Diagnostic yield of the neurologic assessment of the developmentally delayed child

doi:10.1016/S0022-3476(95)70294-6

The Journal of Pediatrics

Volume 127, Issue 2, August 1995, Pages 193-199

Presented in part at the Child Neurology Society meeting, San Francisco, Calif., October 1994.

https://doi.org/10.1016/S0022-3476(95)70294-6 Get rights and content

Abstract

Objective: The aim of this study was to determine the etiologic yield of the neurologic assessment of a consecutive cohort of developmentally delayed children. Study design: A retrospective chart review was carried out on all patients referred to a single university-based pediatric neurologist for evaluation of global developmental delay from July 1991 to December 1993. Patients referred because of isolated speech or motor delay or autism or those who had been previously evaluated by another neurologist were excluded. Results: A total of 77 patients were identified; 47 were male, and 62 were referred by a pediatrician. Neurologic evaluation did not confirm global delay in 10, and 8 did not complete diagnostic evaluation; one child was included in both groups. Of the remaining 60, an etiologic diagnosis was suspected by the referring physician at the time of referral in 13. Although parents suspected a delay at a mean age of 0.66 (±0.69) year, children were examined by the neurologist at a mean age of 3.58 (±2.42) years. Twenty-five were mildly delayed, 23 were moderately delayed, and 12 were severely delayed. Diagnostic studies (history, physical examination, and selected investigations, including screens for metabolic disease, karyotype, fragile X testing, electroencephalography, and neuroimaging) yielded an etiologic diagnosis in 38 (63.3%) of the 60 patients. Etiologic categories included cerebral dysgenesis (16.7%), hypoxic-ischemic encephalopathy (10.0%), chromosomal abnormalities (10%), toxins (8.3%), metabolic disorders (5.0%), and neurocutaneous (3.3%), neuromuscular (3.3%), genetic/dysmorphic (3.3%), and epileptic (3.3%) syndromes. Etiologic yield was equivalent across categories and degree of developmental delay. Conclusion: Referral to a pediatric neurologist and application of a selected battery of investigations yield etiologic findings with important implications with respect to management, prognosis, and recurrence risk estimate in a significant portion of globally delayed children. (J PEDIATR 1995;127:193-9)

Section snippets

Inclusion criteria

All children referred to a single university-based pediatric neurologist (M.I.S.) for evaluation of developmental delay between July 1, 1991, and Dec. 31, 1993, were initially identified through a review of a comprehensive, standardized computerized database (Claris Filemaker Pro C), which includes all patients seen by this neurologist since he commenced practice. The database has multiple “fields” relevant to patient identification, history (including “reason for referral” and “age at onset”),

Sample characteristics

Within the 21/2-year period, 77 children were referred to the pediatric neurologist with a primary diagnosis of developmental delay. Those subsequently excluded from analysis were those with only gross motor (n = 3) or speech delay (n = 2), with no clinical evidence of delay (n = 3), or in whom the delay had resolved by the time of the initial neurologic assessment (n = 2). Eight families elected not to complete all investigations requested, and their children were also excluded. One of the

DISCUSSION

In our consecutive cohort of children referred for evaluation of global developmental delay, an etiologic diagnosis was made in 63.3%. Previous series have been largely restricted to institutionalized cohorts of persons with severe mental retardation.6, 10, 11 Limited data exist on determination of etiologic diagnosis in persons with mild mental retardation; these studies are hampered by the assumption that sociocultural factors play the major role, thus limiting the extent of investigations

