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The largest group of recipients of pediatric gastrostomy have neurological impairment with intellectual disability (ID). This study investigated trends in first gastrostomy insertion according to markers of disadvantage and ID etiology. Linked administrative and health data collected over a 32-year study period (1983-2014) for children with ID born between 1983 and 2009 in Western Australia were examined. The annual incidence rate change over calendar year was calculated for all children and according to socioeconomic status, geographical remoteness, and Aboriginality. The most likely causes of ID were identified using available diagnosis codes in the linked data set. Of 11,729 children with ID, 325 (2.8%) received a first gastrostomy within the study period. The incidence rate was highest in the 0-2 age group and there was an increasing incidence trend with calendar time for each age group under 6 years of age. This rate change was greatest in children from the lowest socioeconomic status quintile, who lived in regional/remote areas or who were Aboriginal. The two largest identified groups of ID were genetically caused syndromes (15.1%) and neonatal encephalopathy (14.8%).Conclusion: Gastrostomy is increasingly used in multiple neurological conditions associated with ID, with no apparent accessibility barriers in terms of socioeconomic status, remoteness, or Aboriginality. What is Known: • The use of gastrostomy insertion in pediatrics is increasing and the most common recipients during childhood have neurological impairment, most of whom also have intellectual disability (ID). What is New: • Nearly 3% of children with ID had gastrostomy insertion performed, with the highest incidence in children under 3 years of age. • Gastrostomy use across different social groups was equitable in the Australian setting. [ABSTRACT FROM AUTHOR]

A mildly retarded infant with failure to thrive developed hypoglycaemia, focal seizures, respiratory failure and hemiparesis during a febrile episode at the age of 16 months. A brain scan was initially normal and showed hemilateral focal edema and gliosis at later stages. 3-Methylcrotonyl-CoA carboxylase deficiency was suggested by elevated urinary excretion of 3-hydroxyisovaleric acid and 3-methylcrotonylglycine, and confirmed by enzyme assays. The patient was treated with protein restriction and carnitine and remained stable during the following 5 years. Hemiparesis and some developmental delay persisted. In acute focal brain disease, metabolic disorders must be considered. 3-Methylcrotonyl-CoA carboxylase deficiency adds to the list of possible causes of "metabolic stroke". [ABSTRACT FROM AUTHOR]

Angelman syndrome (AS) is a congenital syndrome with a prevalence of 1:15,000. Individuals with AS often have severe intellectual disability, typical dysmorphic signs, and behavioral problems. The aim of the study was to investigate the rate of incontinence and associated psychological problems in children and adults with AS. Ninety children (4-18 years) and 54 adults (18-31 years) with AS were recruited through a parent support group (55.6% male, mean age 15.1 years). The Parental Questionnaire: Enuresis/Urinary Incontinence, the Incontinence Questionnaire-Pediatric Lower Urinary Tract Symptoms (ICIQ-CLUTS), as well as the Developmental Behaviour Checklist for parents (DBC-P) or for adults (DBC-A) were filled out by parents or caregivers. 85.6% of individuals with AS were affected by at least one subtype of incontinence (82.7% nocturnal enuresis (NE), 64.7% daytime urinary incontinence (DUI), and 57.1% fecal incontinence (FI)). 52.5% of the children and 32.6% of adults reached a clinically relevant DBC score. Incontinence was not associated with behavioral problems. NE and DUI were associated with genotype and epilepsy.Conclusion: Children with AS have high rates of incontinence. Many adults are still affected by NE, DUI, or even FI. Screening, assessment, and treatment of incontinence in individuals with AS are recommended. What is Known: • Incontinence in persons with Angelman syndrome (AS) is associated with younger age, lower level of adaptive functioning, and epilepsy. What is New: • Children and teens with AS are at special risk for incontinence, but older persons are also affected. • Comorbid epilepsy is significantly associated not only with nocturnal enuresis (NE) but also with daytime urinary incontinence (DUI). Underlying genotype is significantly associated with incontinence. [ABSTRACT FROM AUTHOR]

We present a patient with poikiloderma, severe osteoporosis and a mild intellectual disability. At the age of 9 years, this patient was proposed to suffer from a novel disease entity designated as calcinosis cutis, osteoma cutis, poikiloderma and skeletal abnormalities (COPS) syndrome. At the age of 35, he was diagnosed with Hodgkin's lymphoma. Recently, biallelic pathogenic variants in the RECQL4 gene were detected (c.1048_1049delAG and c.1391-1G>A), confirming a diagnosis of Rothmund-Thomson syndrome (RTS). In the brother of this patient, who had a milder phenotype, a similar diagnosis was made.Conclusion: We conclude that COPS syndrome never existed as a separate syndrome entity. Instead, osteoma cutis may be regarded as a novel feature of RTS, whereas mild intellectual disability and lymphoma may be underreported parts of the phenotype. What is new: • Osteoma cutis was not a known feature in Rothmund-Thomson patients. • Intellectual disability may be considered a rare feature in RTS; more study is needed. What is known: • RTS is a well-described syndrome caused by mutations in the RECQL4 gene. • Patients with RTS frequently show chromosomal abnormalities like, e.g. mosaic trisomy 8. [ABSTRACT FROM AUTHOR]

Unlabelled: Mutations in the L1CAM gene have been identified in the following various X-linked neurological disorders: congenital hydrocephalus; mental retardation, aphasia, shuffling gait, and adducted thumbs (MASA) syndrome; spastic paraplegia; and agenesis of the corpus callosum. These conditions are currently considered different phenotypes of a single entity known as L1 syndrome. We present three families with L1 syndrome. Sequencing of the L1CAM gene allowed the identification of the following mutations involved: a known splicing mutation (c.3531-12G>A) and two novel ones: a missense mutation (c.1754A>C; p.Asp585Ala) and a nonsense mutation (c.3478C>T; p.Gln1160Stop). The number of affected males and carrier females identified in a relatively small population suggests that L1 syndrome may be under-diagnosed.Conclusion: L1 syndrome should be considered in the differential diagnosis of intellectual disability or mental retardation in children, especially when other signs such as hydrocephalus or adducted thumbs are present. [ABSTRACT FROM AUTHOR]

