Two Novel Compound Heterozygous Mutations in the TRAPPC9 Gene Reveal a Connection of Non-syndromic Intellectual Disability and Autism Spectrum Disorder.

INTRODUCTION: Autism spectrum disorder (ASD) is characterized by deficits in communication, social interaction, and repetitive behavior. Up to 70% of ASD cases are linked with intellectual disability (ID). The major genetic causes for ASD and ID are largely unknown, however, a shared genetic etiology between ASD and ID must be assumed. The trafficking protein particle complex subunit 9 (TRAPPC9) is highly expressed in postmitotic neurons of the cerebral cortex, playing a key role in development. Among 43 reported cases with mutations in TRAPPC9, all (100%) showed ID and developmental delay. Among the cases including information about ASD, 26% were affected (19 cases with information, among them 5 with ASD). Nevertheless, in some cases not classified as ASD, descriptions of autistic features like hand-flapping movements were present. CLINICAL FINDINGS: The affected individual presented with delay of speech development. Physical development was normal. Besides lateral slope of the eye-lid axis no facial abnormalities were evident. The individual was diagnosed with ID and ASD by structured testing. Cerebral MRI revealed associated abnormalities. GENETICAL FINDINGS: The chromosome set was 46,XY without structural changes. Array-CGH showed a normal molecular karyotype (arr(1-22)x2,(X,Y)x1). PCR for the FMR1 gene showed 41 ± 1 CGG repeats, and therefore no evidence of fragile X syndrome. A panel diagnostic for syndromal ID (CASK, EP300, HIVEP2, KIF1A, TRAPPC9) revealed two structural changes in TRAPPC9 in the compound heterozygosity. The mutations c.1678C > T (p.Arg560Cys) and c.3370C > T (p.Pro1124Ser) are classified as missense mutations and are both not described in the literature. CONCLUSION: We report two new missense mutations in the TRAPPC9 gene in one individual with ID and ASD. The TRAPPC9 gene should be part of the diagnostic assessment in ID. ASD must be considered as a feature of TRAPPC9-associated ID. It might have been neglected in the literature and should result in specific testing for ASD in affected individuals.

Methylphenidate in children with monogenic obesity due to LEPR or MC4R deficiency improves feeling of satiety and reduces BMI-SDS-A case series.

BACKGROUND: The clinical phenotype of patients with monogenic obesity due to mutations in the leptin receptor (LEPR) or melanocortin 4 receptor (MC4R) gene is characterized by impaired satiety and hyperphagia, leading to extreme, sometimes life-threatening weight gain. SUBJECTS/METHODS: In a case series, we analysed the effect of an off-label methylphenidate (MPH) use for 1 year as an individual treatment approach on eating behaviour (Child Eating Behaviour Questionnaire [CEBQ]), appetite (visual analogue scales) and body mass index (BMI) trajectories in five patients with severe obesity due to mutations in the LEPR (n = 3) or MC4R (n = 2) gene. RESULTS: After 1 year use of MPH (20 mg/day divided in two to three doses), BMI (Δ BMIT0-T1x¯ : -0.7 ± 0.9 kg/m2 ), BMI standard deviation score (SDS) (Δ BMI-SDST0-T1x¯ : -0.32 ± 0.20), and %BMIP95 (Δ %BMIP95T0-T1x¯ : -6.6 ± 7.8%) decreased. BMI-SDS velocity decreased from +0.17 ± 0.22 to -0.30 ± 0.20. Appetite and CEBQ subscale scores for "food responsiveness" and "enjoyment of food" decreased. We observed adverse effects with increase in self-reported frequency of disordered sleep, nervousness, hyperactivity, and tics. CONCLUSIONS: The observed decrease in BMI trajectories with MPH use for one year is clinically meaningful in this group of patients, since the natural course would have been associated with a pronounced increase in BMI, leading to comorbidities and complications over time.

[Risk Factors for Mental Health Problems in Children with Cerebral Palsy and Spina Bifida]. / Risikofaktoren für psychische Auffälligkeiten von Kindern und Jugendlichen mit Infantiler Zerebralparese und Spina bifida.