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Global developmental delay and intellectual disability in the era of genomics: Diagnosis and challenges in resource limited areas
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To report the diagnostic yield of clinical singleton whole exome sequencing (WES) performed among a group of Jordanian children presenting with global developmental delay /intellectual disability (GDD/ID), discuss the underlying identified genetic disorders and the challenges encountered.
This retrospective medical record review study included 154 children who were diagnosed with GDD/ID at our clinic at Jordan University Hospital between 2016 and 2021, and whose diagnostic work up included WES.
Consanguinity among parents was reported in 94/154 (61.0%) patients and history of other affected siblings in 35/154 (22.7%) patients.
Pathogenic and likely pathogenic variants (solved cases) were reported in 69/154 (44.8%) patients, a variant of uncertain significance was reported in 54/154 (35.0%) and a negative result was reported in 31/154 (20.1%) cases.
In the solved cases, autosomal recessive diseases were the most common (33/69; 47.8%). Metabolic disorders were identified in 20/69 (28.9%) patients, followed by developmental and epileptic encephalopathies (9/69; 13.0%) and MECP2 related disorders (7/69; 10.1%). Other single gene disorders were identified in 33/69; 47.8%) patients.
This study had several limitations, as it was hospital-based and only including patients who were able to afford the test. Nevertheless, it yielded several important findings. In resource-limited countries, WES may be a reasonable approach. We discussed the challenges that clinicians meet in the context of shortage of resources.
Clinical approach to developmental delay and intelectual disability
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El diagnóstico precoz de los trastornos del desarrollo permite detectar causas tratables, realizar intervenciones oportunas y dar respuestas a inquietudes de la familia evitando procedimientos innecesarios. Se requiere un enfoque clínico que permita distinguir entre retraso en la emergencia de habilidades, desarrollo atípico o pérdida de habilidades ya adquiridas, como también si se trata de un retraso en un área específica del desarrollo o compromete el desarrollo en forma global. Es necesario considerar el retraso global del desarrollo o discapacidad intelectual como un fenotipo amplio y heterogéneo, manifestación de diversos trastornos o etiologías subyacentes, por lo que se han diseñado algoritmos estructurados por asociaciones académicas, que incluyen estrategias para la sospecha etiológica y recomendaciones de estudios de neuroimagen, metabólicos o genéticos, reconociendo a la historia y el examen físico como fundamentales en el proceso de diagnóstico, permitiendo además la pesquisa de trastornos asociados de visión o audición y el manejo oportuno de comorbilidad psiquiátrica de mayor prevalencia en este grupo de niños. Considerando que el estudio diagnóstico puede requerir bastante tiempo, se deben iniciar intervenciones en los problemas detectados y en apoyo a los padres y al desarrollo del niño mientras se esperan resultados.
Participar en estrategias de prevención de discapacidad intelectual, tanto como en las de promoción de desarrollo óptimo en la infancia, es una responsabilidad para todos los profesionales dedicados a desarrollo infantil.
Early diagnosis of developmental disorders makes it possible to detect treatable causes, carry out timely interventions and respond to family concerns, avoiding unnecessary procedures. A clinical approach is required to distinguish between delay in the emergence of skills, atypical development or loss of skills already acquired, as well as whether it is a delay in a specific area of development or compromises development globally. It is necessary to consider global developmental delay or intellectual disability as a broad and heterogeneous phenotype, a manifestation of various disorders or underlying etiologies, which is why algorithms structured by academic associations have been designed, which include strategies for etiological suspicion and recommendations for studies of neuroimaging, metabolic or genetic, recognizing the history and physical examination as fundamental in the diagnostic process, also allowing the investigation of associated vision or hearing disorders and the timely management of psychiatric comorbidity of greater prevalence in this group of children. Considering that the diagnostic study can take a long time, interventions should be started on the problems detected and in support of the parents and the child's development while the results are awaited.
Participating in strategies for the prevention of intellectual disability, as well as in those for the promotion of optimal development in childhood, is a responsibility for all professionals dedicated to child development
Associations between Human Milk Oligosaccharides at 1 Month and Infant Development throughout the First Year of Life in a Brazilian Cohort
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To investigate the associations between HMO concentrations at 1 month and infant development throughout the first year of life.
A prospective cohort of Brazilian women between 18–40 years of age and their infants was studied from baseline (between 28–35 gestational weeks) and followed at 1 (n = 73), 6 (n = 51), and 12 months (n = 45). A total of 19 HMOs were quantified by HPLC with fluorescence detection. Infant development was evaluated by the Brazilian Ages and Stages Questionnaire. A directed acyclic graph was used to define the minimally sufficient adjustment (gestational age at birth, gestational weight gain, prepregnancy BMI, maternal age, parity, and the mode of breastfeeding at 1 month). Cox regression models with HRs and Benjamini-Hochberg multiple corrections were performed to estimate associations of HMOs with the cumulative risk of inadequate development for 5 developmental domains or for ≥2 developmental domains in all women and in the subset of secretor women (defined as the presence or near absence of 2′-fucosyllactose and lacto-N-fucopentaose I).
The multivariate models with multiple corrections revealed an inverse association between lacto-N-tetrose (LNT) and the risk of inadequate development for personal-social skills (0.06; 95% CI: 0.01–0.76) and for ≥2 developmental domains (0.06; 95% CI: 0.01–0.59). The secretor mothers analysis also showed inverse associations with slightly different results for personal-social skills (0.09; 95% CI: 0.02–0.84) and ≥2 developmental domains (0.05; 95% CI: 0.01–0.70).
Higher concentrations of LNT HMOs in Brazilian women are associated with their infants being less likely to be at risk of inadequate development for personal-social skills or for ≥2 developmental domains during the first year of life.
CASK related disorder: Epilepsy and developmental outcome
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Citation Excerpt :
