Lesson of the week: late diagnosis of Duchenne's muscular dystrophy presenting as global developmental delay.
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Age Factors↗
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Results for “global developmental delay”
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Practice parameter: evaluation of the child with global developmental delay.
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Child↗
Practice parameter: evaluation of the child with global developmental delay.
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Child↗
Postnatal follow-up of prenatally diagnosed trisomy 16 mosaicism.
OBJECTIVE: To determine the long-term outcome of pregnancies prenatally diagnosed with trisomy 16 and identify variables associated with the outcome. METHODS: We reviewed all published and our unpublished data from trisomy 16 pregnancies for which outcomes were available for children of greater than 1 year of age. RESULTS: Nineteen cases were diagnosed with trisomy 16 on chorionic villus sampling (CVS) and 17 cases at amniocentesis. Age at last follow-up ranges from 1 to 13 years. Among the CVS group, four out of five patients, with a birth weight and/or length below -2 SD and postnatal growth information, showed catch-up growth (80%). Among the amniotic fluid (AF) group, the birth weight was available in 13 cases. Eleven of the 13 cases had a birth weight less than -2 SD. In eight cases, the length was also below -2 SD (length data unavailable in one case). Nine out of ten cases (90%) and seven out of eight (87.5%) showed catch-up growth for weight and length, respectively. In terms of development, no cases of CVS mosaicism had global developmental delay. One child had a history of delay in speech development. Among the AF-detected cases, 4/17 cases had global developmental delay. All four children with global developmental delay had more than one major malformation compared to 6 out of 32 children in the group with normal development (p = 0.004). The finding of uniparental disomy (UPD) was not associated with developmental delay. CONCLUSIONS: The majority of prenatally diagnosed trisomy 16 mosaic cases have a good postnatal outcome. However, the finding of mosaicism on AF and the presence of major congenital anomalies are associated with an increased risk of developmental delay.
Amniocentesis↗
Incidence of brain creatine transporter deficiency in males with developmental delay referred for brain magnetic resonance imaging.
Several case reports describe children with global developmental delay who have brain creatine deficiency, where the deficiency was due to a lack of creatine transport into the brain or altered creatine synthesis. The purpose of this study was to determine what percentage of males with developmental delay referred for brain magnetic resonance imaging (MRI) at the authors' institution in a 12-month period was found to have brain creatine deficiency due to a defect in the creatine transporter gene. In the authors' facility, single voxel proton magnetic resonance spectroscopy (MRS) is routinely performed on any male child age 2 to 18 years with a history of language and/or developmental delay referred for a brain MRI. Charts for the 12-month time period were retrospectively reviewed. Fourteen subjects met inclusion criteria for global developmental delay. Two of the 14 patients had brain creatine deficiency on MRS. In the remaining 12, other structural and white matter abnormalities were identified. This study suggests that brain creatine deficiency is an important consideration in the differential diagnosis of males with global developmental delay referred for brain MRI; brain MRS should be considered in such cases.
Adolescent↗
Profile of pediatric hemiparesis.
Our objective was to determine the clinical spectrum of pediatric hemiparesis by identifying the relative frequency of various diagnoses and comorbid conditions seen in these children. Case records of all patients with hemiparesis in a single practice over an 11-year period were reviewed with reference to clinical features, etiologic determination, and comorbid conditions. Ninety-two children were identified: 73 (79.3%) had a congenital hemiparesis and 19 (20.7%) had an acquired hemiparesis. An abnormal perinatal history (P = .003), prematurity (P = .016), and younger age at onset of symptoms (P < .001) were associated with a congenital hemiparesis. The overall etiologic yield was 83.7% (82.2% in the congenital and 89.5% in the acquired). The top four etiologic entities were cerebrovascular ischemia (40.2%), periventricular leukomalacia (18.5%), intracranial hemorrhage (16.3%), and cerebral dysgenesis (13%). Factors predictive of establishing an underlying etiology included birth prior to 34 weeks' gestation (P = .034), global developmental delay (P = .048), epilepsy (P = .024), and having appropriate imaging modalities (P = .001). Half of these children had a concurrent global developmental delay, associated epilepsy (odds ratio 3.67; 95% confidence interval 1.40-9.72), and prematurity (odds ratio 5.41; 95% confidence interval 1.56-18.80). A third of these children developed epilepsy. Multivariate predictive factors for epilepsy included global developmental delay (odds ratio 4.20; 95% confidence interval 1.44-12.27), cerebrovascular ischemia (odds ratio 5.10; 95% confidence interval 1.76-14.77), and term birth (odds ratio 3.87; 95% confidence interval 1.20-12.56). The majority of children with hemiparesis have a congenital etiology. The diagnostic yield is higher than previously reported; however, specific underlying etiologies need to be better determined. Comorbid conditions of global developmental delay and epilepsy have a high prevalence in this population, contributing to overall morbidity.
