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We present a mother and her son, both carrying a deletion of chromosome 22q.11.2. They manifest clinical heterogeneity. The mother has schizophrenia, an IQ of 70. Tetralogy of Fallot, a hypernasal voice, but does not have the characteristic facies. Her son has mild psychomotor developmental delay. Tetralogy of Fallot and mild facial features characteristic of VCFS.
We report on a 7-year-old boy with unusual facial features, severe bilateral sensorineural hearing loss, and broad terminal phalanges. These findings are similar to those described by Keipert et al. in two brothers and by Balci and Dagli in two other male siblings. Our patient has, in addition, developmental delay and abnormal behaviour. To the best of our knowledge, this is only the third report of Keipert syndrome.
PURPOSE: To assess the outcome of fetuses with isolated mild ventriculomegaly (IMVM). MATERIALS AND METHODS: The clinical course of 44 fetuses with IMVM was investigated. Cognitive and motor development was classified as normal or delayed. RESULTS: Clinical data were available for 37 subjects. Three (8%) neonates died. Of the 34 living children, follow-up was limited (< 9 months) in six and the clinical course beyond the 1st year of life was established in 28. Twenty-two (79%) of the 28 children are developing normally, whereas six (21%) are developmentally delayed. More than 90% of fetuses with ventricular atrial diameter of 10-11 mm are normal. Seventy-five percent of fetuses with IMVM were male. With exclusion of the six children with limited follow-up, 78% of boys older than 1 year are developmentally normal compared with only 50% of girls. CONCLUSION: The majority of living children with prenatally detected IMVM are developmentally normal, especially those with borderline ventriculomegaly. Gender differences in prevalence and outcome deserve further investigation.
A 7-month-old infant had the infantile spasm syndrome, consisting of flexor and extensor spasms, developmental delay, and hypsarrhythmia. Corticotropin produced delay, and hypsarrhythmia. Corticotropin produced improvement in the clinical symptoms and reverted the generalized electroencephalographic abnormalities to more focal ones. Removal of a choroid plexus papilloma of the left lateral ventricle was followed by clinical recovery. One year later the child was normal developmentally and neurologically and was seizure free on anticonvulsant therapy.
A patient with typical features of Angelman syndrome--a genetically inherited disorder involving developmental delay, ataxia, episodes of paroxysmal laughter and brachiocephaly--was studied with single-photon emission tomography. Hypoperfusion found in the left frontal and left temporoparietal regions can provide insights into the functional cerebral pathology, which may be due to a disturbance of the developmental process related to a chromosomal abnormality.
Glucose-6-phosphatase is a multicomponent endoplasmic reticulum system comprising at least six different proteins, including a lumenal enzyme and several transport proteins. One of the transport proteins, T2beta, transports the substrate pyrophosphate and the product phosphate and its genetic deficiency is termed type 1c glycogen storage disease. We have used anti-T2beta antibodies for immunohistochemistry with image analysis and kinetic analysis of the glucose-6-phosphatase system to study for the temporal and spatial development of T2beta in human embryonic and fetal kidney. In metanephric kidney, there is an early predominance of T2beta expression in the ureteric bud derivatives and this changes with ontogeny such that developing nephrons, particularly proximal tubules, become dominant by mid-gestation. T2beta has the same spatial and temporal pattern as the glucose-6-phosphatase enzyme in both mesonephric and metanephric kidney. Pyrophosphate transport capacity is appropriate for the amount of glucose-6-phosphatase activity present in mid-gestation fetal kidney, in contrast to liver, where pyrophosphate transport capacity is developmentally delayed. Increasing knowledge of the temporal and spatial expression of the glucose-6-phosphatase proteins and their catalytic roles in early human development is essential for the elucidation of the aetiology of renal disease in both type I glycogen storage diseases and the developmental disorders of the glucose-6-phosphatase system.