BACKGROUND: Children with cerebral palsy (CP) and spina bifida (SB) are at an increased risk for mental health problems. Aim of this study was to correlate disease specific and psychosocial risk factors with characteristic mental health problems. PATIENTS: 271 children with CP and 84 with SB aged 3-17 years were included in a cross sectional study of 15 centers. METHODS: Parents answered the Strengths and Difficulties Questionnaire (SDQ) for mental health problems, rated social participation of their children and gave data to their own educational and professional level. IQ and motor impairment were tested or rated by the caring pediatricians. RESULTS: Abnormal Total-Difficulties Scores were found in CP (30,2%) and SB (18,1%) as compared to the norm (10,0%). Increased prevalences persisted after controlling for IQ as covariate. In both groups, moderate correlations between externalizing problems and levels of cognitive and motor impairment were found. Emotional problems correlated with participation irrespective of level of impairment. Weak correlations were found with age and gender in both groups. After controlling for IQ as covariate mental health problems showed no systematic difference between both groups. DISCUSSION: Mental health problems in children and youth with CP and SB are frequent. They correlated with various risk factors (IQ, motor impairment, age, gender, participation). Early recognition, participation and psychotherapeutic facilities should be strengthened.

Predictive Value of Thompson-Score for Long-Term Neurological and Cognitive Outcome in Term Newborns with Perinatal Asphyxia and Hypoxic-Ischemic Encephalopathy Undergoing Controlled Hypothermia Treatment.

BACKGROUND: The so-called Thompson-score (TS) for newborns with hypoxic-ischemic encephalopathy (HIE) was developed before the introduction of controlled hypothermia as clinical routine. Information on the predictive value of TS in newborns undergoing therapeutic hypothermia to estimate long-term outcome is limited. OBJECTIVES: To determine the predictive value of TS to estimate long-term cognitive and neurological outcome in newborns with perinatal asphyxia treated with controlled hypothermia. METHODS: Thirty-six term newborns with HIE undergoing controlled hypothermia were followed using Wechsler Preschool and Primary Scale of intelligence III test and standardized neurological examination. The primary outcome was survival without cognitive impairment, defined as an IQ ≥85. Secondary outcomes were motor outcomes, survival without relevant neurological impairment, death and epilepsy. RESULTS: Follow-up was done in 33 out of 36 (91.6%) infants at 53 ± 12 months (mean ± SD). For all investigated parameters, a statistically significant relationship with peak TS was demonstrated. A one-point increase in peak TS indicated an OR (95% CI) of 1.5 (1.1-2.0, p = 0.006) for death or cognitive impairment, an OR (95% CI) of 2.2 (1.3-3.8, p = 0.004) for death or relevant neurologic impairment, an OR (95% CI) of 2.1 (1.3-3.5, p = 0.005) for death or epilepsy and an OR (95% CI) of 1.5 (1.1-2.1, p = 0.02) for death. Although the TS for newborns with adverse outcome (death or cognitive impairment) compared to normal outcome tended to be higher (13 [4-16] vs. 9 [0-13], d1; 15 [5-19] vs. 9 [1-14], d2; 14 [5-21] vs. 8 [2-15], d3; median [range]), there was a considerable overlap during the first 3 days of life between both groups. CONCLUSIONS: The TS seems to be a prognostic tool for predicting the long-term outcome in asphyxiated term newborns undergoing controlled hypothermia after the third day of life. A higher score appears to be significantly associated with an adverse outcome.

Effects of Levetiracetam and Sulthiame on EEG in benign epilepsy with centrotemporal spikes: A randomized controlled trial.

PURPOSE: BECTS (benign childhood epilepsy with centrotemporal spikes) is associated with characteristic EEG findings. This study examines the influence of anti-convulsive treatment on the EEG. METHODS: In a randomized controlled trial including 43 children with BECTS, EEGs were performed prior to treatment with either Sulthiame or Levetiracetam as well as three times under treatment. Using the spike-wave-index, the degree of EEG pathology was quantified. The EEG before and after initiation of treatment was analyzed. Both treatment arms were compared and the EEG of the children that were to develop recurrent seizures was compared with those that were successfully treated. RESULTS: Regardless of the treatment agent, the spike-wave-index was reduced significantly under treatment. There were no differences between the two treatment groups. In an additional analysis, the EEG characteristics of the children with recurrent seizures differed statistically significant from those that did not have any further seizures. CONCLUSION: Both Sulthiame and Levetiracetam influence the EEG of children with BECTS. Persistent EEG pathologies are associated with treatment failures.