Introduction: This study investigated the effect of combined exercise training on indices of body composition, physical fitness and lipid profile in adolescents with mental retardation.Materials and Methods: Thirty adolescents with mental retardation (total IQ, 45-70) received exercise training (n = 15) or no training (n = 15). Groups were matched for age, sex and mental retardation. Before and after the intervention period, indices of body composition, physical fitness and lipid profile were measured.Results: In comparison with the control group, weight, body mass index, waist and fat mass decreased significantly, while relative fat-free mass increased. The level of triglycerides, total cholesterol and low-density lipoprotein decreased significantly, while high-density lipoprotein increased. Muscle strength, muscle fatigue resistance and sit-to-stand were ameliorated. PeakVO2/peak power decreased significantly. The distance covered in the 6-min walk test (6MWT) increased with 50 m.Conclusion: In conclusion, combined exercise training has a positive effect on indices of obesity, physical fitness and lipid profile in adolescents with mental retardation. [ABSTRACT FROM AUTHOR]

Since the incidence of shaken baby syndrome in Switzerland was not known, we conducted a nationwide prospective follow-up study for a 5-year period (from 2002 to 2007). The data were collected through the Swiss Pediatric Surveillance Unit. Inclusion criteria were the presence, in a child 6 years or documented accident/disease explaining symptoms/findings. To describe outcome, we used the King's Outcome Scale for Childhood Head Injury (KOSCHI). 56 cases were reported from 13 of 26 Swiss cantons, representing 80% of the Swiss population; 49 cases met the inclusion criteria. Preponderance of male infants was high (31 male and 18 female); median age at admission was 4 months (1-58). Clinical symptoms were present in 42 infants, retinal/vitreous hemorrhages in 39 infants, and pathological brain/head imaging in 46 infants. In 13 cases, the caregivers admitted shaking the child. Outcomes (KOSCHI 1-5; n = 47 patients) were death (KOSCHI 1) 8 (17.7%), vegetative state (KOSCHI 2) 0, severe disability (KOSCHI 3) 11 (22.2%), moderate disability (KOSCHI 4) 14 (31.1%), and good recovery (KOSCHI 5) 14 (28.8%). Based on these data, the incidence of shaken baby syndrome in Switzerland is 14 per 100 000 live births, which corresponds to the incidence in other Western countries. Demographic characteristics and outcomes of Swiss patients were comparable to published studies. [ABSTRACT FROM AUTHOR]

Interstitial deletions of the long arm of chromosome 14 are relatively rare. We report a 8.5-year-old girl with dysmorphic facial features and mental retardation associated with a de novo interstitial deletion of chromosome 14. The comparison between our patient and all published patients is reviewed. The genetic investigations have allowed us to define the critical chromosomal region and to start an accurate follow-up. [ABSTRACT FROM AUTHOR]

Alopecia-contractures-dwarfism mental retardation syndrome (ACD syndrome; OMIM 203550) is a very rare genetic disorder with distinct features. To our knowledge, there have been four cases documented to date. In addition, another three patients, previously described as having IFAP syndrome (OMIM %308205), may also have ACD syndrome. We report on one patient with short stature, total alopecia, ichthyosis, photophobia, seizures, ectrodactyly, vertebral anomalies, scoliosis, multiple contractures, mental retardation, and striking facial and other features (e.g. microdolichocephaly, missing eyebrows and eyelashes, long nose, large ears) consistent with ACD syndrome. Results of laboratory testing in the literature case reports were normal, although in none of them, array-CGH (microarray-based comparative genomic hybridization) analysis was performed. In conclusion, the combination of specific features, including total alopecia, ichthyosis, mental retardation, and skeletal anomalies are suggestive of ACD syndrome. We propose that children with this syndrome undergo a certain social pediatric protocol including EEG diagnostics, ophthalmological investigation, psychological testing, management of dermatologic and orthopedic problems, and genetic counseling. [ABSTRACT FROM AUTHOR]

Fecal incontinence is a common disorder in children. Many children with fecal incontinence have psychosocial co-morbidity. In this study, the effect of psychosocial co-morbidity on the treatment outcome of children with fecal incontinence was evaluated. One hundred and fifty children with fecal incontinence were treated in a multidisciplinary program. All children had been treated unsuccessfully for at least one year before entering the program. The treatment consisted of laxative treatment, psychosocial interventions, and biofeedback training. Psychosocial co-morbidity was classified according to the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV). One hundred and forty-one children were completely analyzed (102 boys, mean age 9.6 (range 6.5-16.5) years). Of these, 31 (22%) children had fecal incontinence without constipation and 110 (78%) children had fecal incontinence associated with constipation. In 95% of children, at least one psychosocial co-morbidity was present. Treatment was successful at 12 months in 69% of patients. Treatment was less successful in children with attention deficit hyperactivity disorder (ADHD), in children with parent-child relational problems, and in mentally retarded children. The results indicate that the early assessment and treatment of psychosocial co-morbidity might improve treatment response in children with fecal incontinence. Children with fecal incontinence are treated less successfully in the first year if they have ADHD, parent-child relational problems, or mental retardation. Psychosocial evaluation and the early assessment and treatment of psychosocial co-morbidity is indicated in order to improve response rate. Family counseling--aimed at improving parent-child relations--should be an integral part of a multidisciplinary treatment program for fecal incontinence. [ABSTRACT FROM AUTHOR]

