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This report describes a 5-year 6-month-old Chinese girl with partial monosomy for the long arm of chromosome 22. The karyotype was 46,XX/46,XX,del (22) (q13.2). She presented with global developmental delay. Clinical features include seizures, failure-to-thrive, prominent ears, long philtrum and abnormal skin pigmentation on the face and limbs.
BACKGROUND: Global developmental delay/intellectual disability (GDD/ID) is among the most common neurodevelopmental disorders, with up to half of cases are attributed to genetic factors. Chromosome microarray (CMA) has traditionally been the primary genetic test for idiopathic GDD/ID. However, whole exome sequencing (WES) and whole genome sequencing (WGS) have recently emerged, substantially increasing diagnostic yields in these populations. METHODS: We conducted a comprehensive literature search of PubMed, Scopus, EMBASE, and the Cochrane Library from inception to April 29, 2025. Studies reporting the diagnostic utility of these tests in children with GDD/ID were included and analyzed. RESULTS: A total of 102 studies, comprising 55,752 children, were reviewed. The pooled diagnostic yield of WES was 0.37 (95% CI: 0.33-0.41; I2 = 93%), significantly higher than that of CMA at 0.19 (95% CI: 0.16-0.21; I2 = 95%). Subgroup analyses showed that WES yielded significantly higher diagnostic rates than CMA in both same-sample comparisons (OR = 2.27, 95% CI: 1.08-4.78) and different-sample comparisons (OR = 1.65, 95% CI: 1.15-2.37). Only one study evaluated WGS, reporting a diagnostic yield of 0.27. Meta-regression revealed a significant association between CMA diagnostic yield and the proportion of male participants (p < 0.01), but not with WES. No significant difference in diagnostic utility was observed between isolated GDD/ID and GDD/ID with comorbidities. CONCLUSION: In children with unexplained GDD/ID, WES demonstrates superior diagnostic and clinical utility compared to CMA. Incorporating WES as a first-line investigation in the diagnostic evaluation of GDD/ID may be warranted.
Two siblings are reported who have features of the Marden-Walker syndrome. They have congenital joint contractures, camptodactyly, talipes equinovarus, abnormal facies, global delay in developmental milestones, hypotonia and failure to thrive. About 20 cases have been reported in the world literature. A summary of some of the cases is presented. This syndrome appears to be an autosomal recessive trait in some families.
OBJECTIVE: To review the management and outcome of bilateral congenital true vocal cord paralysis in 22 patients treated over a 16-year period and to review the role of tracheostomy in these patients. DESIGN: Retrospective chart review. SETTING: Pediatric tertiary hospital. PATIENTS: Twenty-two pediatric patients diagnosed with bilateral congenital true vocal cord paralysis. INTERVENTIONS: Flexible or rigid diagnostic evaluation, tracheostomy, and vocal cord lateralization procedures. MAIN OUTCOMES MEASURES: Vocal cord recovery and decannulation. RESULTS: With a mean follow up of 50 months, 15 of 22 patients (68%) with bilateral vocal cord paralysis required tracheostomy for airway securement. Of the 15 tracheotomized patients, 10 were successfully decannulated (8 had spontaneous recovery, whereas 2 required lateralization procedures). Eleven of these patients with tracheostomy had comorbid factors, including neurologic abnormalities (midbrain/brainstem dysgenesis, Arnold-Chiari malformation, global hypotonia, and developmental delay). Of the 7 patients not requiring tracheostomy, 6 recovered vocal cord function (86%). CONCLUSION: In our series of 22 patients with bilateral vocal cord paralysis, 14 had spontaneous recovery of function. Patients managed with tracheostomy were noted to have a high incidence of comorbid factors. In this series, recovery rates were found to be higher in nontracheostomized patients than in tracheostomized patients. Patients can be carefully selected for observation versus tracheostomy at the time of diagnosis based on underlying medical conditions.
