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A longitudinal study of children with developmental language delay at age three: later intelligence, reading and behaviour problems.

A large sample of Dunedin (New Zealand) children were assessed at age three to identify those with language delay. 2.6 per cent were defined as delayed in verbal comprehension only, 2.3 per cent as delayed in verbal expression only, and 2.3 per cent as delayed in both ('general language delay'). Most of these children, and the remainder of the sample, were assessed for intelligence, reading and behaviour problems at ages seven, nine and 11. Those in every language-delay group had significantly lower mean IQs and lower mean reading scores than the remainder of the sample. They also more often had a low IQ or a lower reading score at ages seven and nine and a lower Verbal and Full-scale IQ at 11. The groups with delayed verbal comprehension and general language delay had significantly more behaviour problems than the remainder of the sample. The group with general language delay was consistently the most disadvantaged in later intelligence, reading and behaviour. Two of the language-delay groups (comprehension and general language) had significantly higher scores on a family disadvantage index. The results of this study confirm the importance of early language delay as a predictor of lower than average intelligence and reading ability and increased behaviour problems.

Child↗

Simple developmental speech delay: a follow-up study.

The authors followed 38 children with delayed speech development approximately two to four years after initial diagnosis, assessing and comparing their subsequent speech and language, and over-all development. Nearly all of the children had appropriate language levels for their general development. Just over half had less articulation competence than expected for their age, but this was not related to language achievement or age. It appears that the prognosis for future language development is favourable for these children. The results suggest that articulation might be a developmentally related process with a good prognosis, but further follow-up is necessary to determine ultimate competence of children in whom this is delayed.

Articulation Disorders↗

Atypical cases of Angelman syndrome.

Angelman syndrome (AS) is a profound disorder notable for mental retardation and severe language deficits that results from lack of function of the maternally inherited copy of the UBE3A gene. Chromosome deletions of 15q11q13, paternal uniparental disomy (UPD), UBE3A gene mutations, and imprinting center defects are all commonly recognized mechanisms that disrupt the function of the maternal copy of the UBE3A gene. We report here two patients with different atypical etiologies of AS. The first patient is a 3-year-old boy with global developmental delay, severe speech deficits, seizures, and very happy disposition. Southern blot analysis for the maternal and paternal chromosome 15 methylation products showed a mosaic methylation pattern, suggesting an imprinting center defect. The second patient is a 4(1/2)-year-old boy with global developmental delay, no expressive language, microcephaly, seizures, and ataxic gait. Array-based comparative genomic hybridization (CGH) demonstrated a loss in copy number for two overlapping clones encompassing the UBE3A gene, indicating a partial deletion within UBE3A. His mother, who was adopted, had an identical pattern, suggesting that her deletion was probably on her paternally imprinted allele. These patients illustrate the expanding spectrum of molecular findings in AS, reinforce the need to maintain suspicion when clinical features suggest AS but initial testing is normal, and show the power of CGH as a tool to uncover partial UBE3A deletions.

Angelman Syndrome↗

Profound hypothermia with alpha-stat pH management during open-heart surgery is associated with choreoathetosis.

A retrospective chart review was conducted to examine risk factors associated with the occurrence of choreoathetosis, a rare but significant complication of open-heart surgery in children. Ten children were identified as having developed choreoathetosis after cardiac surgery. Their charts were reviewed and compared with 33 age- and diagnosis-matched controls who underwent open-heart surgery during the same time period. Children with choreoathetosis reached lower rectal and esophageal temperatures (p = 0.0018 for both) and spent a greater portion of total bypass time at lower rectal and esophageal temperatures (p < 0.001 for both). Duration of cooling below 20 degrees C esophageal temperature and PaCO2 at the end of the cooling period were significant predictors of choreoathetosis (p = 0.023 and p = 0.0497, respectively) in a logistic regression model, and a greater fraction of choreoathetosis patients had prior developmental delays (p = 0.017). No difference was found in the age at surgery, duration of bypass, aortic cross-clamp time, arterial pH, PaCO2 or mean arterial pressure. The combination of extended exposure to profound hypothermia and alpha-stat pH management strategy and preexisting developmental delay are associated with the development of choreoathetosis following open-heart surgery 61 in children.