Major neurological disorders may accompany rare chromosomal abnormalities. As an example of this rare condition, we present a case with microcephaly, mental retardation, developmental delay, hyperactivity, stereotypic movements, seizures and dysmorphic facial appearance in whom a mosaic ring chromosome 18 was found [45,XX,-18/46,XX,r(18)/46,XX,dicr(18)]. Although ring chromosome 18 phenotype has been known for a long time, this is the third reported patient with a dicentric ring chromosome 18 mosaicism. The presented case will contribute to the identification of the genotype-phenotype correlation in chromosome 18 anomalies. [ABSTRACT FROM AUTHOR]

Feeding disorders in ex-prematures do exist and may constitute a major challenge to their families' well being. A cases series of 86 ex-prematures with severe feeding disorders was analysed regarding co-morbidity, response to therapy and the long-term outcome after treatment. These children with a gestational age of <37 weeks had been referred for hospital rehabilitation because of severe feeding disorders, defined as tube feeding or average feeding times of more than 30 minutes. Behavioural therapy was the key element of the treatment. Ex-prematures accounted for 86/266 patients admitted for treatment of feeding disorders between 1995 and 2004. Whereas only 40.8% of these had cerebral palsy, 51.1% had a diagnosis of mental retardation and 87% had interaction problems. Response to treatment up to discharge was achieved in 61.6%. Univariat analyses showed that tube feeding at admission and swallowing difficulties were the best predictors of failure to respond to the intervention. Long-term follow-up data that were collected for 53 of the 86 children with similar initial response to therapy (64.2%) compared to children with no follow-up data (57.6%). Success of therapy after discharge was maintained in 94.1%; however, 25% of the children with normal BMI's at discharge and sustained success of therapy fell below the 3rd BMI percentile. Cerebral palsy, mental retardation and interaction problems appear to be important risk factors for severe feeding disorders in ex-prematures. A therapeutic intervention based on behavioural therapy achieved sustained success in almost two thirds of the children. [ABSTRACT FROM AUTHOR]

Molecular karyotyping by array comparative genomic hybridisation (array CGH) has doubled the detection rate of pathogenic chromosomal imbalances in patients. This has been possible by increasing the resolution level from the 5 Mb obtained using the conventional karyotype to as low as 100 kb by array technology. Moreover, the technology revealed that over 12% of the human genome includes sub-microscopic benign copy number variable regions. These new findings have implications in genetic counselling and patient management. [ABSTRACT FROM AUTHOR]

Unlabelled: We report a 13-year-old female patient with multiple congenital abnormalities (microcephaly, facial dysmorphism, anteverted dysplastic ears and postaxial hexadactyly), mental retardation, and adipose-gigantism. Ultrasonography revealed no signs of a heart defect or renal abnormalities. She showed no speech development and suffered from a behavioural disorder. CNS abnormalities were excluded by cerebral MRI. Initial cytogenetic studies by Giemsa banding revealed an aberrant karyotype involving three chromosomes, t(2;4;11). By high resolution banding and multicolour fluoresence in-situ hybridisation (M-FISH, MCB), chromosome 1 was also found to be involved in the complex chromosomal aberrations, confirming the karyotype 46,XX,t(2;11;4).ish t(1;4;2;11)(q43;q21.1;p12-p13.1;p14.1). To the best of our knowledge no patient has been previously described with such a complex translocation involving 4 chromosomes. This case demonstrates that conventional chromosome banding techniques such as Giemsa banding are not always sufficient to characterise complex chromosomal abnormalities. Only by the additional utilisation of molecular cytogenetic techniques could the complexity of the present chromosomal rearrangements and the origin of the involved chromosomal material be detected. Further molecular genetic studies will be performed to clarify the chromosomal breakpoints potentially responsible for the observed clinical symptoms.Conclusion: This report demonstrates that multicolour-fluorescence in-situ hybridisation studies should be performed in patients with congenital abnormalities and suspected aberrant karyotypes in addition to conventional Giemsa banding. [ABSTRACT FROM AUTHOR]

Unlabelled: This paper presents data obtained by questionnaires sent to local hospitals and metabolic centres in Germany, Austria, Italy and Switzerland concerning the survival and outcome of patients with urea cycle disorders treated between 1975 and 1986. A total of 130 questionnaires were sent out of which 88 questionnaires of patients were returned. This study compares results of conservative long-term management using protein restriction versus protein restriction combined with more extensive treatment (arginine/citrulline, essential amino acid supplements and sodium benzoate as alternate pathway therapy). While survival was improved in neonates receiving extensive therapy, there was an increased risk of mental retardation on long-term follow-up in this group. The time at which the first symptoms of hyperammonaemia appeared, the age at diagnosis, and the time of delay in diagnosis after the first symptom were not helpful in predicting outcome; however, when plasma ammonia concentrations exceeded 300 micromol/l initially or 480 micromol/l at its peak, none of the patients had a normal cognitive outcome.Conclusion: there is a need to establish improved treatment approaches and a network of "rare disease" centres to assure the rapid diagnosis and effective treatment and follow-up of affected children. This should precede any consideration of neonatal screening for urea cycle disorders. [ABSTRACT FROM AUTHOR]

