Disorder Of Early Childhood Research Articles

Psychopharmacological Treatment for Very Young Children: Contexts and Guidelines

Systematic research and practice guidelines addressing preschool psychopharmacological treatment in very young children are limited, despite evidence of increasing clinical use of medications in this population. The Preschool Psychopharmacology Working Group (PPWG) was developed to review existing literature relevant to preschool psychopharmacology treatment and to develop treatment recommendations to guide clinicians considering psychopharmacological treatment in very young children. This article reviews the developmental considerations related to preschool psychopharmacological treatment, presents current evidence bases for specific disorders in early childhood, and describes the recommended algorithms for medication use. The purpose of this effort is to promote responsible treatment of young children, recognizing that this will sometimes involve the use of medications.

Immune pathogenesis of sclerosing cholangitis in biliary atresia

Biliary atresia (BA) is the most frequent single life-threatening hepatic disorder in early childhood in Japan, Europe and North America. It affects one in 9000 live-born infants in our country. BA is characterized by complete inability to excrete bile associated with obstruction, destruction or absence of the extrahepatic bile ducts. Pathologic study of tissues removed from the porta hepatis and of the proximal extrahepatic bile ducts suggests that BA in the vast majority of infants results from a sclerosing, inflammatory lesion initiated in ductular tissues. Kasai procedure (KP) is in the first line of treatment for BA infants in the developed countries all over the world. In KP, bile duct remnants or fibrous tissues in front of the hepatic artery are dissected and a Roux-en -Y anastomosis is fashioned between the area of the porta hepatic and the jejunum. KP has provided opportunities to survive years for some infants with BA with reasonable quality of life. However in BA, bile duct injury and sclerosing inflammation is ongoing even after apparently successful KP. A 10-year survival rates with native liver is still 53% in 1999 according to multi-centre analysis in Japan. BA is still the leading cause of paediatric liver transplantation. Poor prognosis of BA is, of course, due to unknown aetiology. Potential aetiologies for more common perinatal form of BA include viral infections, immune-mediated injuries and autoimmune disease involving biliary systems. Details of each theory including our updated findings will be reviewed and discussed.

Genetic markers of bronchial asthma in children with atopic dermatitis

The aim of the study was to evaluate the usefulness of the -703С/Т polymorphism in IL-5 gene, Q551R polymorphism in IL-4RA gene, and GSTM1 and GSTТ1 gene polymorphism as biological markers of bronchial asthma (BA) in children with atopic dermatitis (AD). We genotyped children with AD (n = 72; mean age, 9.4 ± 0.28 years), children with AD in combination with BA (n = 68; mean age, 7.5 ± 0.7 years) and control subjects (n = 147; mean age, 9.9 ± 0.42 years). We found the associations between BA and the -703С allele of the interleukin-5 (IL-5) gene (OR = 1.73, p = 0.013) and -703СС / 551RR genotype combination (OR = 3.15; p = 0.015) in children with AD; between the 551RR genotype of the IL-4RA gene and atopy (p < 0.05). -703CT / GSТТ1 0/0 genotype combination was found rarer in children with BA than in controls (OR = 0.15; p = 0.049). Thus, -703С/Т allele of the IL-5 gene and -703СС / 551RR genotype combination were associated with BA and could be used as valuable markers of the disease in children with AD, whereas the Q551R polymorphism in the IL-4RA gene was associated with predisposition to atopic disease and could be used for administration of preventive therapy of allergic disorder in early childhood. The -703CT / GSТТ1 0/0 genotype combination can prevent BA occurrence in children with AD.

Eating disorders in early childhood

Der folgende Artikel beschäftigt sich mit dem Phänomen des zunehmenden Vorkommens von Essstörungen im frühen Kindesalter. Kinderärzte sind damit oftmals zu Unrecht überfordert, weil der Eindruck besteht, „dem Kind fehle ja nichts“. Die Diskrepanz des mütterlichen Leidensdrucks und die selten perakute Symptomatik beim Säugling oder Kleinkind (auch Gedeihstörungen entwickeln sich nicht über Nacht) führen leider häufig zu vermeidbaren Irritationen auf beiden Seiten. Es wird ein Einblick in die häufigsten Vorstellungssituationen gegeben. Die Autoren empfehlen in allen Fällen das Einführen einer Fütterungsbeobachtung. Diese kann rasch (nicht länger als 5 min) und billig (Eltern bringen Essen selbst mit) viel zur höheren Effizienz in der diagnostischen Einschätzung beitragen. In vielen Fällen genügt eine begleitende Beratung, um den Teufelskreis der Verunsicherung mit zunehmendem Erwartungsdruck auf der Seite der involvierten Erwachsenen zu unterbrechen und dem Kind zu helfen, seine selbst gesteuerte orale Ernährung autonomer und altergemäß zu gestalten.