Acid-Base Equilibrium↗

A genomewide linkage-disequilibrium scan localizes the Saguenay-Lac-Saint-Jean cytochrome oxidase deficiency to 2p16.

Leigh syndrome (LS) affects 1/40,000 newborn infants in the worldwide population and is characterized by the presence of developmental delay and lactic acidosis and by a mean life expectancy variously estimated at 3-5 years. Saguenay-Lac-Saint-Jean (SLSJ) cytochrome oxidase (COX) deficiency (LS French-Canadian type [LSFC] [MIM 220111]), an autosomal recessive form of congenital lactic acidosis, presents with developmental delay and hypotonia. It is an LS variant that is found in a geographically isolated region of Quebec and that occurs in 1/2,178 live births. Patients with LSFC show a phenotype similar to that of patients with LS, but the two groups differ in clinical presentation. We studied DNA samples from 14 patients with LSFC and from their parents, representing a total of 13 families. Because of founder effects in the SLSJ region, considerable linkage disequilibrium (LD) was expected to surround the LSFC mutation. We therefore performed a genomewide screen for LD, using 290 autosomal microsatellite markers. A single marker, D2S1356, located on 2p16, showed significant (P < 10(-5)) genomewide LD. Using high-resolution genetic mapping with additional markers and four additional families with LSFC, we were able to identify a common ancestral haplotype and to limit the critical region to approximately 2 cM between D2S119 and D2S2174. COX7AR, a gene encoding a COX7a-related protein, had previously been mapped to this region. We determined the genomic structure and resequenced this gene in patients with LSFC and in controls but found no functional mutations. Although the LSFC gene remains to be elucidated, the present study demonstrates the feasibility of using a genomewide LD strategy to localize the critical region for a rare genetic disease in a founder population.

Base Sequence↗

Effect of partial exchange transfusion in asymptomatic polycythemic LBW babies.

This randomized controlled trial was conducted to determine the effect of partial exchange transfusion in polycythemic babies. Forty five asymptomatic polycythemic babies with birth weight < or = 2000 g were included and randomly assigned to undergo either partial exchange transfusion using isotonic saline within 4 hours of screening or routine medical management. Outcome measures were neonatal morbidity (especially hypoglycemia and neurological alterations) and mortality; developmental delays using DDST-II, neurological deficits, tone and DTR abnormalities over 18 months follow up period. The overall neonatal morbidity in this study was low and comparable in the two groups. Some of the polycythemic babies in the non-exchanged group found initially at 3 months age with "suspected development" grew out of their developmental delay at 18 months of age or later while those who underwent exchange transfusion and with retarded development at 3 months of age remained so even at 18 months of age.

Developmental Disabilities↗

Video analysis of sensory-motor features in infants with fragile X syndrome at 9-12 months of age.

This study utilized retrospective video analysis to distinguish sensory-motor patterns in infants with fragile X syndrome (FXS) (n = 11) from other infants [i.e., autism (n = 11), other developmental delay (n = 10), typical (n = 11)] at 9-12 months of age. Measures of development, autistic features, and FMRP were assessed at the time of entry into the study. Home videos collected from families were edited and coded with previously validated procedures. Findings revealed a pattern of sensory-motor features (e.g., repetitive leg movements, posturing, less sophistication/repetitive use of objects) associated with FXS, and suggest these infants were most similar to the group of infants with other developmental delays, irrespective of co-existing autistic symptoms later in life. Infant sensory-motor features in the FXS group were more predictive of an early developmental milestone (i.e., age walking) than later, more broad, developmental outcomes, or FMRP. Implications for early identification and differential diagnosis are discussed.

Female↗

A new dose-response curve for bilateral medial rectus recessions for infantile esotropia.