Unlabelled: The aim of the study was to determine risk factors for the development of cystic periventricular leucomalacia (PVL) and to correlate ultrasound findings with neurodevelopmental outcome. By means of a retrospective case-control study (matched for gestational age, birth weight, sex, and year of birth) and a cohort analysis of all preterm infants with cystic PVL documented by ultrasound scans hospitalised at a local tertiary care centre between 1988 and 1998, 98 preterm infants with a gestational age ranging from 26 to 35 weeks were diagnosed as having cystic PVL. The mean day of diagnosis of periventricular echodensities was 3 +/- 2 days (range 1-11 days), and of cystic PVL 21 +/- 8 days (range 2-47 days). Of 79 infants (1988-1997) eligible for neurodevelopmental follow-up (91%), hemi-, di-, or tetraplegia was diagnosed in 61 (77%), normal mental outcome in 22 (28%), associated visual disorders in 41 (52%) and seizure disorders in 12 (15%) infants. Significant risk factors associated with the development of cystic PVL were premature rupture of membranes, chorioamnionitis, and hyperbilirubinaemia (odds ratios 4.665, 6.026, and 2.460 respectively). Subgroup analysis according to gestational age (26-28, 29-32, 33-35 weeks) revealed similar results despite spontaneous labour (26-28 weeks; odds ratio 4.808) and pre-eclampsia (33-35 weeks; odds ratio 3.517). Multiple pregnancy was associated with a twofold increased risk (odds ratio 2.075). The white matter damage probably accounted for the significantly higher prevalence of apnoeas (P < 0.001) and neonatal seizures (P < 0.001). Cysts located bilateral or parieto-occipital were associated with a higher risk of cerebral palsy (odds ratios 6.933 and 4.327 respectively). Solely anterior located cysts were associated with normal neurological outcome. Increasing size of the cysts was associated with increasing risk of cerebral palsy with a cut-off value of 10 mm (odds ratio 3.300 and above) and all infants with cysts of more than 20 mm diameter had cerebral palsy.Conclusion: The high prevalence of premature rupture of the membranes and chorioamnionitis further supports the role of intra-uterine infection in the pathogenesis of periventricular leucomalacia. The overall prognosis of cystic periventricular leucomalacia is poor. [ABSTRACT FROM AUTHOR]

Glucose transporter type 1 (GLUT1) deficiency is an inborn error of glucose transport. Clinical manifestations are presumed secondary to reduced glucose transport across the blood brain barrier, and include seizures, abnormal tone, developmental delay and hypoglycorrhachia. A high index of suspicion is important as GLUT1 deficiency is a potentially treatable cause of mental retardation. We studied two affected children by continuous video-EEG in order to better understand the cause of the clinical manifestations and improvement on a ketogenic diet. The EEG was characterized by generalized paroxysmal 2-2.5 Hz spike-wave discharges, although normal EEGs were also obtained. Atypical absence seizures were the most prominent clinical seizure. Epileptiform activity and clinical seizures occurred in both children while acutely ketotic and non-ketotic, but were markedly more frequent in one child when non-ketotic. Discharges were not associated with a reduction in substrate for brain metabolism in the blood at that time. Conclusion Atypical absence seizures are common in glucose transporter type 1 deficiency and should alert the clinician to the possibility of this treatable disorder when present in a young child with developmental delay. Our data suggest that the therapeutic mechanism of the ketogenic diet in this disorder is more complicated than simply delivering ketones as an alternative substrate for brain metabolism. [ABSTRACT FROM AUTHOR]

Unlabelled: A new X-linked variant of spondylo-epimetaphyseal dysplasia with distinctive phenotype and severe mental retardation in three boys of one family is reported. The children were normal at birth. After several months of normal development progressive physical disability and slow mental deterioration were observed. Extensive biochemical tests were normal.Conclusion: These patients represent a new form of X-linked spondylo-epimetaphyseal dysplasia. [ABSTRACT FROM AUTHOR]

We report on a 16-year-old girl with tetrasomy 9p mosaicism. Clinical investigations disclosed a malformation syndrome with craniofacial abnormalities, dysplasia of the right clavicle, short neck with cervical ribs, patella dislocation, Dandy-Walker malformation, mental retardation and blindness. Karyotype analysis of blood lymphocytes indicated an additional marker in the size of a C-group chromosome with a large heterochromatic block in 88% of the investigated metaphases. The origin and structure of this additional marker could not be determined by chromosome banding. Application of fluorescence in situ hybridisation and comparative genomic hybridisation identified the origin of the marker chromosome, demonstrating the effectiveness of molecular-cytogenetic investigations in the diagnosis of structural and numerical chromosome abnormalities. [ABSTRACT FROM AUTHOR]

We describe a boy who excreted massive amounts of formiminoglutamic acid and hydantoin-5-propionic acid in his urine. He was mildly mentally retarded and epileptic, whereas his twin-brother was completely normal. Loading with L-histidine enhanced the excretion of both metabolites. Treatment was attempted with high doses of folic acid and methionine, but both were without effect on the excretion levels. [ABSTRACT FROM AUTHOR]

A mentally retarded female with aniridia, microcephaly and no other major malformations has been studied using G-banded prometaphase chromosomes. This study revealed a reciprocal translocation of chromosome 8 and chromosome 11 with one break point in 8q and two breakpoints in 11p. An interstitial segment of 11p is lost. Both parents have a normal karyotype. The importance of chromosome analyses of patients with aniridia and mental retardation is discussed. [ABSTRACT FROM AUTHOR]

Measurement of various craniofacial structures was compared with clinical assessment of craniofacial anomalies. Different diagnostic groups of children were studied. Anomalies were seen more often in patients with congenital heart defect, mental retardation and multiple congenital anomalies syndromes than in control children. Comparative study of quantitative data and qualitative (clinical) assessment showed some agreement but also many discrepancies. Therefore, in describing craniofacial anomalies both methods should be used. This is particularly true in the differential diagnosis of multiple congenital anomalies syndromes and variant familial developmental patterns. [ABSTRACT FROM AUTHOR]

We analyzed the gestational, parturitional, neonatal (GPN) histories of 281 severely mentally retarded patients with cerebral palsy to define the etiology or pathogenesis of cerebral palsy in each patient. No association between type of cerebral palsy and GPN histories was found except for an increase in spastic-athetoid patients in the breech delivery subgroup. Significant findings include: increased incidence of prematurity and postmaturity, small and large for-gestational age (GA) fetal size, a normal birthweight for GA distribution of patients with diabetic mothers, an excess of mothers greater than or equal to 35 and less than or equal to 20 years old, an increased immediately-previous sib interval of 2.59 years suggestive of an "infertility factor", an unremarkable GPN history in one third of the cases, in another one third GPN problems not usually associated with a high risk of CNS damage, and in one third gross complications which were probably responsible for the CP, including: an increased incidence of breech deliveries, twinning, prolonged and precipitous labor and placental complications; no increased association of athetosis and Rh incompatibility or incidence of toxemia was found. Disseminated intravascular coagulation due to prenatal death of a twin may have been the cause of brain damage in several patients. [ABSTRACT FROM AUTHOR]