Therapeutic Approaches to Speech and Language Disorders in Early Childhood

Therapeutic Approaches to Speech and Language Disorders in Early Childhood

Adipokines in cord blood and risk of wheezing disorders within the first two years of life

Adipokines are involved in the regulation of many inflammatory processes and are present at very high concentrations in cord blood of term infants. We analysed data of a large prospective birth cohort study to examine whether adiponectin and leptin concentration in cord blood are determinants of wheezing disorders in children within the first 2 years of life. Seven hundred and forty mothers and their newborns were included in this analysis. Adiponectin and leptin concentrations were measured in cord blood. The cumulative incidence of physician-reported asthma or obstructive bronchitis was recorded during a 2-year follow-up. During the first 2 years of life, asthma or obstructive bronchitis was reported by the caring paediatricians for 157 (19.6%) of the children. We found a strong interaction of cord blood adiponectin and history of atopic disease in the mother with respect to the risk of physician-reported asthma or obstructive bronchitis (P=0.006). Compared with children with cord blood levels in the middle quintile (reference category), the odds ratios for physician-reported asthma or obstructive bronchitis in the bottom quintile and top quintile were 0.14 [95% confidence interval (CI) 0.02-0.90] and 2.12 (95% CI 0.67-6.66), respectively (P for trend=0.0003), among children of mothers with a history of atopy. This association was independent of other established risk factors. Leptin levels in cord blood were not associated with risk of asthma or obstructive bronchitis. In children of mothers with a history of atopy, concentrations of adiponectin in cord blood could play an important role in determining risk of wheezing disorders in early childhood.

Targeting RAS Signaling Pathways in Juvenile Myelomonocytic Leukemia

The RAS proteins function as fundamental signaling switches that control normal cell growth and differentiation. Deregulated activation of RAS-dependent signaling pathways constitutes a potent mechanism of malignant cell transformation. Juvenile myelomonocytic leukemia (JMML) is a rapidly fatal myeloproliferative disorder of early childhood for which no effective treatment other than hematopoietic stem cell transplantation is currently available. Many aspects of JMML pathobiology are linked to deregulated RAS signaling. Hence, targeting RAS or its interactors on a molecular level is a promising strategy in the development of novel rational therapies for this menacing disease. Here we give an overview of current concepts on the pathogenesis of JMML, present important aspects of cellular RAS biology that can be exploited for pharmacologic manipulation, and discuss mouse models that have greatly advanced our understanding of the role RAS plays in JMML. In addition, we review recent approaches to develop agents that interfere with the RAS network at the level of the granulocyte-macrophage colony-stimulating factor receptor, posttranslational RAS processing (prenylation and endoprotease cleavage), RAF serine/threonine kinase, MEK mitogen-activated protein kinase, and target of rapamycin activity. Preclinical and clinical data of these pharmaceuticals in JMML and other myeloid malignancies is discussed.

Autism spectrum disorder and Klinefelter syndrome

Autism is a severe handicapping disorder of early childhood characterized by a distinct pattern of social and communication impairment with rigid ritualistic interests. In about 10-25% of cases, it is associated with known medical conditions. Population-based studies of autism have found that Klinefelter's syndrome (KS), a common chromosome abnormality, is sometimes associated with autism. However, few detailed case descriptions of patients with KS and autism have not been published. In this paper, we describe the occurrence of autistic features in two cases of Klinefelter syndrome, one with the typical XXY karyotype and the other with the XXYY variant. Autistic features may be more common in persons with Klinefelter syndrome than generally believed. We propose that all patients with KS should be screened for the presence of autism.