Periventricular leukomalacia (PVL) occurring in premature infants, represents a major precursor for neurological and intellectual impairment, and cerebral palsy in later life. The disorder is characterized by multifocal areas of necrosis found deep in the cortical white matter, which are often symmetrical and occur adjacent to the lateral ventricles. There is no known cure for PVL. Factors predisposing to PVL include birth trauma, asphyxia and respiratory failure, cardiopulmonary defects, premature birth/low birthweight, associated immature cerebrovascular development and lack of appropriate autoregulation of cerebral blood flow in response to hypoxic-ischemic insults. The intrinsic vulnerability of oligodendrocyte precursors is considered as central to the pathogenesis of PVL. These cells are susceptible to a variety of injurious stimuli including free radicals and excitotoxicity induced by hypoxic-ischemic injury (resulting from cerebral hypoperfusion), lack of trophic stimuli, as well as secondary associated events involving microglial and astrocytic activation and the release of pro-inflammatory cytokines TNF-alpha and IL-6. It is yet unclear whether activated astrocytes and microglia act as principal participants in the development of PVL lesions, or whether they are representatives of an incidental pathological response directed towards repair of tissue injury in PVL. Nevertheless, the accumulated evidence points to a pathological contribution of microglia towards damage. The topography of lesions in PVL most likely reflects a combination of the relatively immature cerebrovasculature together with a failure in perfusion and/or hypoxia during the greatest period of vulnerability occurring around mid-to-late gestation. Mechanisms underlying the pathogenesis of PVL have so far been related to prenatal ischemic injury to the brain initiated within the third trimester, which result in global cognitive and developmental delay and motor disturbances. Over the past few years, several epidemiological and experimental studies have implicated intrauterine infection and chorioamnionitis as causative in the pathogenesis of PVL. In particular, recent investigations have shown that inflammatory responses in the fetus and neonate can contribute towards neonatal brain injury and development-related disabilities including cerebral palsy. This review presents current concepts on the pathogenesis of PVL and emphasizes the increasing evidence for an inflammatory pathogenic component to this disorder, either resulting from hypoxic-ischemic injury or from infection. These findings provide the basis for clinical approaches targeted at protecting the premature brain from inflammatory damage, which may prove beneficial for treating PVL, if identified early in pathogenesis.
OBJECTIVES: To correlate the presence and levels of total mercury (THg) in cord blood and meconium indicating prenatal exposure with developmental milestones at 2 years and to compare these subjects with controls of comparable age using cognitive adaptive test and clinical linguistic auditory milestone scale (CAT/CLAMS). METHODS: In 48 of the original Tagum (T) subjects, cord blood and meconium Hg levels, head circumference (HC) at birth, and duration of breastfeeding were correlated with CAT/CLAMS at 2 years. At 2 years, THg levels using cold atomic vapor absorption spectrometry were determined in the hair of 46 T subjects and 88 Saranggani (S) controls; THg levels in blood were tested in 48 T subjects and 45 S controls. These levels were correlated with CAT/CLAMS. Both groups had standard physical and neurologic examinations, hearing screen using transitory evoked otoacoustic emissions, serum glutamate pyruvate transaminase, and routine urinalysis. A prevalidated Socioeconomic Means Test was given to both groups. RESULTS: The Hg level in cord blood was negatively correlated with CAT/CLAMS at 2 years. The HC at birth was negatively correlated with levels of Hg in hair of T subjects 2 years later. HC at birth and 2 years hence were positively correlated with CAT/CLAMS. The following were significantly higher in S controls than in T subjects: expressive language quotient 82.569 +/- 2.21 versus 71.57 +/- 2.61; CLAMS 87.96 +/- 2.43 versus 77.67 +/- 2.51; CAT 90.57 +/- 2.22 versus 83.15 +/- 1.43; and full-scale developmental quotient 89.31 +/- 2.14 versus 80.56 +/- 1.86. Fifteen percent of T subjects had global delay (full-scale developmental quotient <or=70) versus 5.48% in S controls. Hg levels in hair and blood in both T subjects and S controls at 2 years showed no correlation with CAT/CLAMS. The duration of breastfeeding in both groups likewise showed no correlations with CAT/CLAMS. CONCLUSION: The study suggests that prenatal Hg exposure is correlated with lower scores in neurodevelopmental screening, but more so in the linguistic pathway. Other confounding factors cannot be eliminated.
The isoprenoid pathway produces three key metabolites--endogenous digoxin, dolichol, and ubiquinone. Since endogenous digoxin can regulate neurotransmitter transport and dolichols can modulate glycoconjugate synthesis important in synaptic connectivity, the pathway was assessed in patients with dyslexia, delayed recovery from global aphasia consequent to a dominant hemispheric thrombotic infarct, and developmental delay of speech milestone. The pathway was also studied in right hemispheric, left hemispheric, and bihemispheric dominance to find out the role of hemispheric dominance in the pathogenesis of speech disorders. The plasma/serum--activity of HMG CoA reductase, magnesium, digoxin, dolichol, ubiquinone--and tryptophan/tyrosine catabolic patterns, as well as RBC (Na+)-K+ ATPase activity, were measured in the above mentioned groups. The glycoconjugate metabolism and membrane composition was also studied. The study showed that in dyslexia, developmental delay of speech milestone, and delayed recovery from global aphasia there was an upregulated isoprenoidal pathway with increased digoxin and dolichol levels. The membrane (Na+)-K+ ATPase activity, serum magnesium and ubiquinone levels were low. The tryptophan catabolites were increased and the tyrosine catabolites including dopamine decreased in the serum contributing to a speech dysfunction. There was an increase in carbohydrate residues of glycoproteins, glycosaminoglycans, and glycolipids levels as well as an increased activity of GAG degrading enzymes and glyco hydrolases in the serum. The cholesterol:phospholipid ratio of RBC membrane increased and membrane glycoconjugates showed a decrease. All of these could contribute to altered synaptic inactivity in these disorders. The patterns correlated with those obtained in right hemispheric chemical dominance. Right hemispheric chemical dominance may play a role in the genesis of these disorders. Hemispheric chemical dominance has no correlation with handedness or the dichotic listening test.