The effects of relying on outmoded IQ-test norms and the use of arbitrary classifications of developmental delay on estimates of cognitive impairment of very preterm infants (VPI) was evaluated in a prospective population study. Cognitive assessments included the Griffiths test at 5 and 20 months and the Columbia Mental Maturity Scales (CMM) and a vocabulary test (Aktiver Wortschatz Test, AWST) at 56 months of age. Rates of cognitive impairment of 321 very preterm infants (VPI; < 32 weeks gestation or < 1500 g birth weight) were determined according to the published test norms, to scores of a full-term control group (FC n = 321), and to scores from a representative sample of children (NC n = 431) of the same birth cohort. IQ-scores were higher in the FC and NC children than in the original standardisation sample (SS). Using the concurrent test norms (FC, NC) up to 2.4 times more VPI were identified as seriously impaired (<-2 SD) than if the published (outdated) norms were used. Serious developmental delay was underestimated when arbitrary (e.g. DQ < 70) rather than across age comparable definitions (DQ <-2 SD) were used. VPI study drop-outs had mothers with lower educational qualifications and poorer cognitive developmental scores at 5 or 20 months of age. In conclusion, a lack of appropriate control groups and use of arbitrary criteria for judging serious delay leads to large underestimations of cognitive impairment in VPI. Findings from previous uncontrolled studies of VPI need re-interpretation. [ABSTRACT FROM AUTHOR]

Fourteen children aged 9 months-4 years with moderate to severe mental retardation and varying neurologic lesions were referred for severe and continuous nocturnal sleep disturbances and very abnormal day/night schedules. All children had previously been given hypnotic medications and behavioral treatments which had little or no effect on nocturnal sleep. The severity of the sleep disturbances significantly affected family life and was a major handicap to the children. All children were treated with light therapy (minimum 4000 lux). Five children responded to treatment and had normal sleep-wake cycles at the most recent post-treatment evaluation (2-5 years after the first treatment). Two of the patients' families were unable to follow the prescribed regimen. Treatment failed in 7 children. One of these seven children spontaneously improved 3 years later. In three of the failure children the neurologic problem progressively worsened, leading to death in one of them. Phototherapy is a treatment worth pursuing in children with very significant sleep/wake disruption which is unresponsive to behavioral or other treatments. It has few side-effects and may lead to normalization of the sleep-wake cycle. Recent improvement in the technology used to monitor the 24-h temperature rhythm over several days and the present commercial availability of "light boxes" should render these therapeutic trials easier than at the time of these initial investigations. [ABSTRACT FROM AUTHOR]

The intellectual performance of 22 children aged 3-16 years with maple syrup urine disease (MSUD) was assessed and compared to a group of early treated phenylketonuria (PKU) children and normal subjects matched by age, sex, nationality, and socio-economic status. All subjects were tested by one examiner only using the age related versions of the non-verbal Snijders-Oomen intelligence test. The mean IQ (+/- SD) score was 74 +/- 14 (range 50-103) in patients with MSUD, 101 +/- 12 (range 87-125) in early treated PKU patients, and 107 +/- 9 (range 90-122) in normal subjects. Intercorrelations indicated that length of time after birth that plasma leucine concentration remained > 1 mmol/l and quality of long-term metabolic control have important influences on IQ. [ABSTRACT FROM AUTHOR]

The spontaneous growth of 165 patients (75 girls and 90 boys) with Williams-Beuren syndrome was analysed in a mixed longitudinal and cross-sectional manner. Mean (+/- 1 SD) length at birth was 48.2 +/- 2.6 cm in girls (n = 52) and 49.0 +/- 3.0 cm in boys (n = 65). Intrauterine growth retardation (length below -2 SD of the normal population) was present in 35% of the girls and 22% of the boys. Poor growth was noted during the first 2 years of life. Until age 9 years in girls and 11 years in boys, mean growth followed the 3rd percentile. A pubertal growth spurt with normal growth rate was seen at age 10 years in girls and 13 years in boys, i.e. 1 to 2 years earlier than normal. Menarche also occurred earlier than normal at a mean age of 11.6 +/- 1.5 years (n = 28). Mean adult height was 153.9 +/- 6.9 cm in girls (n = 17) and 168.2 +/- 6.9 cm in boys (n = 27), approximately corresponding to the 3rd percentile in both sexes and correlating with the genetic height potential (target height). The mean deficit of adult height compared to target height was 10.2 cm in girls and 9.1 cm in boys. Skeletal development progressed at an approximately normal rate in both sexes. [ABSTRACT FROM AUTHOR]

A new triosephosphate isomerase (TPI) variant is described in an 8-year-old Turkish girl suffering from chronic haemolytic anaemia, myopathy and developmental retardation since early infancy. The enzyme activity profile revealed a generalized deficiency in erythrocytes, granulocytes, mononuclear blood cells, skeletal muscle tissue and cerebrospinal fluid. The concentration of enzyme substrate dihydroxyacetone phosphate was distinctly elevated. Biochemical examination showed accelerated enzyme deamidation, the first step in the normal catabolism of TPI during aging of the erythrocyte. The specific activity of the variant TPI, determined by antibody titration, was reduced to 61% of normal. Its heat stability was markedly decreased. Muscle biopsy and neuropsychological testing further clarified the pathogenesis of the disorder. A prevalent alteration of mitochondria similar to that seen in mitochondrial myopathy and an elevated amount of intracellular glycogen were found. The patient's retarded intellectual development was mainly due to impaired visual perception and sensory-motor co-ordination in addition to a lack of syllogistic reasoning. The findings indicate that the low TPI activity leads to a metabolic block of the glycolytic pathway and hence to a generalized impairment of cellular energy supply. [ABSTRACT FROM AUTHOR]