The Genetic Bases of Speech Sound Disorders: Evidence From Spoken and Written Language

The purpose of this article is to review recent findings suggesting a genetic susceptibility for speech sound disorders (SSD), the most prevalent communication disorder in early childhood. The importance of genetic studies of SSD and the hypothetical underpinnings of these genetic findings are reviewed, as well as genetic associations of SSD with other language and reading disabilities. The authors propose that many genes contribute to SSD. They further hypothesize that some genes contribute to SSD disorders alone, whereas other genes influence both SSD and other written and spoken language disorders. The authors postulate that underlying common cognitive traits, or endophenotypes, are responsible for shared genetic influences of spoken and written language. They review findings from their genetic linkage study and from the literature to illustrate recent developments in this area. Finally, they discuss challenges for identifying genetic influence on SSD and propose a conceptual framework for study of the genetic basis of SSD.

Genome-Wide Single Nucleotide Polymorphism Analysis in Juvenile Myelomonocytic Leukemia Uncovers Long-Range Uniparental Disomy Surrounding the NF1 Locus in Cases Associated with Type 1 Neurofibromatosis but Not in Cases with Mutant RAS or PTPN11.

Juvenile myelomonocytic leukemia (JMML) is a malignant hematopoietic disorder of early childhood with myeloproliferative and myelodysplastic properties. The proliferative component is a result of RAS pathway deregulation caused by somatic mutation in the RAS or PTPN11 oncogenes (60% of cases) or by underlying neurofibromatosis type 1 (NF-1) with a germline NF1 gene defect (clinically 11% of cases). To search for potential collaborating genetic abnormalities, we used Affymetrix GeneChip Mapping 50K arrays to analyze over 116,000 single nucleotide polymorphisms (SNPs) across the genome using DNA from bone marrow or peripheral blood granulocytes from 16 children with JMML and normal karyotype (mutant RAS, n=4; mutant PTPN11, n=7; NF-1, n=5). Quantitative evaluation of hybridization intensities at each SNP locus failed to identify recurrent allelic gains or losses in the 16 cases. We were specifically interested in chromosome 7 because monosomy 7 or interstitial/terminal 7q deletions are found in about 30% of JMML cases and it is conceivable that submicroscopic 7q lesions occur in the other cases but remain undetected by standard techniques. However, at the resolution provided by the arrays used here, we saw no evidence for genomic copy number alterations on chromosome 7. Interestingly, evaluation of the SNP allelotypes identified large regions of copy-neutral loss of heterozygosity (LOH) on chromosome 17q, including the NF1 locus, in 4 of the 5 samples from patients with JMML and NF-1. The LOH region spanned a genomic range of approximately 55 Mbp in each case and included more than 1,400 contiguous SNPs. Allelic copy numbers were normal within the homozygous regions, indicating uniparental isodisomy (UPD). Compatible with isodisomy, 17q was normal in the corresponding conventional karyotypes. By contrast, the array data provided no evidence for 17q UPD in any of the 12 JMML cases without NF-1. In all four cases with 17q UPD, the recombination breakpoints appeared to be confined to a 400-kbp region on 17q11.1–17q11.2; however, lack of parental or nonleukemic DNA precluded definitive mapping of the breakpoints. Of note, the 17p chromosomal arm retained heterozygosity in all cases, indicating that the p53 tumor suppressor was not affected by the UPD event. We confirmed 17q disomy in the four NF-1 samples using matrix-based comparative genomic hybridization and are currently verifying homozygosity of multiple microsatellites spaced across chromosome 17. Furthermore, NF1 mutational analysis is under way to show that the individual lesion within this tumor suppressor gene is biallelic in leukemic cells from patients with JMML and NF-1. In summary, we assume that a mitotic recombination event in an early hematopoietic progenitor cell led to UPD involving the NF1 locus. Our observations provide strong confirmatory evidence that it is indeed the NF1 gene that is responsible for the increased incidence of JMML in NF-1 patients. In addition, our data support the emerging role of mitotic recombination as a second hit in leukemogenesis and corroborate the concept that RAS pathway deregulation is central to JMML pathogenesis.