This study assessed midsagittal corpus callosum cross sectional areas in 3-4 year olds with autism spectrum disorder (ASD) compared to typically developing (TD) and developmentally delayed (DD) children. Though not different in absolute size compared to TD, ASD callosums were disproportionately small adjusted for increased ASD cerebral volume. ASD clinical subgroup analysis revealed greater proportional callosum reduction in the more severely affected autistic disorder (AD) than in pervasive developmental disorder-not otherwise specified (PDD-NOS) children. DD children had smaller absolute callosums than ASD and TD. Subregion analysis revealed widely distributed callosum differences between ASD and TD children. Results could reflect decreased inter-hemispheric connectivity or cerebral enlargement due to increase in tissues less represented in the corpus callosum in ASD.
The cri-du-chat syndrome is a contiguous gene syndrome that results from a deletion of the short arm of chromosome 5 (5p). Patients present with a cat-like cry at birth, which is usually considered diagnostic of this syndrome. Additional features of the syndrome include failure to thrive, microcephaly, hypertelorism, epicanthal folds, hypotonia, and severe mental retardation. We report on four families in which patients with 5p deletions have only the characteristic cat-like cry, with normal to mildly delayed development. The precise locations of the deletions in each family were determined by FISH using lambda phage and cosmid clones. All of the deletion breakpoints map distal to a chromosomal region that is implicated with the facial features and severe mental and developmental delay in the cri-du-chat syndrome. DNA clones mapping in the chromosomal region associated with the cat-like cry feature will be useful diagnostic tools. They will allow for the distinction between 5p deletions that will result in the severe delay observed in most cri-du-chat syndrome patients and those deletions that result in the isolated cat-like cry feature, which is associated with a better prognosis.
5 male children who had idiopathic external hydrocephalus are described; all were all in the first year of life. Macrocephaly and hypotonia were present in all, as well as mild to moderate delay in language and gross motor development; cognition was normal. CT-scan showed in all enlarged subarachnoid spaces but normal or mildly dilated lateral ventricles. Macrocephaly was present in the fathers of 4 of the 5 families. In all cases the course of this condition was benign. There was clinical and roentgenological improvement between the ages of 2 and 2.5 years; the developmental delay resolved at about age 4, at which time the CT pattern had become normal.
We report on two patients with rare 6q duplications. The karyotype of patient 1 is 46,XY,dup(6)(q21q23.3). The karyotype of patient 2 is 46,XX,dup(6)(q21.15q23.3). These two patients have some nonspecific physical findings in common including a depressed nasal bridge, epicanthal folds, mild heart defects, and developmental delay, but each had other congenital anomalies.
We report the first case of an apparent de novo pericentric inversion of chromosome 2 at the breakpoints p13q11.2 that was detected prenatally. Follow-up performed over 4 years showed phenotypic abnormalities including minor craniofacial dysmorphism, hypotonia, hearing loss, gustatory flushing syndrome, and severe developmental delays. The literature on chromosome 2 inversion is reviewed.
Increased fetal nuchal translucency (NT) thickness between 11 and 14 weeks' gestation is a common phenotypic expression of chromosomal abnormalities, including trisomy 21. However, even in the absence of aneuploidy, nuchal thickening is clinically relevant because it is associated with an increase in adverse perinatal outcome caused by a variety of fetal malformations, dysplasias, deformations, dysruptions, and genetic syndromes. Once the presence of aneuploidy is ruled out, the risk of perinatal outcome dose not statistically increase until the nuchal translucency measurement reaches 3.5 mm or more (>99th percentile). This increase in risk occurs in an exponential fashion as the NT measurement increases. However, if the fetus survives until midgestation, and if a targeted ultrasound at 20 to 22 weeks fails to reveal any abnormalities, the risk of an adverse perinatal outcome and postnatal developmental delay is not statistically increased.