Influence of PCO2 Control on Clinical and Neurodevelopmental Outcomes of Extremely Low Birth Weight Infants.

BACKGROUND: Levels or fluctuations in the partial pressure of CO2 (PCO2) may affect outcomes for extremely low birth weight infants. OBJECTIVES: In an exploratory analysis of a randomized trial, we hypothesized that the PCO2 values achieved could be related to significant outcomes. METHODS: On each treatment day, infants were divided into 4 groups: relative hypocapnia, normocapnia, hypercapnia, or fluctuating PCO2. Ultimate assignment to a group for the purpose of this analysis was made according to the group in which an infant spent the most days. Statistical analyses were performed with analysis of variance (ANOVA), the Kruskal-Wallis test, the χ2 test, and the Fisher exact test as well as by multiple logistic regression. RESULTS: Of the 359 infants, 57 were classified as hypocapnic, 230 as normocapnic, 70 as hypercapnic, and 2 as fluctuating PCO2. Hypercapnic infants had a higher average product of mean airway pressure and fraction of inspired oxygen (MAP × FiO2). For this group, mortality was higher, as was the likelihood of having moderate/severe bronchopulmonary dysplasia (BPD), necrotizing enterocolitis (NEC), and poorer neurodevelopment. Multiple logistic regression analyses showed an increased risk for BPD or death associated with birth weight (p < 0.001) and MAP × FiO2 (p < 0.01). The incidence of adverse neurodevelopment was associated with birth weight (p < 0.001) and intraventricular hemorrhage (IVH; p < 0.01). CONCLUSIONS: Birth weight and respiratory morbidity, as measured by MAP × FiO2, were the most predictive of death or BPD and NEC, whereas poor neurodevelopmental outcome was associated with low birth weight and IVH. Univariate models also identified PCO2. Thus, hypercapnia seems to reflect greater disease severity, a likely contributor to differences in outcomes.

[Preschool Examination in Baden-Wuerttemberg: Results of a Survey by Local Health Authorities]. / Einschulungsuntersuchung in Baden-Württemberg ­ Ergebnisse einer Befragung der Gesundheitsämter.

AIMS: German federal states conduct preschool examinations of children, to assess risks to their success in school. In 2009, step 1 of the preschool examination (ESU) in the German federal state Baden-Wuerttemberg (BaW) was preponed to the second-to-last year of kindergarten (age 4-5) to gain enough time for developmental interventions. Procedures and practice of ESU by local health authorities (HAs) in step 1 and step 2 (last year of kindergarten) were analyzed to infer strengths, weaknesses and requirements for change in the current ESU format. METHODS: The staff of 38 local HAs completed an extensive questionnaire on basic data, resources, acceptance, cooperation, content, methods and effects of ESU and enhanced their responses in free-text comments. The questionnaire was based on the statewide, standardized procedures of the ESU. RESULTS: In step 1, a median number of 2091 children were examined per HA. In step 2, the median number of children was 192. Staff resources were rated as insufficient by some HAs. ESU was rated as indispensable or helpful by most HAs. Much emphasis was placed on communication with parents and kindergarten teachers. ESU was performed completely or largely in accordance with the state-wide standards. Some changes in developmental screening were desired. Ratings of kindergarten teachers and parental questionnaires were regarded as helpful. According to HA estimates, about 20% of children suffer from health or developmental problems that are relevant to success in school, especially language problems. Information on developmental interventions following ESU is often missing. CONCLUSION: According to HAs, conducting step 1 of the ESU earlier, i. e. in the second-to-last year of kindergarten, has been a success and this change is well accepted. It seems sensible to further refine ESU screening methods and questionnaires. Feedback on developmental interventions following ESU should be the rule. Step 2 of the ESU in the last year of kindergarten should focus on children with special needs and their parents and teachers.

Mutations of PTPN23 in developmental and epileptic encephalopathy.