For the purposes of this study, we considered a developmental delay (DD) when a delay in two or more developmental areas was present (gross motor, fine motor, cognition, speech/language, personal/social, or activities of daily living) [19]. Mild DD was defined as a functional age of 66% of the chronological age, moderate DD as a functional age of 34%–66% of the chronological age, severe DD as a functional age below 33% and profound when below 25% of chronological age [20,21]. An EEG activation during sleep was considered when spikes in NREM sleep covered at least more than 25% of the sleep EEG tracing (as assessed by 2 clinical neurophysiologists) [22,23].
CASK pathogenic variants are associated with variable features, as intellectual disability, optic atrophy, brainstem/cerebellar hypoplasia, and epileptic encephalopathy. Few studies describe the electroclinical features of epilepsy in patients with CASK pathogenic variants and their relationship with developmental delay.
this national multicentre cohort included genetically confirmed patients with different CASK pathogenic variants. Our findings were compared with cohorts reported in the literature.
we collected 34 patients (29 females) showing from moderate (4 patients) to severe (22) and profound (8) developmental delay; all showed pontine and cerebellar hypoplasia, all except three with microcephaly. Seventeen out of 34 patients (50%) suffered from epileptic seizures, including spasms (11 patients, 32.3%), generalized (5) or focal seizures (1). In 8/17 individuals (47.1%), epilepsy started at or beyond the age of 24 months. Seven (3 males) out of the 11 children with spasms showed EEG features and a course supporting the diagnosis of a developmental and epileptic encephalopathy (DEE). Drug resistance was frequent in our cohort (52.9% of patients with epilepsy). EEG abnormalities included poorly organized background activity with diffuse or multifocal epileptiform abnormalities and sleep-activation, with possible appearance over the follow-up period. Developmental delay degree was not statistically different among patients with or without seizures but feeding difficulties were more frequent in patients with epilepsy.
epilepsy is a frequent comorbidity with a high incidence of spasms and drug resistance. Overall developmental disability does not seem to be more severe in the group of patients with epilepsy nor to be linked to specific epilepsy/EEG characteristics. A childhood onset of epilepsy is frequent, with possible worsening over time, so that serial and systematic monitoring is mandatory.
Novel truncating and missense variants extending the spectrum of EMC1-related phenotypes, causing autism spectrum disorder, severe global development delay and visual impairment
2020, European Journal of Medical Genetics
Citation Excerpt :
Global development delay is a clinically and etiologically heterogeneous group of disorders that affects up to 3% of children (Shevell et al., 2003). It can be related to exogenous, metabolic or non-metabolic genetic diseases with inconstant structural brain abnormalities (Majnemer and Shevell, 1995). Making the precise diagnosis is all the more important as the prognosis and management differ between the different etiologies.
The EMC1 gene, located on 1p36.13, encodes the subunit 1 of the endoplasmic reticulum-membrane protein complex, a highly conserved and ubiquitous multiprotein transmembrane complex. Pathogenic monoallelic and biallelic variants in EMC1 in humans have been reported only in six families, causing isolated visual impairment or in association with psychomotor retardation and cerebellar atrophy. We report a ten-year-old boy, born to unrelated parents, with early-onset severe global development delay due to novel EMC1 biallelic pathogenic variants. A truncating variant, p.(Tyr378*) and a missense variant, p.(Phe953Ser), located in exon 11 and 23 of EMC1 gene respectively, have been found by reanalysis of exome sequencing data. The proband's phenotype included several signs that overlap with the phenotype of previously reported patients, associating severe global developmental delay, abnormal ophthalmological examination, and postnatal slow-down of the head circumference growth. Some distinguishing clinical signs were observed in comparison to patients from literature, such as autism spectrum disorder, absence of seizures, scoliosis or facial dysmorphic features, thus extending the spectrum of EMC1-related phenotypes. Similarly, brain MRI, performed at 2 years, showed normal cerebellar volume and structure, whereas cerebellar atrophy was described in literature. Moreover, difficulties of clinical differential diagnosis between EMC1-associated disease and other etiologies of global development delay support the importance of large-scale genetic investigations. Our diagnostic approach, through reanalysis of exome sequencing data, highlights the importance of reconsidering initial negative results for patients with a strong suspicion of genetic disease, and to update analytic pipelines in order to improve the diagnostic yield of exome sequencing.
Accuracy of in-utero MRI to detect fetal brain abnormalities and prognosticate developmental outcome: postnatal follow-up of the MERIDIAN cohort
2020, The Lancet Child and Adolescent Health
In utero MRI (iuMRI) detects fetal brain abnormalities more accurately than ultrasonography and provides additional clinical information in around half of pregnancies. We aimed to study whether postnatal neuroimaging after age 6 months changes the diagnostic accuracy of iuMRI and its ability to predict developmental outcome.
Families enrolled in the MERIDIAN study whose child survived to age 3 years were invited to have a case note review and assessment of developmental outcome with the Bayley Scales of Infant and Toddler Development, the Ages and Stages Questionnaire, or both. A paediatric neuroradiologist, masked to the iuMRI results, reviewed the postnatal neuroimaging if the clinical report differed from iuMRI findings. Diagnostic accuracy was recalculated. A paediatric neurologist and neonatologist categorised participants' development as normal, at risk, or abnormal, and the ability of iuMRI and ultrasonography to predict developmental outcome were assessed.
210 participants had case note review, of whom 81 (39%) had additional investigations after age 6 months. The diagnostic accuracy of iuMRI remained higher than ultrasonography (proportion of correct cases was 529 [92%] of 574 vs 387 [67%] of 574; absolute difference 25%, 95% CI 21 to 29; p<0·0001). Developmental outcome data were analysed in 156 participants, and 111 (71%) were categorised as normal or at risk. Of these 111 participants, prognosis was normal or favourable for 56 (51%) using ultrasonography and for 76 (69%) using iuMRI (difference in specificity 18%, 95% CI 7 to 29; p=0·0008). No statistically significant difference was seen in infants with abnormal outcome (difference in sensitivity 4%, 95% CI −10 to 19; p=0·73).
iuMRI remains the optimal tool to identify fetal brain abnormalities. It is less accurate when used to predict developmental outcome, although better than ultrasonography for identifying children with normal outcome. Further work is needed to determine how the prognostic abilities of iuMRI can be improved.
National Institute for Health Research Health Technology Assessment programme.