The concept of prevention, while implicit in most early intervention efforts, has not been comprehensively articulated as a basis for conceptualizing early intervention services. The growing recognition of the importance of early identification and intervention for infants and young children, and involvement of the family, are factors which contribute to conceptualizations of services which are preventive in nature. This recognition parallels broader concerns for family support programmes which have a preventive focus and seek to enhance the development of children and families. The purpose of this paper is to present a comprehensive framework for the provision of child and family service by conceptualizing early intervention in terms of levels of prevention. Specifically, the concept of primary, secondary, and tertiary levels of prevention will be presented as a framework suitable to encompass the preventive function of community based rehabilitation. The relevance of early prevention is based on the premise that the condition of childhood disability can be prevented at primary, secondary, and tertiary levels. Viewed in this way, the problem or condition of developmental delay or disability in children can be addressed at each of the three levels to effect a reduction of its expression, its duration or extended impact. Primary, secondary, and tertiary prevention can be implemented in the context of community based rehabilitation to address these goals: (a) enhance development and minimize the potential for delay; (b) minimize the need for special education and related services; and (c) minimize the likelihood of institutional or other restrictive care outcomes.
BACKGROUND: PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Published in the public domain by the American Academy of Pediatrics. Speech and language development is a useful indicator of a child's overall development and cognitive ability and is related to school success. Identification of children at risk for developmental delay or related problems may lead to intervention services and family assistance at a young age, when the chances for improvement are best. However, optimal methods for screening for speech and language delay have not been identified, and screening is practiced inconsistently in primary care. PURPOSE: We sought to evaluate the strengths and limits of evidence about the effectiveness of screening and interventions for speech and language delay in preschool-aged children to determine the balance of benefits and adverse effects of routine screening in primary care for the development of guidelines by the US Preventive Services Task Force. The target population includes all children up to 5 years old without previously known conditions associated with speech and language delay, such as hearing and neurologic impairments. METHODS: Studies were identified from Medline, PsycINFO, and CINAHL databases (1966 to November 19, 2004), systematic reviews, reference lists, and experts. The evidence review included only English-language, published articles that are available through libraries. Only randomized, controlled trials were considered for examining the effectiveness of interventions. Outcome measures were considered if they were obtained at any time or age after screening and/or intervention as long as the initial assessment occurred while the child was < or =5 years old. Outcomes included speech and language measures and other functional and health outcomes such as social behavior. A total of 745 full-text articles met our eligibility criteria and were reviewed. Data were extracted from each included study, summarized descriptively, and rated for quality by using criteria specific to different study designs developed by the US Preventive Services Task Force. RESULTS: The use of risk factors for selective screening has not been evaluated, and a list of specific risk factors to guide primary care physicians has not been developed or tested. Sixteen studies about potential risk factors for speech and language delay in children enrolled heterogeneous populations, had dissimilar inclusion and exclusion criteria, and measured different risk factors and outcomes. The most consistently reported risk factors included a family history of speech and language delay, male gender, and perinatal factors. Other risk factors reported less consistently included educational levels of the mother and father, childhood illnesses, birth order, and family size. The performance characteristics of evaluation techniques that take < or =10 minutes to administer were described in 24 studies relevant to screening. Studies that were rated good to fair quality reported wide ranges of sensitivity and specificity when compared with reference standards (sensitivity: 17-100%; specificity: 45-100%). Most of the evaluations, however, were not designed for screening purposes, the instruments measured different domains, and the study populations and settings were often outside of primary care. No "gold standard" has been developed and tested for screening, reference standards varied across studies, few studies compared the performance of > or =2 screening techniques in 1 population, and comparisons of a single screening technique across different populations are lacking. Fourteen good- and fair-quality randomized, controlled trials of interventions reported significantly improved speech and language outcomes compared with control groups. Improvement was demonstrated in several domains including articulation, phonology, expressive language, receptive language, lexical acquisition, and syntax among children in all age groups studied and across multiple therapeutic settings. Improvement in other functional outcomes such as socialization skills, self-esteem, and improved play themes were demonstrated in some, but not all, of the 4 studies that measured them. In general, studies of interventions were small and heterogeneous, may be subject to plateau effects, and reported short-term outcomes based on various instruments and measures. As a result, long-term outcomes are not known, interventions could not be compared directly, and generalizability is questionable. CONCLUSIONS: Use of risk factors to guide selective screening is not supported by studies. Several aspects of screening have been inadequately studied to determine optimal methods, including which instrument to use, the age at which to screen, and which interval is most useful. Trials of interventions demonstrate improvement in some outcome measures, but conclusions and generalizability are limited. Data are not available addressing other key issues including the effectiveness of screening in primary care settings, role of enhanced surveillance by primary care physicians before referral for diagnostic evaluation, non-speech and language and long-term benefits of interventions, and adverse effects of screening and interventions.