Adolescent↗
Neuromotor spectrum of periventricular leukomalacia in children born at term.
The spectrum of neuromotor abnormalities of term children with periventricular leukomalacia (PVL) has never been specifically defined. We report 12 term children with PVL to delineate its long-term clinical correlates. A retrospective review of a standardized computer database and files of a single pediatric neurologist during a 7-year period was performed. The imaging studies were reviewed independently by two neuroradiologists. The mean age of the patients at the initial neurologic assessment was 24. 4 months (range 5-60); nine were males. The reason for the assessment was developmental delay in 10 (83.3%), seizure in one, and attention-deficit-hyperactivity disorder in one. Three children (25%) had normal motor examinations, three (25%) were hypotonic, three (25%) had spastic diplegia, two (16.7%) had spastic quadriplegia, and one (8.3%) had fine-motor abnormalities. Nine children (75%) had developmental delay (severe global delay in six), and two children (16.7%) had epilepsy; electroencephalograms were abnormal in six (50%). PVL was mild in five (41.7%), moderate in two (16.6%), and severe in five (41.7%) children. Four of eight children with global developmental delay had enlargement of cerebral sulci in addition to white matter changes. PVL in term children presents with a spectrum of neurologic abnormalities, particularly developmental delay and heterogeneous motor findings not limited to classic spastic diplegia. The clinician should consider the diagnosis of PVL in the context of term children with developmental delay and motor abnormalities, even in the absence of perinatal difficulties.
Child, Preschool↗
Profile of referrals for early childhood developmental delay to ambulatory subspecialty clinics.
The objective of this study was to determine the profile and pattern of referral to subspecialty clinics of young children with suspected developmental delay together with the factors prompting their referral. All children under 5 years of age referred to either developmental pediatrics or pediatric neurology clinics at a single tertiary hospital over an 18-month period were prospectively identified. Standardized demographic and referral information were collected at intake, final developmental delay subtype diagnosed was identified, and referring physicians were surveyed regarding factors prompting referral. A total of 224 children met study criteria. There was a marked male preponderance (166/224), especially among those with either cognitive or language delay. Two delay subtypes, global developmental delay and developmental language disorder, accounted for two thirds of the diagnoses made. For slightly more than one third of the children (75/224), the delay subtype diagnosed following specialty evaluation was different from that initially suspected by the referring physician. A mean delay of 15.5 months was observed for the cohort as a whole between initial parental concern and specialty assessment. For referring physicians, the major factor prompting referral was the severity of the observed delay. The most important aspects of the specialty evaluation according to referral sources were the identification of a possible etiology and confirmation of delay. A profile of referrals and the rationale thereof for a cohort of children with suspected developmental delay is presented that, although locale specific, has implications for service provision and training.
Ambulatory Care↗
Identification of a recurrent breakpoint within the SHANK3 gene in the 22q13.3 deletion syndrome.
INTRODUCTION: The 22q13.3 deletion syndrome (MIM 606232) is characterised by neonatal hypotonia, normal to accelerated growth, absent to severely delayed speech, global developmental delay, and minor dysmorphic facial features. We report the molecular characterisation of the deletion breakpoint in two unrelated chromosome 22q13.3 deletion cases. METHODS: The deletions were characterised by FISH, checked for other abnormalities by array-CGH, and confirmed by Real-Time PCR, and finally the breakpoints were cloned, sequenced, and compared. RESULTS: Both cases show the cardinal features of the 22q13.3 deletion syndrome associated with a deletion involving the last 100 kb of chromosome 22q13.3. The cases show a breakpoint within the same 15 bp repeat unit, overlapping the results obtained by Wong and colleagues in 1997 and suggesting that a recurrent deletion breakpoint exists within the SHANK3 gene. The direct repeat involved in these 22q13 deletion cases is presumably able to form slipped (hairpin) structures, but it also has a strong potential for forming tetraplex structures. DISCUSSION: Three cases with a common breakpoint within SHANK3 share a number of common phenotypic features, such as mental retardation and developmental delay with severely delayed or absent expressive speech. The two cases presented here, having a deletion partially overlapping the commercial subtelomeric probe, highlight the difficulties in interpreting FISH results and suggest that many similar cases may be overlooked.
Abnormalities, Multiple↗
Etiologic determination of childhood developmental delay.