Developmental and epileptic encephalopathies (DEE) are a heterogeneous group of neurodevelopmental disorders with poor prognosis. Recent discoveries have greatly expanded the repertoire of genes that are mutated in epileptic encephalopathies and DEE, often in a de novo fashion, but in many patients, the disease remains molecularly uncharacterized. Here, we describe a new form of DEE in patients with likely deleterious biallelic variants in PTPN23. The phenotype is characterized by early onset drug-resistant epilepsy, severe and global developmental delay, microcephaly, and sometimes premature death. PTPN23 encodes a tyrosine phosphatase with strong brain expression, and its knockout in mouse is embryonically lethal. Structural modeling supports a deleterious effect of the identified alleles. Our data suggest that PTPN23 mutations cause a rare severe form of autosomal-recessive DEE in humans, a finding that requires confirmation.

Neurodevelopmental outcomes of extremely low birthweight infants randomised to different PCO2 targets: the PHELBI follow-up study.

BACKGROUND: Tolerating higher partial pressures of carbon dioxide (PCO2) in mechanically ventilated extremely low birthweight infants to reduce ventilator-induced lung injury may have long-term neurodevelopmental side effects. This study analyses the results of neurodevelopmental follow-up of infants enrolled in a randomised multicentre trial. METHODS: Infants (n=359) between 400 and 1000 g birth weight and 23 0/7-28 6/7 weeks gestational age who required endotracheal intubation and mechanical ventilation within 24 hours of birth were randomly assigned to high PCO2 or to a control group with mildly elevated PCO2 targets. Neurodevelopmental follow-up examinations were available for 85% of enrolled infants using the Bayley Scales of Infant Development II, the Gross Motor Function Classification System (GMFCS) and the Child Development Inventory (CDI). RESULTS: There were no differences in body weight, length and head circumference between the two PCO2 target groups. Median Mental Developmental Index (MDI) values were 82 (60-96, high target) and 84 (58-96, p=0.79). Psychomotor Developmental Index (PDI) values were 84 (57-100) and 84 (65-96, p=0.73), respectively. Moreover, there was no difference in the number of infants with MDI or PDI <70 or <85 and the number of infants with a combined outcome of death or MDI<70 and death or PDI<70. No differences were found between results for GMFCS and CDI. The risk factors for MDI<70 or PDI<70 were intracranial haemorrhage, bronchopulmonary dysplasia, periventricular leukomalacia, necrotising enterocolitis and hydrocortisone treatment. CONCLUSIONS: A higher PCO2 target did not influence neurodevelopmental outcomes in mechanically ventilated extremely preterm infants. Adjusting PCO2 targets to optimise short-term outcomes is a safe option. TRIAL REGISTRATION NUMBER: ISRCTN56143743.

Effect of supplementation with long-chain ω-3 polyunsaturated fatty acids on behavior and cognition in children with attention deficit/hyperactivity disorder (ADHD): a randomized placebo-controlled intervention trial.

OBJECTIVE: To determine whether supplementation with the long-chain omega-3 polyunsaturated fatty acids eicosapentaenoic (EPA) and docosahexaenoic acid (DHA) affects behavioral symptoms and cognitive impairments in children 6-12 years of age diagnosed with attention-deficit/hyperactivity disorder (ADHD). STUDY DESIGN: The randomized, double-blind placebo-controlled 16 weeks trial was conducted with 95 children diagnosed with ADHD according to DSM-IV criteria. Behavior was assessed by parents, teachers and investigators using standardized rating scales and questionnaires. Further outcome variables were working memory, speed of information processing and various measures of attention. For a subgroup of 81 participants, erythrocyte membrane fatty acid composition was analyzed before and after the intervention. RESULTS: Supplementation with the omega-3 fatty acid mix increased EPA and DHA concentrations in erythrocyte membranes and improved working memory function, but had no effect on other cognitive measures and parent- and teacher-rated behavior in the study population. Improved working memory correlated significantly with increased EPA, DHA and decreased AA (arachidonic acid).

Long-term outcome at age 7-10 years after extreme prematurity - a prospective, two centre cohort study of children born before 25 completed weeks of gestation (1999-2003).