Parents of children with significant behavioral or emotional problems have tended to be concerned about their behavior or emotional well-being, whereas parents of children with speech-language impairments were more concerned about speech-language development. The present study was designed to assess whether a parallel relationship between type of parental concern and type of developmental problem continues when children have global delays. Subjects were 95 parents and their children from birth to 6 years of age who attended day-care centers. Parents' concerns were categorized into developmental domains. Children were given a criterion battery of intelligence and adaptive behavior tests. Global delay was identified in 18 children (19%). Concerns about global development were raised by only 5% of all parents. Concerns about speech-language and/or behavior were sensitive in detecting global deficits (83%), while the absence of such concerns had modest specificity in detecting normal development (47%). Parents' concerns continue to be useful in prescreening and can identify patients in need of further screening. However, pediatricians should anticipate that parents of children with global delays may raise concerns, not about global development, but rather about behavior/emotional status and/or speech-language skills. The best response to such concerns is to administer screening measures which assess multiple developmental domains.
BACKGROUND/PURPOSE: Extracorporeal membrane oxygenation (ECMO) is an accepted therapy for acute respiratory failure but more recently has been used in infants with bronchopulmonary dysplasia (BPD) and superimposed acute pulmonary insults. The purpose of this study was to review the outcomes of such infants. METHODS: Charts of infants at The Children's Hospital of Philadelphia (CHOP) who had a diagnosis of BPD before ECMO were reviewed. In addition, to obtain survival data in a larger population, the Extracorporeal Life Support Organization (ELSO) Registry was searched for infants with BPD before ECMO. RESULTS: Of 204 patients who received noncardiac ECMO at CHOP, 9 had BPD before ECMO. Of 7 survivors, 4 were still ventilator dependent at 9 to 39 months of corrected age. Developmentally, 4 had significant global delays, whereas 3 had significant language and motor delays with average to mildly delayed cognitive abilities. The ELSO Registry search showed 76 patients with BPD before ECMO, with a 78% survival. CONCLUSIONS: The survival rate of infants with BPD who receive ECMO is comparable to, or better than, the survival rates in most other ECMO populations. However, there appears to be a high risk of severe pulmonary and neurodevelopmental sequelae.
INTRODUCTION AND AIMS: The identification of the causes of mental retardation (MR) is of great importance because of the consequences it has in the intervention, prognosis, knowledge of risk of recurrence and its prevention. The purpose of this review is to provide a global evaluation of the child with developmental delay or with MR in day-to-day clinical praxis of the neuropaediatrician who has to put aetiological diagnosis in practice. DEVELOPMENT: To this end we conduct a review of the evidence-based guidelines published by the leading groups of experts that assess the weight of diagnostic tests in the initial evaluation of children with MR and propose an algorithm that helps the clinician to make decisions. CONCLUSIONS: A good patient record including the familial and personal history, the examination and observation of behaviour is essential before starting the laboratory and imaging tests in a rational manner. At the outset, cytogenetic and molecular genetic studies are indicated to study fragile X syndrome and neuroimaging, preferably magnetic resonance, should be employed above all when anomalies are observed in the examination. Ophthalmologic and auditory evaluation is recommended in all cases. Routine metabolic screening is not indicated at the outset; studies to investigate thyroid (T4 and TSH) and other metabolic pathologies can be considered when the child has not been subject to neonatal metabolic screening or when there is clinical evidence of it. Routine electroencephalogram studies are not recommended, but can be considered if suggested by the clinical history. Likewise, the clinician may consider a study for toxins, if the clinical history suggests it, and a genetic study of Rett syndrome, in the case of girls with MR that cannot be accounted for by other causes.