To determine the etiologic yield in young children with developmental delay referred to sub-specialty clinics for evaluation. Over an 18-month period, all children less than 5 years of age referred to the ambulatory pediatric neurology or developmental pediatrics clinics of the Montreal Children's Hospital for initial evaluation of a suspected developmental delay were enrolled. Features evident on history or physical examination were determined at intake as were the laboratory tests (and their rationale) requested by the evaluating physicians. Six months post initial assessment, detailed chart review was undertaken to determine if an etiology was found and the basis for such a determination. Bivariate and multivariate logistic regression was used to test for associations between factors present at intake and successful ascertainment of an underlying etiology. Two hundred and twenty-four children met study criteria. Etiologic yield varied across childhood developmental delay subtypes, and was 44/80 for global developmental delay [GDD] (55%), 13/22 for motor delay [MD] (59.1%), 3/72 for developmental language disorders [DLD] (4.2%), and 1/50 for autistic spectrum disorders [ASD] (2%). For GDD, the presence of historical features or findings on physical examination was associated with greater likelihood for successful etiologic determination with the following items significant in multiple logistic regression analysis; microcephaly, antenatal toxin exposure, focal findings. For MD, physical findings or the co-existence of a cerebral palsy symptom complex predicted a successful search for etiology. For both groups, the severity of the delay did not predict etiologic yield. For both groups, a small number of etiologic categories accounted for the majority of diagnoses made. Etiologic yield in childhood developmental delay is largely dependent on the specific developmental delay subtype. Paradigms for systematic evaluation of this common child health problem can be suggested, however they await validation.
Autistic Disorder↗
CHAMP1-Related Neurodevelopmental Disorder: Two Turkish Cases with Novel Truncating Variants and Literature Review.
INTRODUCTION: CHAMP1-related neurodevelopmental disorder (CHAMP1-NDD; neurodevelopmental disorder with hypotonia, impaired language, and dysmorphic features; MIM: 616579) is a rare autosomal-dominant condition caused by de novo truncating variants leading to haploinsufficiency. The phenotype is characterized by global developmental delay, intellectual disability, severe speech impairment, hypotonia, distinctive craniofacial features, and variable multisystem involvement. CASE PRESENTATION: We describe two unrelated girls harboring novel de novo truncating CHAMP1 variants. Both presented with global developmental delay, profound speech impairment, hypotonia, postnatal growth impairment, and characteristic craniofacial features. Neuroimaging demonstrated normal findings in 1 patient and a thin corpus callosum in the other. Additional manifestations included high-grade vesicoureteral reflux in one individual and sensory dysregulation, reduced pain sensitivity, early-onset hyperphagia, and recurrent respiratory infections in the other. Perinatal complications were noted in one case; however, the overall phenotype was considered primarily attributable to the underlying genetic diagnosis. Exome sequencing identified heterozygous truncating variants, NM_032436.4:c.2081_2082del; p.Ser694* and NM_032436.4:c.2062dup; p.Glu688Glyfs*8, both confirmed as de novo and classified as likely pathogenic according to American College of Medical Genetics and Genomics (ACMG) criteria. CONCLUSION: These cases expand the mutational spectrum of CHAMP1 and further delineate the phenotypic variability of this disorder, highlighting under-recognized systemic and behavioral features. Recognition of these additional clinical observations may facilitate earlier diagnosis and multidisciplinary management, although further studies in larger cohorts are required to clarify their clinical relevance.
CHAMP1↗
Neurodevelopmental delay associated with nonconvulsive status epilepticus in a toddler.
Nonconvulsive status epilepticus is a prolonged and continuous state of increased unawareness without overt motor seizures linked with repetitive generalized epileptic discharges. In children, it may occur de novo but more commonly may complicate a preexisting epileptic disorder. We report on a 2-year-old female who presented with global developmental delay as the main manifestation of nonconvulsive status epilepticus. Following valproic acid treatment, her motor, cognitive, and speech delays had gradually subsided and nearly completely resolved, in concert with normalization of electroencephalography (EEG). Hence, given a possible, albeit rare, presentation of nonconvulsive status epilepticus with global developmental delay, we suggest that EEG should be recommended in any infant who manifests neurodevelopmental delay.
Cerebral Cortex↗
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↗
Plantar lipomatosis, unusual facial phenotype and developmental delay: a new MCA/MR syndrome.
We describe two boys with global developmental delay and a phenotype of microcephaly, midface hypoplasia, enlarged fleshy ears, depressed nasal bridge, anteverted nostrils, central palatal ridge, and high forehead. Bilateral congenital fat pads are present anteromedial to the heels. Fetal finger and toe pads are present and palmar and plantar grooves are deeper than normal with "pillowing" of the areas between the grooves. No patients with similar clinical findings have been located, but these two children have a remarkably similar clinical presentation which we consider a "new" syndrome.
Child↗
Microcephaly, seizures, genital hypoplasia, and abnormalities of the hands and feet in a 4-year-old boy with possible Wiedemann syndrome.