OBJECTIVE: We aimed to determine the long-term neurodevelopmental outcome in extremely preterm infants of 22-23 completed weeks' gestation as compared to infants of 24 weeks with immediate postnatal life support born in two German tertiary perinatal centres between 1999 and 2003. METHODS: Children were assessed for cognitive and neurological outcomes at the age of 7-10 years. The test battery included a neurological examination, the Wechsler Intelligence Scale for children (WISC-IV) and the Frostigs Developmental Test of Visual Perception (DTVP-2). Gross motor function was classified according to the GMFCS and functional activity was assessed with the Lincoln Oseretzky Motor Development Scale (LOS KF 18). RESULTS: Outcome data were available for 79/105 children. 75.9% of the entire study cohort showed no or mild impairment. There was no difference seen between the two gestational age groups. Risk factors for moderate or severe impairment were an intracerebral haemorrhage >II° and/or periventricular leukomalacia or a retinopathy of prematurity >II°. Neither the gestational age (GA) nor the birth weight was associated with long-term outcome. CONCLUSIONS: Gestational age was not a predictor for long-term impairment of preterm infants born <25 completed weeks' GA. Other prognostic factors should be taken into account for counselling in the grey zone of viability.

Biallelic SZT2 mutations cause infantile encephalopathy with epilepsy and dysmorphic corpus callosum.

Epileptic encephalopathies are genetically heterogeneous severe disorders in which epileptic activity contributes to neurological deterioration. We studied two unrelated children presenting with a distinctive early-onset epileptic encephalopathy characterized by refractory epilepsy and absent developmental milestones, as well as thick and short corpus callosum and persistent cavum septum pellucidum on brain MRI. Using whole-exome sequencing, we identified biallelic mutations in seizure threshold 2 (SZT2) in both affected children. The causative mutations include a homozygous nonsense mutation and a nonsense mutation together with an exonic splice-site mutation in a compound-heterozygous state. The latter mutation leads to exon skipping and premature termination of translation, as shown by RT-PCR in blood RNA of the affected boy. Thus, all three mutations are predicted to result in nonsense-mediated mRNA decay and/or premature protein truncation and thereby loss of SZT2 function. Although the molecular role of the peroxisomal protein SZT2 in neuronal excitability and brain development remains to be defined, Szt2 has been shown to influence seizure threshold and epileptogenesis in mice, consistent with our findings in humans. We conclude that mutations in SZT2 cause a severe type of autosomal-recessive infantile encephalopathy with intractable seizures and distinct neuroradiological anomalies.

A case of phace syndrome and acquired hypopituitarism?

BACKGROUND: PHACE is a neurocutaneous syndrome associated with: Posterior fossa brain malformations, large "segmental" facial hemangiomas, arterial cerebrovascular-, cardiovascular-, and eye anomalies. CASE VIGNETTE: We are reporting a girl with PHACE syndrome. The patient had a congenital right-sided facial hemangioma with plaque-morphology. At age 11 years and 2 months she presented with short stature, markedly decreased growth velocity and signs and symptoms suggestive of hypothyroidism. Magnetic Resonance Imaging (MRI) of the brain revealed complex structural and cerebrovascular arterial anomalies, including an empty sella. Testing of pituitary function revealed multiple pituitary dysfunctions, including absolute growth hormone deficiency, hypogonadotropic hypogonadism, central hypothyroidism, and secondary adrenal insufficiency. CONCLUSIONS: This case suggests the necessity to screen all patients with PHACE syndrome and intracranial malformations for pituitary dysfunction at regular intervals.

Dihydrofolate reductase deficiency due to a homozygous DHFR mutation causes megaloblastic anemia and cerebral folate deficiency leading to severe neurologic disease.