PURPOSE: In 1982, Mims et al generated the first rigorous dose-response curve for bilateral medial rectus recessions for infantile esotropia (ET). Curve fitting calculations were hampered by substantial variability of surgical effect for the larger angles of ET, and an exponential curve was chosen for angles below 30 ET and a straight line for angles above 30 ET. In a continuing effort to improve the surgical success rate, a new series of results of 113 bilateral medial rectus recessions performed from 1990 to 1998 for infantile ET has been analyzed to produce a new dose-response curve and to study other potentially useful variables. METHODS: The amount of medial rectus recession performed in this series was the original dose-response curve from 1982, with conjunctival recessions performed for angles above 35 ET. RESULTS: The best curve that could be fitted to the effect versus millimeters of bilateral medial rectus recession was a single exponential curve. Other parameters explored with multivariate analysis, including head circumference, developmental delay, and intraoperative angles under anesthesia were not helpful in predicting effect of surgery at 6 weeks postoperative. A total of 87% were aligned at 6 months after surgery. Surgical failure at 6 months was more prevalent with larger preoperative angles (P =.0007) and with developmental delay (age when child first sat alone; P =.0078). CONCLUSION: Between 1982 and 1990, decreased variability of results of bilateral medial rectus recessions for larger angles of infantile ET enabled the generation of a single exponential dose-response curve for the entire range of angles of infantile ET.

Algorithms↗

Generalized anxiety disorder in adolescents and young adults with mild mental retardation.

This report examines clinical features of generalized anxiety disorder in adolescents and young adults with mild mental retardation (MR), compared with children and adolescents with normal IQ. Frequency of symptoms, comorbidity, agreement between reports of subjects and parents, correlation between IQ and severity of disorder, and comparison between frequency of symptoms in the experimental and control groups are described. Twenty-two subjects with MR (12 males and 10 females aged 11-25 years; mean age = 16.3), 30 children (19 males and 11 females aged 7-11.11; mean age = 10), and 30 adolescents (18 males and 12 females aged 12.1-18; mean age = 15.2) participated in the study. All the subjects were comprehensively diagnosed with diagnostic interviews (K-SADS or DICA-R). According to our data, generalized anxiety disorder can be diagnosed in adolescents with mild MR, with high agreement between self-reports and parent reports. Phenomenology of GAD in mildly developmentally delayed persons grossly paralleled that of normal IQ people, except for brooding, somatic complaints, and sleep disorders. Number and severity of symptoms did not correlate with Full Scale and Verbal IQs. High rates of comorbidity with depression were evident both in normal IQ and in developmentally delayed subjects.

Adolescent↗

Effect of maternal multivitamin supplementation on the mental and psychomotor development of children who are born to HIV-1-infected mothers in Tanzania.

OBJECTIVES: To determine the association between maternal multivitamin supplementation and the mental and psychomotor development of children who are born to HIV-1-infected mothers in Tanzania, as secondary endpoints in a randomized trial that investigated the effect of maternal multivitamin supplementation on HIV-1 vertical transmission and progression. METHODS: The Bayley Scales of Infant Development, 2nd Edition, were administered at 6, 12, and 18 months of age to a subset of children (N = 327). We assessed the effect of vitamin A and multivitamin (vitamins B, C, and E) supplementation using linear regression models and Cox proportional hazard models for the Mental Development Index, the Psychomotor Development Index, and raw scores separately. RESULTS: Multivitamin supplementation was associated significantly with a mean increase in Psychomotor Development Index score of 2.6 (95% confidence interval: 0.1-5.1). Multivitamins were also significantly protective against the risk for developmental delay on the motor scale (relative risk: 0.4; 95% confidence interval: 0.2-0.7) but not on the Mental Development Index. Vitamin A supplementation had no significant effect on these outcomes. CONCLUSIONS: Maternal multivitamin supplements provide a low-cost intervention to reduce the risk for developmental delays among infants who are born to HIV-positive mothers in developing countries.

Child Development↗

An investigation into sub-telomeric deletions of chromosome 22 and pervasive developmental disorders.