Morbidity and Development in Childhood of Infants Born After Temporizing Treatment of Early Onset Preeclampsia

Although immediate termination of pregnancy in cases of preeclampsia does benefit the mother, it often is not in the best interest of the fetus, especially if carried out long before term. A program of temporizing management has been adopted for use in severe early-onset preeclampsia, the goal being to correct maternal hemodynamics through plasma expansion and pharmacologic vasodilatation. Short-term benefit has been demonstrated with this approach. The question of whether this benefit is sustained was examined in 222 consecutive infants who lived at least 12 months and whose mothers had severe preeclampsia (diastolic blood pressure of 110 mm Hg or above with proteinuria of at least 0.3 g/L/24 hours after 20 weeks gestation). The mothers received the vasodilator dihydralazine in addition to pasteurized plasma. Each infant was matched for gestational age, gender, and year of birth with 2 infants whose mothers were not preeclamptic. One of them was at the gestational age at which temporizing treatment began (control group I). The other (control group II) was delivered at the same gestational age at which the preeclamptic patient was delivered. The children were evaluated at least 4 years after birth using the Child Behavior Checklist. Temporizing treatment delayed delivery by 2 weeks on average. Median birth weight was lower in the study group than in both control groups. Infants in control group I required mechanical ventilation significantly more often than did study infants or those in control group II. Bronchopulmonary dysplasia was least prevalent in control group II. Substantially more control than study mothers received corticosteroids before delivery to hasten maturation of the fetal lungs. All types of morbidity tended to occur less often in the study group than in control group I, but the only significant difference was for acute and chronic respiratory disorders (14% of study children and 37% of those in control group I). Respiratory disorders also correlated with a lower gestational age at birth. Although fewer children in the study group had minor or major handicaps, the differences were not statistically significant. Children with a single major handicap were significantly more frequent in control group I than in control group II. These findings indicate that the risk of respiratory disorders in early childhood may be less when temporizing management, prolonging gestation by 2 weeks, is adopted for women with early-onset preeclampsia.

RAS-blocking bisphosphonate zoledronic acid inhibits the abnormal proliferation and differentiation of juvenile myelomonocytic leukemia cells in vitro

AbstractJuvenile myelomonocytic leukemia (JMML) is a clonal myeloproliferative/myelodysplastic disorder of early childhood with a poor prognosis. JMML cells are characterized by hypersensitivity to granulocyte-macrophage colony-stimulating factor (GM-CSF) caused by a continuously activated GM-CSF receptor–retrovirus-associated sequence (RAS) signal transduction pathway through various molecular mechanisms, resulting in spontaneous GM colony formation in vitro. Bisphosphonate zoledronic acid (ZOL), a RAS-blocking compound, suppressed colony formation from bone marrow (BM) cells of 8 patients with JMML and 5 healthy control subjects without and with GM-CSF (10 ng/mL), respectively, in a dose-dependent manner in clonal culture. At 10 μM ZOL, however, spontaneous GM colony formation from JMML BM cells decreased to 3%, but the formation of G colonies containing granulocytes, but no macrophages, was enhanced, whereas 40% of GM colonies were retained and G colony formation was not affected in culture of normal BM cells with GM-CSF. In suspension culture, cytochemical and flow cytometric analyses showed that 10 μM ZOL also inhibited spontaneous proliferation and differentiation along monocyte/macrophage lineage of JMML BM cells but not the development of normal BM cells by GM-CSF. The inhibitory effect of ZOL on JMML cells was confirmed at a single-clone level and observed even at 3 μM. The current result offers a novel approach to therapy in JMML.

Glial fibrillary acidic protein is elevated in superior frontal, parietal and cerebellar cortices of autistic subjects

Autism is a debilitating neurodevelopmental disorder of early childhood with both genetic and environmental origins. Immune system dysregulation has been hypothesized to be involved in this disorder. We quantified levels of glial fibrillary acidic protein (GFAP) and ss-actin in three areas of the brain, namely, area 9, area 40 and cerebellum, in age matched autistic and control postmortem specimen using SDS-PAGE and western blotting techniques. Significant elevations in levels of GFAP were observed in all three brain areas in autism. This report confirms a recent report showing microglial and astroglial activation in autism. Increased GFAP levels in autistic brains signify gliosis, reactive injury, and perturbed neuronal migration processes.