The importance of intracellular folate metabolism is illustrated by the severity of symptoms and complications caused by inborn disorders of folate metabolism or by folate deficiency. We examined three children of healthy, distantly related parents presenting with megaloblastic anemia and cerebral folate deficiency causing neurologic disease with atypical childhood absence epilepsy. Genome-wide homozygosity mapping revealed a candidate region on chromosome 5 including the dihydrofolate reductase (DHFR) locus. DHFR sequencing revealed a homozygous DHFR mutation, c.458A>T (p.Asp153Val), in all siblings. The patients' folate profile in red blood cells (RBC), plasma, and cerebrospinal fluid (CSF), analyzed by liquid chromatography tandem mass spectrometry, was compatible with DHFR deficiency. DHFR activity and fluorescein-labeled methotrexate (FMTX) binding were severely reduced in EBV-immortalized lymphoblastoid cells of all patients. Heterozygous cells displayed intermediate DHFR activity and FMTX binding. RT-PCR of DHFR mRNA revealed no differences between wild-type and DHFR mutation-carrying cells, whereas protein expression was reduced in cells with the DHFR mutation. Treatment with folinic acid resulted in the resolution of hematological abnormalities, normalization of CSF folate levels, and improvement of neurological symptoms. In conclusion, the homozygous DHFR mutation p.Asp153Val causes DHFR deficiency and leads to a complex hematological and neurological disease that can be successfully treated with folinic acid. DHFR is necessary for maintaining sufficient CSF and RBC folate levels, even in the presence of adequate nutritional folate supply and normal plasma folate.

Intrauterine, early neonatal, and postdischarge growth and neurodevelopmental outcome at 5.4 years in extremely preterm infants after intensive neonatal nutritional support.

OBJECTIVE: Extremely preterm infants are at risk for poor growth and impaired neurodevelopment. The objective of this study was to determine whether intrauterine, early neonatal, or postdischarge growth is associated with neurocognitive and motor-developmental outcome in extremely preterm infants. METHODS: Surviving children who were born between July 1996 and June 1999 at <30 weeks' gestation and with a birth weight <1500 g were evaluated at the age of school entry by application of (1) a standardized neurologic evaluation, (2) the Kaufmann Assessment Battery for Children, and (3) the Gross Motor Function Classification Scale. Growth was assessed on the basis of SD scores of weight and head circumference measured at birth, at discharge, and at the time of the follow-up examination. All infants had received intensive early nutritional support. RESULTS: A total of 219 (83%) of 263 long-term survivors were evaluated at a median corrected age of 5.4 years. Increasing SD scores for weight and head circumference from birth to discharge were associated with a reduced risk for an abnormal neurologic examination. Catch-up growth of head circumference from birth to discharge was also associated with a reduced risk for impaired mobility. Weight SD score at birth, an increase of weight SD score from birth to discharge, and an increase of head circumference SD score from discharge to follow-up had an effect on the mental processing composite score. The effects of growth on neurodevelopment were by far exceeded by the consequences of intraventricular and periventricular hemorrhage. CONCLUSIONS: Growth from birth to discharge seemed to be associated with long-term motor development. Cognitive development was associated with intrauterine growth measured as weight at birth, early neonatal weight gain, and postdischarge head circumference growth. Improving particularly early neonatal growth may improve long-term outcome in extremely preterm infants, but the effects of improved growth may only be small.

Orofacial findings in conjunction with infantile cerebral paralysis in adults of two different age groups--a cross-sectional study.

OBJECTIVES: The objective of this cross-sectional study was to assess differentiated malocclusion symptoms and dental findings such as caries prevalence in patients suffering from infantile cerebral paralysis (CP, ICP), as well as the amount of dental and orthodontic treatment. SUBJECTS AND METHODS: Sixty-two patients suffering from infantile cerebral paralysis (ICP) aged from 18 to 78 years were included in the study and assigned to one of two groups according to age. The analysis was carried out on study models that had been measured using a caliper gauge and an electronic model-measuring procedure. Clinical caries status and sociological data were evaluated and statistically analyzed. RESULTS: While the group of older patients underwent no orthodontic treatment, we observed a statistically-significant increase in orthodontic treatment in the younger group with infantile cerebral paralysis. The model analysis revealed a mean overjet of 4.8 mm (SD+/-3.9 mm). There was a tendency toward open bite in terms of the vertical relation, with the mean overbite measuring 1.6 mm (+/-3.7 mm). Comparing the two age groups, we noted that greater age correlated significantly with reduced dental crowding symptoms in the lower jaw, contrary to the more common development of crowding in the normal population. The resulting value of the palatal height index was 40.8%, with no differences between the age groups. Compared to the index of 42.0% (according to the average data in the literature), those participating in this study and suffering from ICP had a flatter palatal vault. Our study parameter "dental intervention per year" revealed that 2/3 of the patients had three dentist appointments per year with no significant difference between the age groups. The ICP patients' mean DMF/T index value was 13.4, which appears to be generally lower than the published values concerning disabled persons in Germany and the healthy population. CONCLUSIONS: We observed an overall correlation between the frequency of malocclusions and severity of mental retardation. The amount of orthodontic treatment was significantly higher in the younger group (32.3%) than the older group (0%). In diagnostic terms, orthodontic treatment should follow the general guidelines, namely, the recommendation of removable devices as treatment appliances, and multidisciplinarily speaking, modified sequences of myofunctional therapy in consideration of the individual compliance prognosis and parental cooperation. In the multidisciplinary coordination of rehabilitation under general anesthesia, specific orthodontic measures may be undertaken (such as taking impressions, limited fixed appliance insertions, controlled extractions). An early treatment start in combination with the appropriate orthodontic device is desirable because of the improved, trainable reflex pattern. The dental therapy results are generally positive due to the fact that our patients met a tight dental recall schedule.