Williams-Beuren syndrome (WBS) is a disorder of unknown aetiology. The classical features of the syndrome include a typical ('elfin') facies, mental retardation and heart defects. Myopathy has not so far been part of the spectrum of WBS. We studied six patients with WBS aged 3-25 years, five of whom showed clinical and morphological evidence of myopathy. The clinical manifestations of myopathy included hypotonia in infancy, walking delay, joint contractures, scoliosis, and increased exhaustion on exertion. These symptoms were present in variable expression but part of a typical postural pattern. Examination of muscle biopsies showed lipid storage in four patients and increased variability of fibre size in three. In one patient a muscle biopsy gave normal results. Biochemical investigation in four patients with morphological evidence of lipid storage in muscle revealed muscle carnitine deficiency in three. In addition, enzyme activities of fatty acid beta-oxidation were low in one of two specimens tested. It is concluded that a clinically relevant myopathy is part of the multi-system manifestation of WBS and a clinical trial of carnitine supplementation is justified. [ABSTRACT FROM AUTHOR]

An EEG study has been carried out on 19 children (including siblings in 3 families) with clinical features of Angelman syndrome. The age at time of the first EEG ranged from 11 months to 11 years with the majority under 5 years. Six children had no history of seizures at the time of the first EEG. One or more of the following EEG abnormalities were seen in all patients: 1. Persistent rhythmic 4-6/s activities reaching more than 200 microV not associated with drowsiness. 2. Prolonged runs of rhythmic 2-3/s activity (200-500 microV) often more prominent anteriorly, sometimes associated with discharges (ill-defined spike/wave complexes). 3. Spikes mixed with 3-4/s components usually more than 200 microV mainly posteriorly and facilitated by, or only seen with, eye closure. Two and sometimes three of these EEG features could be present in the same record particularly at a young age. The appearance of discharges mixed with slow components on eye closure was the commonest finding seen at some stage in 17 patients (aged from 11 months to over 12 years). The EEG features of Angelman syndrome appear to be sufficiently characteristic to help identify patients at an early age before the clinical features become obvious and at a time when genetic counselling may be particularly important. [ABSTRACT FROM AUTHOR]

Eight patients (three sporadic, five from two families) with the velo-cardio-facial syndrome (VCFS) or Shprintzen syndrome are reported. Major clinical findings of this syndrome include a characteristic pattern of facial dysmorphisms, cleft palate, cardio-vascular malformations, and (mostly mild-to-moderate) mental retardation or learning difficulties. The syndrome probably is caused by a dominant gene with very variable expression. From previous reports mostly ascertained from cardio-vascular or cleft palate clinics, the incidence of cleft palate and heart defects was calculated to be 98% and 82%, respectively. Out of eight patients of this study who were diagnosed mainly through their pattern of facial dysmorphisms, only two and four had clefts and heart defects, respectively, further demonstrating the variability in the expression of this gene. Similarly, mental retardation, noted in 100% of previous publications, was not present in all of our patients. In two instances, examination of the mother revealed that she probably carried the mutant gene, but that she showed a milder clinical expression than the index patient. It is suggested that careful family investigations should be performed following detection of an index patient, and that the rate of fresh mutations might be not as high as previously assumed. [ABSTRACT FROM AUTHOR]

The neurodevelopmental outcome and school performance of 50 appropriate for gestational age (AGA) and 33 small for gestational age (SGA) very-low-birth-weight (VLBW) infants, compared to a control group (41 Term infants) were assessed at 8 years of age. The incidence of major handicaps among AGA and SGA/VLBW infants respectively, was 16% and 6%. No major handicap was found in the control group. The incidence of neurodevelopmental abnormalities (NDA) among AGA's (40%) and SGA's (57.6%) compared with the control group (31.7%) was found to be significantly higher. School failure occurred more frequently among VLBW infants (22.9%) and was related in children with NDA--and more particularly among AGA's--to the presence of language disorders or associated NDA. Evaluation of the consequences of NDA and school problems for later academic and professional achievement now requires further follow-up studies. [ABSTRACT FROM AUTHOR]

A 16-year-old boy with classical phenylketonuria (PKU) and mild mental retardation (IQ 69) was detected by the screening of mentally retarded school children in Taiwan with Guthrie's bacterial inhibition assay. The follow-up family study showed that one of his married elder sisters suffered from borderline mental retardation (IQ 75) and was also diagnosed as a classical case of PKU. She had borne one boy and one girl, both suffering from mild mental retardation, microcephaly, delay in linguistic development and severe growth retardation. This is the first known Chinese family with maternal PKU. To prevent future mental retardation caused by maternal PKU, the simultaneous establishment of a register system with a neonatal screening programme, is indicated for the follow-up of PKU girls, screening of the whole family of newly discovered PKU cases, and to exclude unrecognized maternal PKU in women who have given birth to a microcephalic child. [ABSTRACT FROM AUTHOR]

Sisters with a mild variant of non-ketotic hyperglycinaemia resulting from a defect in the T-protein of the glycine cleavage system had different clinical outcomes. The older sister was ascertained at 6 months of age because of mental retardation. She received only brief treatment with sodium benzoate from 11-15 months and at 15 years of age is profoundly retarded and has epilepsy. The younger sister was diagnosed 36 h after birth, was treated with strychnine, sodium benzoate and arginine from the neonatal period and at 27 months of age is only moderately retarded and free of seizures. The possible role of strychnine in the improved outcome is discussed. [ABSTRACT FROM AUTHOR]