Ataxia-Telangiectasia genes and breast cancer risk in a French family study

Ataxia-telangiectasia (AT) is a rare autosomal recessive early childhood disorder, characterized by progressive neuronal degeneration, immunological deficiency, radiosensitivity and an increased risk of cancer caused in most cases by mutations in the AT-mutated gene (ATM). Epidemiological studies on AT families have shown that AT heterozygous women have an increased risk of developing breast cancer (BC). The ATM protein plays a central role in the recognition and repair of DNA double-strand breaks and the subsequent activation of cell-cycle checkpoints. Whilst AT is a rare disease, 0.5-1 % of the general population are estimated to be AT mutation carriers, thus any increases in the risks of cancer associated with ATM carrier status are of public health relevance. The main results of our published studies on the risk of BC in 34 French AT families according to heterozygote status, type of ATM mutation and exogenous factors are summarized here. The risk of BC was higher in ATM heterozygous (HetATM) women and did not differ significantly according to the type of ATM mutation (missense vs truncating) carried by the AT family members but appeared associated with the position of some truncating mutations in certain binding domains of the ATM protein. The effect of exogenous factors, such as reproductive life factors and exposure to ionizing radiation, on the risk of BC according to ATM heterozygote status was assessed. There was no evidence for interaction (except for age at first full-term pregnancy). These findings does not appear to justify a separate screening program from that already available to other women with a first-degree relative affected by BC, as their risks have similar amplitude. Chest X-rays did not appear to be a risk factor for BC in our study population. More powerful studies, using data sets pooled from international sources are being set up to confirm these observations.

Troubles du comportement entre 18 et 36 mois : symptomatologie et psychopathologie associées

Studies on behavior disorders in early childhood (ages 0–3) are more recent and less numerous than studies conducted about school-age children. Thus, the discrepancy between behaviors posing a clinical problem and normal development in toddlers needs to be better defined. The symptomatology and psychopathology comorbid with behavior disorders has not yet been answered using empirical and longitudinal data. The study presented here compares a clinical group (40 children, aged 18 to 36 months, with behavioral problems) with a non-clinical group (30 typically developing children from the same age group). Data were collected with the Symptom Check-List and the diagnostic classification Zero to Three. The results showed that behavioral symptoms (including opposition, aggression, hyperactivity, and inattention) were much more frequent and intense in the clinical group than in the non-clinical group. Most of the clinical group demonstrated comorbid separation, sleep and feeding problems. The clinical group's symptoms also were associated to a problematic relational context and to criteria for disorder of affect (including anxiety disorder in early childhood and mixed disorder of emotional expressiveness). Given that multiple risk factors point to an unfavorable prognosis in the majority of clinical cases, the present report emphasizes the importance of early intervention and treatment for behavior disorders.

Donor leukocyte infusion after hematopoietic stem cell transplantation in patients with juvenile myelomonocytic leukemia

Juvenile myelomonocytic leukemia (JMML) is a clonal myeloproliferative disorder of early childhood. In all, 21 patients with JMML who received donor leukocyte infusion (DLI) after allogeneic hematopoietic stem cell transplantation (HSCT) for either mixed chimerism (MC, n=7) or relapse (n=14) were studied. Six patients had been transplanted from an HLA-matched sibling and 15 from other donors. Six of the 21 patients (MC: 3/7 patients; relapse: 3/14 patients) responded to DLI. Response rate was significantly higher in patients receiving a higher total T-cell dose (> or =1 x 10(7)/kg) and in patients with an abnormal karyotype. None of the six patients receiving DLI from a matched sibling responded. Response was observed in five of six patients who did and in one of 15 children who did not develop acute graft-versus-host disease following DLI (P=0.01). The overall outcome was poor even for the responders. Only one of the responders is alive in remission, two relapsed, and three died of complications. In conclusion, this study shows that some cases of JMML may be sensitive to DLI, this providing evidence for a graft-versus-leukemia effect in JMML. Infusion of a high number of T cells, strategies to reduce toxicity, and cytoreduction prior to DLI may improve the results.