Deletions of the sub-telomeric region of chromosome 22 have been associated with mental retardation, developmental delay, and autistic behaviors. This study investigated sub-telomeric anomalies of chromosome 22 using fluorescent in situ hybridization (FISH) probes in 82 subjects diagnosed with autism and atypical autism. No microdeletions were detected in this group. Similar FISH analyses were undertaken on two children with developmental delay, who were ascertained to be ring 22 during routine cytogenetic investigations. One subject was shown to have a microdeletion in the sub-telomeric region tested. Both children met the social and communication cut off for autism on the ADI and but did not meet the cut off for restrictive and repetitive behaviors. Only one of the two children met the criteria for PDD on the ADOS.

Child↗

Periodic lateralized epileptiform discharges in asphyxiated neonates.

Electrographic seizures (EGS) were detected in 13 of 16 asphyxiated neonates who were undergoing continuous electroencephalographic monitoring for detection of evidence of central nervous system injury. Five of the 13 neonates with EGS also had periodic lateralized epileptiform discharges (PLEDs). The electrographic characteristics of PLEDs in these infants were similar to those reported in neonatal herpes simplex encephalitis and in older children and adults. Of the 5 neonates with PLEDs, 2 died, 2 are developmentally delayed and only 1 is normal at 12 months. This is in contrast to the normal outcome for 8 of the 11 infants who did not have PLEDs. One other was neurologically normal but died of pulmonary disease at 3 months and the other two were developmentally delayed. PLEDs in neonates, as in other age groups, lack diagnostic specificity, but when associated with neonatal asphyxia, may indicate a poor prognosis. Continuous EEG monitoring is helpful in identifying PLEDs in these cases.

Asphyxia Neonatorum↗

Visual evoked potentials in disproportionately growth-retarded human neonates.

To study brain function in the neonatal period, disproportionately growth-retarded (n = 33) and appropriately grown (n = 21) infants were examined using Doppler flow velocities prenatally and visual evoked potentials postnatally. Visual evoked potentials recordings were made at gestation of 40 and 46 weeks. The group of growth-retarded infants had significantly prolonged latencies to both of the two major peaks (designated P and N), most pronounced for the P peak. This result was observed at both ages investigated and corresponds to a developmental delay of 3 weeks. For individuals, the increase in P latency correlated to prenatal flow indices and to neonatal anthropometric parameters indicative of growth retardation. We conclude that in utero growth retardation affects brain development as assessed by visual evoked potentials in the neonatal period. This developmental delay may be produced by intracerebral factors during the process of growth retardation, and these alterations may have a prognostic value.

Anthropometry↗

Gray matter heterotopia.

Gray matter heterotopia are common malformations of cortical development. From a clinical perspective, affected patients are best divided into three groups: subependymal, subcortical, and band heterotopia (also called double cortex). Symptomatic women with subependymal heterotopia typically present with partial epilepsy during the second decade of life; development and neurologic examinations up to that point are typically normal. Symptoms in men with subependymal heterotopia vary, depending on whether they have the X-linked or autosomal form. Men with the X-linked form more commonly have associated CNS and visceral anomalies; their development is typically abnormal. Symptomatic men with the autosomal variety have clinical courses similar to symptomatic women. Both men and women with subcortical heterotopia typically have congenital fixed neurologic deficits and develop partial epilepsy during the second half of the first decade of life. The more extensive the subcortical heterotopia, the greater the deficit; bilateral heterotopia are almost invariably associated with severe developmental delay or mental retardation. In general, band heterotopia are seen exclusively in women; men with a mutation of the related gene (called XLIS or DCX) usually die in utero or have a much more severe brain anomaly. Symptoms in affected women vary from normal to severe developmental delay or mental retardation; the severity of the syndrome is related to the thickness of the band of arrested neurons. Nearly all affected patients that come to medical attention have epilepsy, with partial complex and atypical absence epilepsy being the most common syndromes. Some of the more severely affected patients develop attacks.

Brain↗

Mode of delivery and outcome of 699 term singleton breech deliveries at a single center.