The purpose of this study was to identify the functional domains and etiological risk factors of children with developmental delay (DD). During a 41-month period, a retrospective chart review was carried out on all 1192 patients who visited pediatric clinics for evaluation of developmental delay or behavioral problems. Etiological risk factors or associated disorders were identified after the completion of clinical evaluation and a series of laboratory investigations. Clinical psychologists examined the functional domains of those patients who underwent developmental and psychological assessments. Those children who met the criteria of DD were subdivided into six functional subtypes, including cognitive, motor, language, social adaptation, global and non-specific developmental delay. A total of 1192 children were diagnosed as DD, 86.7% had cognitive DD, 58.4% had language DD and 47.9% had motor DD. Of 1192 children, 831 were male, and the ratio male to female was 2.3 to 1. Only 20.5% (244) of children had identifiable etiological risk factors and 35.6% (424) had associated disorders. Results showed DD was more prevalent in males, and cognitive delay was the most common subtype. Identifying the etiological risk factors of DD remains difficult because of its heterogeneity.
We investigated the relationship between dyslexia and three aspects of language: speech perception, phonology, and morphology. Reading and language tasks were administered to dyslexics aged 8-9 years and to two normal reader groups (age-matched and reading-level matched). Three dyslexic groups were identified: phonological dyslexics (PD), developmentally language impaired (LI), and globally delayed (delay-type dyslexics). The LI and PD groups exhibited similar patterns of reading impairment, attributed to low phonological skills. However, only the LI group showed clear speech perception deficits, suggesting that such deficits affect only a subset of dyslexics. Results also indicated phonological impairments in children whose speech perception was normal. Both the LI and the PD groups showed inflectional morphology difficulties, with the impairment being more severe in the LI group. The delay group's reading and language skills closely matched those of younger normal readers, suggesting these children had a general delay in reading and language skills, rather than a specific phonological impairment. The results are discussed in terms of models of word recognition and dyslexia.
OBJECTIVE: Early intervention (EI) programs provide services to children with developmental conditions, regardless of whether such children have an underlying medical diagnosis. We aim to (1) Determine the proportion of general pediatricians who believe an established diagnosis is important when considering EI referral; and (2) Determine whether this perception is associated with lower reported likelihood of referral. METHODS: Mailed survey to random sample of pediatricians. We used multivariable logistic regression to study the association between the perception that a medical diagnosis is important when referring to EI, and the reported likelihood of EI referral for children with common developmental conditions. RESULTS: Response rate was 55% (894 of 1617). A total of 64% of respondents considered an established diagnosis important for EI referral. Likelihood of referral for delayed speech was lower among those who considered a diagnosis important than among those who did not (77% vs 87%; P = .02). Similar patterns held for global delay (91% vs 97%; P = .02), loss of developmental milestones (80% vs 88%; P = .03), and parental concern for inappropriate development (45% vs 60%; P = .002). In multivariable models, perception of the importance of an established diagnosis was associated with lower likelihood of referral for children with delayed speech (adjusted odds ratio [aOR] 0.48; 95% confidence interval [CI] 0.26-0.87) and for parental concern for inappropriate development (aOR 0.46; 95% CI 0.30-0.72). CONCLUSIONS: A majority of general pediatricians believe that an established diagnosis is important when considering EI referral. This perception is associated with decreased reported referral for children with speech delay and those whose parents express concern for inappropriate development.
Ratings on the Global Assessment Scale for Children (GASC) were assessed in relation to a battery of objective developmental and behavioural measures. Children aged three to six years (N = 55) attending a day treatment program for developmental delays, language disorders, and behavioural and emotional problems comprised the sample. A battery of tests was administered to the children. Parents and teachers completed standardized questionnaires to measure developmental, behavioural and emotional problems. The results indicated that the GASC score correlated significantly with child developmental level, impulse control, and with teacher ratings of social withdrawal. The GASC was unrelated to ratings of behavioural problems. Ratings on the GASC also were highly consistent over time. These results are discussed with respect to the strengths and limitations of using global ratings with preschool children.