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^☆: The authors make a good case for "working up" the young child with global developmental delay when the cause is not apparent. However, most of the recommended examinations and studies could be accomplished or ordered by a well-trained general pediatrician, and as the authors point out, cost containment is a significant concern. Perhaps consultation with a neurologist is not always needed in the evaluation of developmental delay in such children unless specific neurlogic issues need to be addressed.—J.M.G., Editor

^☆☆: From the School of Physical and Occupational Therapy, Departments of Neurology/Neurosurgery, Pediatrics, and Human Genetics, Montreal Children's Hospital-McGill University, Montreal, Quebec, Canada

^★: Reprint requests: Annette Majnemer, PhD, Montreal Children's Hospital, 2300 Tupper St., Room A-509, Montreal, Quebec H3H 1P3, Canada.

^★★: 0022-3476/95/$3.00 + 0 9/20/64849

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Diagnostic yield of the neurologic assessment of the developmentally delayed child☆,☆☆,★,★★

Abstract

Section snippets

Inclusion criteria

Sample characteristics

DISCUSSION

Pediatr Clin North Am

Pediatr Clin North Am

Brain Dev

J PEDIATR

J PEDIATR

Pediatr Neurol

Pediatr Neurol

Pediatr Neurol

Pediatr Neurol

J PEDIATR

Predictive value of screening for difficult areas of development

Dev Med Child Neurol

Developmental delays

Impetus from public law 99-457

Pediatrics

Review of recent epidemiological studies of mental retardation: prevalence, associated disorders, and etiology

Am J Ment Retard

The biologic origin of mild mental retardation

Acta Psychiatr Scand

The infant or young child with developmental delay

N Engl J Med