A 4-year-old girl with neonatal onset of chronic diffuse urticarial rash, head enlargement, protruding eye balls, bilateral arthritis of the knees, growth and mental retardation, and signs in blood and cerebrospinal fluid of chronic inflammation is presented and compared to two similar cases reported by us previously. Including this new patient there are now 14 documented cases with this specific inflammatory syndrome whose aetiology remains unknown. In the present case, however, elevated antibody titres against I.ric. Borrelia antigen were found in the serum. [ABSTRACT FROM AUTHOR]

A patient is presented who had therapy-resistant epileptic seizures from the 7th day of life. Examination at the age of 17 months revealed a mentally retarded boy with epileptic seizures, generalised myoclonic contractions, and abnormal ocular movements. A cerebral CT scan showed central and cortical atrophy. Lactate levels in serum, cerebrospinal fluid and urine were elevated, the pyruvate level was raised in serum. A quadriceps muscle biopsy revealed aspecific morphologic signs of a myopathy. Biochemical analysis showed decreased substrate oxidation rates in the mitochondria associated with low rates of ATP production. Total and free carnitine levels were decreased. Investigation of the respiratory chain revealed a defect in the proximal part of respiratory chain involving the region of coenzyme Q. Based on clinical and chemical data it is likely that the patient is suffering from a multi-system disorder. [ABSTRACT FROM AUTHOR]

A Turkish girl presented with a history of fever, diarrhoea, convulsions, recurrent infections and failure to thrive from the age of 5 months. Megaloblastic anaemia was present and profound folate deficiency was evidenced in plasma and in CSF. Treatment with oral folic acid cured the anaemia, diarrhoea and infections but failed to prevent convulsions and the appearance of mental retardation and cerebral calcifications. Loading tests with folic acid and its derivatives led to the conclusion that the folate deficiency was caused by a defect in folate transport both across the gut and the blood-brain barrier. Low plasma concentrations of methionine prompted a therapeutic trial with methionine associated with vitamin B12 and folic acid that spectacularly improved the convulsions. [ABSTRACT FROM AUTHOR]

Two adult, mentally retarded males with the typical features of the Coffin-Lowry syndrome are reported. Further family investigation led to the same diagnosis in a 2.5-year-old male cousin, and to the identification of five female carriers, with variable clinical expression of this X-linked inherited mental retardation syndrome. [ABSTRACT FROM AUTHOR]

Six patients with both choanal atresia (ChA) and additional malformations are described and another 110 cases with this combination reviewed from the literature. Our study of these cases supports the existence of the CHARGE-association (Coloboma, Heart Disease, Atresia of choanae, Retarded mental development and growth, Genital hypoplasia, Ear anomalies and deafness). Our findings suggest the inclusion of orofacial clefts and oesophageal atresia among the main symptoms of this association. A certain degree of facial dysmorphism (low set, dysplastic ears, retrogenia, antimongoloid slant of palpebral fissures and anteverted nares) was observed in each of our cases. Infants with the bilateral type of ChA plus cardiac defects and those with ChA plus renal malformations have a high mortality rate. The aetiology of the association is not clear. The recurrence risk may be low. [ABSTRACT FROM AUTHOR]

Johanson-Blizzard syndrome is a rare autosomal recessive disorder, characterized by exocrine pancreatic deficiency and a wide range of other abnormalities. We present here an infant with failure to thrive, exocrine pancreatic deficiency, short stature and developmental delay, cutis aplasia on the scalp, aplasia of alae nasi, hypospadias, hypothyroidism, myxomatous mitral valve, and patent ductus arteriosus. Molecular studies revealed a novel homozygous nonsense mutation in exon 38 of the UBR1 gene, which confirmed the diagnosis of Johanson-Blizzard syndrome. It should be acknowledged that the combination of exocrine pancreatic insufficiency and nasal wing hypo-aplasia is pathognomonic for this syndrome. Prompt diagnosis and exact monitoring of the patients with JBS are required to avoid further complications. [ABSTRACT FROM AUTHOR]

Unlabelled: A 23-year-old man was diagnosed with pulmonary alveolar proteinosis at the age of 11 months, and primary hypothyroidism gradually developed during infancy. He had delayed developmental milestones and severe hypotonia that evolved into non-progressive chorea during childhood. He died from large cell lung carcinoma at the age of 23 years. A de novo heterozygous insertion mutation 859-860insC in the TITF-1 gene was demonstrated.Conclusion: TITF-1 gene mutations should be considered in paediatric and adult patients with unexplained (combinations of) chorea, mental retardation, primary hypothyroidism, and chronic lung disease. Introduction of a name for the disorder, e.g. Brain-Thyroid-Lung syndrome, would probably facilitate further recognition. Whether the TITF-1 gene mutation in this patient predisposed to the development of lung cancer remains speculative. [ABSTRACT FROM AUTHOR]

We report here a mentally retarded 32-month-old boy whose initial diagnosis was Angelman syndrome based on his clinical features. Cytogenetic studies showed a normal karyotype. Due to an elevated level of serum creatine kinase activity, we performed analyses to rule out a myopathic process. Although the electromyogram was normal, a few scattered necrotic fibres were seen in the muscle biopsy. DNA and dystrophin studies revealed an in-frame deletion in the 5' region of the dystrophin gene and an abnormal form of the protein product, consistent with a diagnosis of dystrophinopathy. We cannot totally rule out the possibility that this boy has the two separate conditions. [ABSTRACT FROM AUTHOR]

A case study of a child with Sotos syndrome, normal intelligence, and autistic disorder is presented. Initial descriptions of Sotos syndrome included severe to mild mental retardation. More recent studies indicate language and learning disabilities with normal intelligence. Our patient met criteria for a diagnosis of autistic disorder. Sotos syndrome is another genetic and neurodevelopmental syndrome that can be associated with autistic as well as communication and language disorders. [ABSTRACT FROM AUTHOR]