Prevalence of obesity, binge eating, and night eating in a cross‐sectional field survey of 6‐year‐old children and their parents in a German urban population

To assess the prevalence of obesity, obesity-related binge eating, non-obesity-related binge eating, and night eating in five- to six-year-old children and to examine the impact of parental eating disturbances. When 2020 children attended their obligatory health exam prior to school entry in the city of Aachen, Germany, 1979 parents (97.9%) filled out a questionnaire on their child's eating habits and weight development in a cross-sectional survey. Anthropometric measurements were collected for all children in a standardized form. Episodes of binge eating were found in 2.0% of the children surveyed and night eating in 1.1%. There was a significant relationship between binge eating and obesity but not between night eating and the child's weight. Children's binge eating and night eating were strongly associated with eating disturbances on the part of their mothers (adjusted odds ratios [95% confidence intervals]: 6.1 [2.7-13.5] and 7.8 [2.1-29.4], respectively) and with a non-German native language (adjusted odds ratios [95% confidence intervals]: 2.6 [1.2-5.5] and 11.6 [3.5-38.7], respectively). In concurrence with studies on adulthood, binge eating is linked to obesity already in early childhood. Children of mothers with eating disorders and children of mothers with a non-German native language are at increased risk of developing eating disorders themselves. Future studies should focus on obesity and eating disorders in early childhood; prevention programs should seek to target young children at risk as early as possible.

Glycosaminoglycans Modulate Activation, Activity, and Stability of Tripeptidyl-peptidase I in Vitro and in Vivo

Tripeptidyl-peptidase I (TPP I, CLN2 protein) is a lysosomal exopeptidase that sequentially removes tripeptides from the N termini of polypeptides and shows a minor endoprotease activity. Mutations in TPP I lead to classic late-infantile neuronal ceroid lipofuscinosis, a neurodegenerative lysosomal storage disease. TPP I proenzyme is converted in lysosomes into a mature enzyme with the assistance of another protease and is able to autoactivate in acidic pH in vitro via a unimolecular mechanism. Because autoactivation in vitro at the pH values reported for lysosomes generated inactive enzyme, we intended to determine whether physiologically relevant factors can modify this process to also make it plausible in vivo. Here, we report that high ionic strength and glycosaminoglycans (GAGs) increase yields (ionic strength) or yields and rates (GAGs) of activation, enhance degradation of liberated TPP I prosegment fragments, and switch effective autoactivation of TPP I proenzyme toward less acidic pH values (up to pH 6.0). Although ionic strength and GAGs also inhibited TPP I activity in vitro and in living cells, the degree of inhibition (from 20 to 60%) appears to be of rather limited functional significance. Importantly, binding to GAGs improved thermal stability of TPP I and protected the enzyme against alkaline pH-induced denaturation in vitro (t((1/2)) of mature enzyme at pH 7.4 increased by approximately 8-fold in the presence of heparin) and in vivo ( approximately 2-fold higher loss of TPP I in cells deficient in GAGs than in control cells after bafilomycin A1 treatment). These findings elucidate a potent physiologically relevant mechanism of TPP I regulation by GAGs and suggest that generation of the active enzyme via autoactivation can be accomplished not only in vitro but in vivo as well.

Transient eating disorder in early childhood A case report

Although children in infancy present eating problems of multifarious nature, the diagnostic classification of infant eating disorders remains markedly deficient. The authors present a case exhibiting transient eating disorder in early childhood, alongside discussion of some considerations relevant to this age group. The subject was a boy aged 5 years 6 months at first presentation. Starting with an inability to swallow "sushi" at dinner, he was brought to the clinic for inability to ingest food or liquids. Treatment was planned as play therapy for the patient, and psychological interviews for the mother. The child's symptoms were improved in five sessions, but interviews of the mother revealed eating disorders such as bulimia and vomiting, and sexual problems in the marital relationship, necessitating long-term therapy.

Prevalence and Prediction of Disorders in Early Childhood: A Community Study

AbstractThis article examines the prevalence and prediction of internalising and externalising disorders from temperament and parenting in children aged 4 to 6 years (N = 491). Children were assessed via parent and teacher reports over 14 months and clinical interviews with parents were included at follow-up, along with parent and teacher reports of behavioural and emotional difficulties. Prevalence rates for internalising disorders (8.7%) were higher than for externalising disorders (5.8%), and internalising rates were similar to that found for older children in the same city. Accuracy of prediction of disorders, as well as overall behavioural and emotional difficulties, was low to moderate, and externalising problems were better predicted than internalising problems. The results highlight that while psychological disorders can be predicted from measures of temperament in infancy, the accuracy is too low to recommend these children receive selective prevention and treatment programs.