Neurodevelopmental follow-up of very preterm infants after proactive treatment at a gestational age of > or = 23 weeks.

OBJECTIVE: To determine the long-term neurodevelopmental outcome in extremely preterm infants after offering life support to all infants > or = 23 weeks gestation ("pro-active management"). STUDY DESIGN: With parental consent, all infants born at 23 to 25 completed weeks gestation were treated proactively. Surviving infants born from July 1996 to June 1999 were assessed for standardized cognitive and neurological outcomes at 5 years corrected age. RESULTS: 70 of 91 infants admitted to the neonatal intensive care unit survived until follow-up. 67 of the 70 surviving infants were examined at a median corrected age of 5.6 years; 12% had cerebral palsy and a Gross Motor Function Classification Scale score > 2; 4% were blind; 1% required a hearing aid; and 12% had a Kaufmann Assessment Battery for Children mental processing composite < 51, resulting in 18% sustaining a severe disability. 43% had normal results on a neurological examination, Gross Motor Function Classification Scale score = 0, mental processing composite > 85, and had neither severe visual nor hearing impairment. 57% qualified for regular schooling. CONCLUSION: Improved survival was not associated with an increased risk of severe disability when compared with results of earlier publications. These findings may result from proactive management and are important for counseling patients at risk of imminent extremely preterm delivery.

Randomized trial of early versus late enteral iron supplementation in infants with a birth weight of less than 1301 grams: neurocognitive development at 5.3 years' corrected age.

BACKGROUND: Iron deficiency in early childhood may impair neurodevelopment. In a masked, randomized, controlled trial of early versus late enteral iron supplementation in preterm infants with birth weights of <1301 g, early iron supplementation reduced the incidence of iron deficiency and the number of blood transfusions. OBJECTIVE: We sought to examine whether early enteral iron supplementation improves neurocognitive and motor development in these infants. METHODS: Children who participated in the above mentioned trial were evaluated by applying the Kaufmann Assessment Battery for Children and the Gross Motor Function Classification Scale at the age of school entry. RESULTS: Of the 204 infants initially randomized, 10 died and 30 were lost to follow-up. A total of 164 (85% of the survivors) were evaluated at a median corrected age of 5.3 years. In this population (n = 164), the mean (+/-SD) mental processing composite in the early iron group was 92 (+/-17) versus 89 (+/-16) in the late iron group. An abnormal neurologic examination was found in 17 of 90 versus 26 of 74, and a Gross Motor Function Classification Scale score of >1 was found in 2 of 90 versus 5 of 74, respectively. Fifty-nine of 90 children in the early iron group were without disability, compared with 40 of 74 in the late iron group. Severe disability was found in 5 of 90 versus 6 of 74 children and 67 of 90 versus 49 of 74 qualified for regular schooling, respectively. CONCLUSIONS: Early enteral iron supplementation showed a trend toward a beneficial effect on long-term neurocognitive and psychomotor development and showed no evidence for any adverse effect. Because the initial study was not designed to evaluate effects on neurocognitive development, the power was insufficient to detect small but potentially clinically relevant improvements. Additional studies are required to confirm the trend towards a better outcome observed in the early iron group.