We report on a 4-year-old boy with short stature, microcephaly, BNS (Blitz-Nick-Salaam) seizures, and global developmental delay. In addition, small and fleshy hands and feet as well as hypoplastic scrotum and testes were observed. The clinical features of the patient are compared with the patients previously described by Wiedemann et al. and Nevin et al. They reported three patients with a syndrome characterized by short stature, microcephaly, global developmental delay, abnormalities of hands and feet, seizures, large anterior fontanelle, scrotal hypoplasia, micropenis, cryptorchism, urinary tract abnormalities, and inguinal hernia (Wiedemann syndrome).
Abnormalities, Multiple↗
Fine motor deficit: an etiologically distinct entity.
The prevalence of risk and adverse factors associated with fine motor disorder (n = 35) were compared with gross motor deficit (n = 158), global developmental delay (n = 336), and combined fine and gross motor deficit among 1,241 children up to 3 years of age identified in the Haifa health district. A significantly increased preponderance of males was observed among the study group as compared to the group with gross motor deficit. Intranatal problems were significantly increased among children with fine motor deficits as compared to those with gross motor deficits as were minor physical anomalies, seizures, and behavioral deficits. Less significant differences were observed between the study group and children with global developmental delay or fine and gross motor deficit. The different risk factor profiles indicated that the children with fine motor deficits constituted an etiologically distinct group highly associated with early antepartum, possibly genetic, origins.
Brain Damage, Chronic↗
Molecular characterisation of patients with subtelomeric 22q abnormalities using chromosome specific array-based comparative genomic hybridisation.
The 22q13 deletion syndrome is associated with global developmental delay, absent or delayed speech, and generalised hypotonia. In this study, the size and nature of 22q13 deletions (n=9) were studied in detail by high-resolution chromosome specific array-based comparative genomic hybridisation (array CGH). The deletion sizes varied considerably between the different patients, that is, the largest deletion spanning 8.4 Mb with the breakpoint mapping to 22q13.2 and the smallest deletion spanning 3.3 Mb with the breakpoint mapping to 22q13.31. In one case, a unique subtelomeric 3.9 Mb deletion associated with a 2.0 Mb duplication of 22q13 was observed, adding to a growing number of similar cases identified for other chromosome ends. Remarkably, this patient had signs suggestive of retinitis pigmentosa, which has never been reported before in the 22q13 deletion syndrome. The identification of two pairs of recurrent proximal breakpoints on 22q13 suggests that these specific regions may be prone to recombination, due to yet unknown genome architectural features. In addition to the copy number changes on 22q13, a duplication of approximately 330 kb on 22q11.1 was observed and shown to be a genetic large-scale copy number variation without clinical consequences. The current study failed to reveal relationships between the clinical features and the deletion sizes. Global developmental delay and absent or severely delayed speech were observed in all patients, whereas hypotonia was present in 89% of the cases (8/9). This study underscores the utility of array CGH for characterising the size and nature of subtelomeric deletions, such as monosomy 22q13, and underlines the considerable variability in deletion size in the 22q13 deletion syndrome regardless of the clinical phenotype.
Adolescent↗
Cohen syndrome in the Ohio Amish.
We describe eight members from two large Amish kindreds who share a phenotype characterized by early-onset pigmentary retinopathy and myopia, global developmental delay and mental retardation, microcephaly, short stature, hypotonia, joint hyperextensibility, small hands and feet, common facial appearance, and friendly disposition. Several of the children had intermittent granulocytopenia. The phenotypic occurrence in three siblings coupled with the increased coefficient of inbreeding in the Amish suggested that this disorder is autosomal recessive and due to a single founder allele. Despite similarity to the clinical features of Cohen syndrome, experienced dysmorphologists attending the 23rd David W. Smith Workshop suggested the facial gestalt of the Amish children was inconsistent with this diagnosis. We mapped the locus responsible for these individuals' phenotype to chromosome 8q22-q23, which contains the recently discovered Cohen syndrome gene, COH1. Complete sequencing of the COH1 gene identified a likely disease-causing frameshift mutation and a missense mutation in the Amish patients. A comparison of features among different Cohen syndrome populations with shared linkage to the COH1 locus or known COH1 gene mutations may allow for the determination of improved clinical criteria on which to suspect the diagnosis of Cohen syndrome. We conclude that facial gestalt seems to be an unreliable indicator of Cohen syndrome between ethnic populations, although it is quite consistent among affected individuals within a particular ethnic group. Other features common to almost all individuals with proven COH1 mutations, such as retinal dystrophy, myopia, microcephaly, mental retardation, global developmental delay, hypotonia, and joint hyperextensibility appear to be better clinical indicators of this disorder.
Abnormalities, Multiple↗