Bruton's tyrosine kinase (Btk) is a cytoplasmic signaling molecule that is crucial for precursor (pre-B) cell differentiation in humans. In this study, we show that during the transition of large cycling to small resting pre-B cells in the mouse, Btk-deficient cells failed to efficiently modulate the expression of CD43, surrogate L chain, CD2, and CD25. In an analysis of the kinetics of pre-B cell differentiation in vivo, Btk-deficient cells manifested a specific developmental delay within the small pre-B cell compartment of about 3 h, when compared with wild-type cells. Likewise, in in vitro bone marrow cultures, Btk-deficient large cycling pre-B cells showed increased IL-7 mediated expansion and reduced developmental progression into noncycling CD2(+)CD25(+) surrogate L chain-negative small pre-B cells and subsequently into Ig-positive B cells. Furthermore, the absence of Btk resulted in increased proliferative responses to IL-7 in recombination-activating gene-1-deficient pro-B cells. These findings identify a novel role for Btk in the regulation of the differentiation stage-specific modulation of IL-7 responsiveness in pro-B and pre-B cells. Moreover, our results show that Btk is critical for an efficient transit through the small pre-B cell compartment, thereby regulating cell surface phenotype changes during the developmental progression of cytoplasmic mu H chain expressing pre-B cells into immature IgM(+) B cells.
We present here a unique expression of dystrophin on biopsied muscle from 2 siblings with Becker muscular dystrophy (BMD). They had neither muscle weakness nor atrophy. Clustered dystrophin-deficient fibers were constituted to regenerating basophilic fibers (mainly type 2C fiber) based on histochemical stainings. We speculate that the developmental delay in the expression of dystrophin is a characteristic finding in regenerating fibers from asymptomatic and young BMD patients, such as the siblings in this report.
Toluene embryopathy is characterised by microcephaly, central nervous system dysfunction, attentional deficits and hyperactivity, developmental delay with greater language deficits, minor craniofacial and limb anomalies, and variable growth deficiency. Previously, three affected children, born to women who inhaled toluene regularly throughout pregnancy, have been reported. Two more cases are described emphasising the importance of toluene as a potential human teratogen.
BACKGROUND: Double genetic diagnoses are increasingly identified with the advent of genome-wide sequencing techniques. While MECP2 mutations are associated with Rett syndrome and EPHB4 mutations with vascular malformation syndromes, their co-occurrence has not been previously described. CASE PRESENTATION: We describe an 8-year-and-2-month-old girl presenting with global developmental delay, autism spectrum disorder, and stereotypic behaviors, along with multiple well-demarcated cutaneous vascular lesions. Although she had no clinical seizures, electroencephalogram revealed epileptiform discharges. Physical examination showed dysmorphic features and vascular anomalies, including telangiectatic pink-to-red macular vascular lesions. Whole exome sequencing (WES) identified two de novo heterozygous pathogenic variants: a missense mutation in MECP2 (c.433C>T; p.Arg145Cys), a gene classically implicated in Rett syndrome, and a nonsense mutation in EPHB4 (c.1093C>T; p.Arg365Ter), which has been previously associated with capillary malformation-arteriovenous malformation syndrome type 2. The neurodevelopmental findings, while consistent with the broader spectrum of MECP2-related disorders, along with coexisting vascular anomalies, were best accounted for by a dual genetic diagnosis involving both MECP2 and EPHB4. CONCLUSION: This case underscores the diagnostic value of considering dual genetic diagnoses in patients with complex phenotypes and highlights the role of WES in uncovering multilocus variation, thereby expanding the known phenotypic spectrum associated with MECP2 and EPHB4 mutations.