for organisational attributes of the study centre (such as direct involvement in follow up and access to an address register), and infection with congenital toxoplasmosis. Age at completion was associated with study centre, presence of neurological abnormalities in early infancy, and duration of prenatal treatment. Completion rates for individual questions exceeded 92% except for child completed drawings of a man (70%), which were completed more by girls, older children, and in certain centres. Conclusion Differences in response across European centres were predominantly related to the organisation of follow up and access to correct addresses. The questionnaire was acceptable in all six countries and offers a low cost tool for assessing development, behaviour, and parental concerns and anxiety, in multinational studies.

Aim: To identify a gene linking microphthalmia with cyst with early onset medulloblastoma. Methods: Mutation analysis of the PTCH gene. Results: A mutation in exon 10 of the PTCH gene was identified, confirming a diagnosis of Gorlin syndrome. Conclusions: This is the first genetically identified mutation giving rise to microphthalmia with cyst and provides a valuable link in the eye developmental gene pathway.

The area of child disability is the 'Cinderella' of community child health services. It lacks a clear commissioning model, agreed quality standards or guidance on the level of resources required. In this climate of uncertainty, a national survey of Child Development Teams was undertaken in order to describe their basic structure and processes. The paper reports information from 242 multidisciplinary teams providing local services, with statutory funding, to children with neurodevelopmental disability and their families. The picture presented is encouraging in part. For example, 79% of teams operate from a Child Development Centre, which may be expected to enhance team communication. In terms of the initial assessment process for a developmentally delayed child, most teams (91%) report that they would hold a case discussion afterwards, although only 74% would always include parents, and only 70% always give their report(s) to parents. The impression of management practices is weak, with only 62% giving a clear answer about who manages the team, and less than half having a written policy or contract for the team's work. The survey findings provide a sampling framework from which further evaluative research can be generated.

Four children with tyrosinaemia type I received liver transplants. The metabolic disorder was corrected and all four had normal liver function on an unrestricted diet. Two children, transplanted at age five and seven years, proved to have occult hepatocellular carcinoma and both subsequently developed pulmonary metastases. One child was well 32 months after removal of a single pulmonary metastasis but the other child died with multiple metastases. The two younger children, transplanted at age 19 and 21 months, were well 28 and 44 months after operation, one after a second liver transplant. Our experience confirms the high risk of hepatocellular carcinoma in this disease and the potential value of early liver transplantation.

OBJECTIVE--To review the results of the Addenbrooke's and King's College Hospital children's liver transplantation programme. DESIGN--Retrospective analysis of the first 100 children to receive liver grafts at Addenbrooke's Hospital, Cambridge, from December 1983 to March 1990. SETTING--Addenbrooke's Hospital, Cambridge, and King's College Hospital, London. SUBJECTS--153 children assessed for liver transplantation, of whom 22 died before a donor became available and 31 were considered unsuitable. 100 children received grafts, of whom 27 had second grafts. RESULTS--One year actuarial patient survival was 71%, with 57% one year graft survival. In the last two years survival rates had improved considerably, with 86% of patients and 63% of grafts surviving for at least one year. Sixty five children were alive 12 to 86 months after transplantation; 63 were well and leading normal active lives and 56 had entirely normal liver function. Children's growth and development were essentially normal, with many showing remarkable catch up growth. CONCLUSIONS--Liver transplantation offers children with terminal liver disease a high chance of a return to full quality life and normal development. Improved surgical and medical care have progressively improved survival. The timing of transplantation is critical but has been constrained particularly by the availability of donors and resources.