Children with epilepsy, as a group, have a greater risk for developing learning problems as comorbid disorders. It is unknown which factors contribute to the development of such learning problems; therefore, our current knowledge does not allow the prediction of educational delay in an individual child with epilepsy. This study aimed at excluding as many factors as possible that could interfere with the analysis of the impact of epilepsy on learning. From patients referred to us in 1997 (N = 123), children were included with mild global learning impairment, defined as educational delay between 6 months and 1 year and no other apparent reason for learning impairment except for epilepsy (ie, excluding children with dyslexia, attention-deficit hyperactivity disorder, or mental handicap). A total of 44 patients fulfilled this criterion: 31 also had epilepsy (experimental group); the remaining 13 patients with similar mild learning impairment but without epilepsy were used as controls. In the experimental group two subgroups were distinguished on the basis of onset of learning impairment: in group A (n = 17) the learning problems are not unexpected as they were preceded by mild developmental delay; in group B (n = 14) the problems are unexpected and had a sudden onset. The two experimental groups differed from the control group on a number of variables, such as gender and the incidence of perinatal complications. More differences have been found between the two experimental groups: group B is selected from a larger group: all children with mild global learning impairment with sudden onset. In this group considerably more children with epilepsy have been found compared to the children with developmental delay; moreover the epilepsy is more often characterized in these children as "unexpected," that is, there was no previous established diagnosis of epilepsy, the symptoms were mostly unclear and behavioral in make-up (attentional lapses, etc); the electroencephalogram plays a much greater role in the diagnosis in this group, especially in demonstrating seizures; finally, the children in this group more frequently have neuropsychologic impairment. Children with epilepsy can have mild global learning difficulties, especially in the period after the onset of seizures. This group can be divided in a group with "trait-dependent learning difficulties," that is learning difficulties based on developmental delay, and a group with "state-dependent learning difficulties." The focus in our study was on this latter group, consisting of children with sudden and unexpected decline of results in school. The crucial finding in this group is the relatively frequent demonstration of difficult-to-detect seizures, demonstrating that an uncontrolled epilepsy can cause a decline in school results even when the seizures are of short duration and have subtle symptoms.
OBJECTIVE: The aim of this preliminary pilot study was to investigate the safety and efficacy of open-label nadolol as an adjunctive pharmacological treatment for aggression and/or inattention/overactivity in a developmentally delayed child, adolescent, and young adult population. METHOD: Twelve subjects enrolled and completed (mean age 13.8 years, range 9 through 24) a 5-month, open, prospective protocol of nadolol (mean dose 109 mg, range 30 through 220 mg) with systematic baseline and outcome evaluations and weekly clinical assessment. RESULTS: All subjects were developmentally delayed and most were cognitively delayed. Ten subjects (83%) showed clinical improvement while receiving nadolol. Significant improvements were noted on observer-rated overt categorical aggression, severity of illness, and global impressions of improvement. No significant effects were found for inattention/overactivity. Nadolol was well tolerated, with few side effects. CONCLUSIONS: Overt categorical aggression presenting in developmentally delayed children, adolescents, and young adults may respond to nadolol treatment.
Lead poisoning is a global public health problem. In pregnant women it may result in developmental delays of the fetus, in children it my produce learning disability. Available chelators are nephrotoxic when eliminated as lead-chelator complexes. For safe removal of lead from the body we developed a "Lead-Hemopurifier" (L-HP), a device with an immobilized chelator. In vitro, applied to lead solutions, this device reduced the lead concentration. Applied to dogs with lead intoxication, Lead-HP-s removed lead from the blood; this was continuously replaced by lead from the bones until the skeleton was cleared from lead deposit. Treatment of lead poisoning in dogs with Lead-HP-s compared favorably with Versenate treatment of children with lead toxicity. This report demonstrates the in vivo efficiency and safety of this new detoxfication method. Methods to induce lead poisoning in dogs and procedures to identify lead released from skeletal deposits are described.
UNLABELLED: BACKGROUND. The preterm infant is subject to the force of gravity: when its body lies pressed against the mattress on which it is placed. AIMS: The purpose of this study was to investigate short-term effects of varied post-natal lying positions in order to prevent neuromuscular and postural abnormalities. METHODS: 60 low risk preterm infants of 31-36 weeks gestational age were enrolled for this randomised clinical trial. Initially each child underwent neurological and psychomotor assessments which included tonus and reflex protocols as well as behavioral, sensory motor and postural examinations. The lying positions of the treated group were varied (back, prone, and side) using a specially designed moldable mattress that maintained the functional position of the infant's body. The control group was placed on their stomachs, (the standard lying position used in 1994) with a standard orthopaedic bolster support under their hips. All infants underwent a second round of examinations upon discharge to assess any changes in neurological and psychomotor outcomes. RESULTS: The sensory-motor skills examinations showed significant abnormalities in the control group: (1) dominance of the extensor muscles due to muscle shortening, (2) hyper abduction and flexion of the arms, and (3) global neuromuscular rigidity. Psychomotor and neurological exams of the control and treatment groups showed delayed developmental muscular acquisitions for infants in the control group. CONCLUSION: Regular changes in posture, while retaining correct functional positions, allowed maintenance of normal neuromuscular and osteo-articular function and permitted the development of spontaneous and functional motor activity in low-risk perterm infants.