A child presenting with mild psychomotor retardation, hypotonia, microcephaly and hyperkinesis is described. Urinary organic acid analysis by combined gas chromatography-mass spectrometry revealed 4-hydroxybutyric aciduria. Succinic semialdehyde dehydrogenase activity in extracts of white cells derived from the patient was less than 10% of control values. [ABSTRACT FROM AUTHOR]

A 1 year birth cohort in the provinces of Oulu and Lapland in the Northern part of Finland consisted of 12058 live-born infants, this being 96% of all children born in 1966 in this area. Information on morbidity up to the age of 14 years was collected prospectively by means of questionnaires, special examinations and from national and regional registers of hospital admissions and social services contacts. The total number of children with epilepsy, defined as the occurrence of at least one afebrile epileptic seizure, was 208, 113 boys and 95 girls. The cumulative incidences for epilepsy up to the age of 14 years was 17.3 per 1000. Primary generalised epilepsy was present in 63% and partial seizures in 37%. At least one additional handicapping condition, such as cerebral palsy, mental retardation, and visual or auditory defect was present in 74 children (35.5%). Mental retardation was the most frequent additional handicap, being present in 28%, whereas 16% of the children had cerebral palsy. A total of 75% of the children were able to attend an ordinary school. The high frequency of epilepsy in this study, as compared to other studies, is explained by the cumulative registration of the cases and a high degree of ascertainment of cases with epilepsy. [ABSTRACT FROM AUTHOR]

A 5-year-old male child presented with progressively increasing asymmetrical overgrowth of limbs, hyperpigmentation on the right half of the body, and mental retardation since 9 months of age. [ABSTRACT FROM AUTHOR]

An essential part of the care of children with Down syndrome is secondary screening for comorbidity. It is well known that comorbidity frequently occurs in these children. A new update of the Dutch Down syndrome medical guideline was developed to create a sound evidence base for several of these conditions. We present the latest insights and recommendations from this Dutch medical guideline which are based on the most relevant literature currently available and developed with rigorous methodology. The main focus of this revision of the guideline was on obstructive sleep apnea and other airway problems and hematologic disorders, such as transient abnormal myelopoiesis, leukemia, and thyroid disorders. Conclusion: This is a short summary of the latest insights and recommendations from the updated Dutch medical guideline for children with Down syndrome. [ABSTRACT FROM AUTHOR]

The baseline risk for multiple febrile seizures within the same febrile illness is largely unknown. Estimates range from 5 to 30%. Imprecise estimates can lead to incorrectly powering studies investigating the management of febrile seizures. To estimate the risk of multiple febrile seizures in the same febrile illness, we systematically reviewed and conducted a meta-analysis of studies from January 2000 to December 2021 that contained data for the number of children for both simple and complex febrile seizures in the same febrile illness. We searched MEDLINE, EMBASE, and Web of Science for randomized, quasi-randomized, prospective, and retrospective trials that involved children with febrile seizures. A total of 23,131 febrile illnesses with febrile seizures met the inclusion criteria. The estimated baseline risk of multiple febrile seizures in the same febrile illness was 17% (95% CI, 16–19%). However, the 30 cohorts that included both admitted and non-admitted patients had a lower percentage of multiple FSs within the same illness (14%; 95% CI, 12–15%) than the 30 cohorts that enrolled only admitted patients (20%; 95% CI, 16–25%). Conclusion: Researchers can use estimates in this paper to design future studies. Taking into the account the substantial heterogeneity between countries and studies, clinicians could cautiously use our estimates in their clinical assessment and be better able to set parental expectations about a child's chances of having another febrile seizure during the current illness. Trial registration: PROSPERO CRD42020191784. Registered July 18, 2020. What is Known: • There is renewed interest in the diagnostic workup and prophylactic treatment of febrile seizures to prevent repeat seizures in the same febrile illness. • There is a lack of accurate estimates of the baseline risk for multiple febrile seizures in the same illness to properly design studies investigating management. What is New: • This study provides the most robust estimates for the baseline risk for multiple febrile seizures in the same illness. [ABSTRACT FROM AUTHOR]

The incidence of cancer in children with intellectual disability has been poorly documented. We report our experience of treating children and adolescents with cancer and intellectual disability (40 patients), from 2004 to 2018. A treatment-sparing approach was adopted for 6 patients with severe intellectual impairment to minimize toxicity: a child with postpartum asphyxia and medulloblastoma did not receive radiotherapy; 1 patient with mitochondrial encephalopathy and a testicular germ cell tumor did not receive bleomycin and lung metastasectomy; 2 patients (1 with Down + West syndrome + Wilms tumor (WT) and 1 with Denys-Drash syndrome + WT) did not receive vincristine; 1 child with corpus callosum agenesis and anaplastic ependymoma did not receive chemotherapy; 1 child with structural chromosomal aberrations and a primitive neuro-ectodermal tumor received personalized chemotherapy. Heminephrectomy was performed in 4 patients with WT to preserve their kidney function. We found no statistically significant correlation between relapse or mortality rates and the use of a treatment-sparing approach. The 5-year overall survival (OS) and event-free survival (EFS) rates were 84.5% and 66.1% as opposed to 82.5% and 46.9%, respectively, for patients in our usual-treatment and treatment-sparing groups. Conclusion: We only opted for a treatment-sparing approach for patients with severe disabilities, and their OS was in line with that of children without intellectual disability. What is Known: • There are few reports on children/adolescents with cancer and intellectual disability (ID). • It is not clear how to manage them and whether a treatment sparing should be considered, especially in the case of severe disability. What is New: • Most patients received the standard cancer treatment and only in the case of severe disability, a therapeutic saving approach was applied. • No statistically significant correlations between relapse/mortality rates and the use of a treatment-sparing approach were found. [ABSTRACT FROM AUTHOR]