OBJECTIVE: Elective cesarean delivery has been postulated to improve the outcome of term fetuses in breech presentation. We retrospectively compared the short- and long-term outcomes of term infants who were delivered from a breech presentation at a single center. STUDY DESIGN: We reviewed 699 consecutive term breech presentations according to the intended mode of delivery at a single center between January 1993 and December 1999. The short-term outcome measures were perinatal death, neonatal death, or serious neonatal morbidity; the long-term outcome measures were developmental delay and spasticity. RESULTS: The rate of serious perinatal morbidity in the trial-of-labor and cesarean delivery groups was 2.3% and 0.5%, respectively (P =.12). There was no perinatal or neonatal death in either group. With a median follow-up period of 57 months (range, 13-100 months), the rate of developmental delay was 1.9% and 0.5%, respectively (P =.29). Spasticity was not noted in any of the children. CONCLUSION: Our data suggest that planned vaginal delivery remains an option for selected term breech presentations.

Adult↗

Maternal uniparental disomy in a patient with Prader-Willi syndrome with an additional small inv dup(15) chromosome.

Prader-Willi syndrome (PWS) is a complex genetic disorder. About 70% of cases have a paternal deletion at 15q11-q13, and most of the remaining cases are caused by maternal uniparental disomy (UPD). In rare cases of PWS with maternal UPD, small marker chromosomes are identified. Patients with inv dup(15) are at an increased risk of developing PWS or Angelman syndrome (AS) due to UPD. They may be also at increased risk for developmental delay due to additional copies of genes located within the PWS/AS critical region. Therefore, molecular investigations in patients with a supernumerary marker chromosome (SMC) are necessary to provide proper genetic counseling. We report a female infant with central hypotonia, weak crying, feeding problems, failure to thrive, and developmental delay after birth. Chromosome analysis revealed an SMC in 55% of metaphase cells. Fluorescence in situ hybridization showed that this marker chromosome was constituted by a small isodicentric inverted duplication of chromosome 15 [inv dup(15)]. Microsatellite analysis showed uniparental isodisomy of maternal chromosome 15 in the proband. Diagnosis of PWS was further confirmed by methylation-specific polymerase chain reaction. The inv dup(15) marker chromosome was also of maternal origin. Follow-up at the age of 18 months revealed a height in the 10th percentile and weight in the 50th percentile. She had poor activity and muscle tone, and was unable to walk independently. There was no psychomotor retardation, behavior disturbance or seizure.

Adult↗

Fetal alcohol delays the developmental expression of myelin basic protein and transferrin in rat primary oligodendrocyte cultures.

This study has examined the development of immunoreactive myelin basic protein and transferrin in primary glial cell cultures. Cultures were initiated from control and experimental Sprague-Dawley rats 1-2 days postnatally. Experimental treatment involved exposure to 5% (w/v) ethanol in a liquid diet during the last two weeks of gestation. Prenatal alcohol administration delayed the expression of myelin basic protein and transferrin during the first three weeks postnatally. Other oligodendroglial and astroglial markers were little affected, if at all, by fetal alcohol exposure.

Animals↗

Two patients with Kabuki syndrome presenting with endocrine problems.

A 4 year-old boy with mental retardation and seizures presented to the pediatric endocrinology clinic because of a history of hypoglycemia; a 16 month-old girl with developmental delay presented with bilateral breast tissue enlargement; in both, a diagnosis of Kabuki syndrome was made because of typical facial features, neurodevelopmental delay and other stigmata consistent with Kabuki syndrome. Kabuki syndrome is a mental retardation-malformation syndrome affecting multiple organ systems with a broad spectrum of abnormalities. The facial features of the syndrome are specific and independent of ethnic origin. In addition to presenting with endocrine problems, the patients reported here exhibit some novel findings such as congenital alopecia areata and hyperpigmented skin lesion. The diagnosis of Kabuki syndrome should be considered in patients with hypoglycemia or premature thelarche when associated with developmental delay and a peculiar facies.

Child, Preschool↗