Onset In Early Childhood Research Articles

Early-onset childhood atopic dermatitis is related to NLRP2 repression

Capsule summary Early-onset atopic dermatitis (AD) related repression of the immune regulatory NLRP2 is driven by promoter hypermethylation starting already at time of birth providing an early opportunity to modulate innate immunity to potentially mitigate AD development.

Preferences and Ratings of Partner Traits in Female Survivors of Childhood Abuse With PTSD and Healthy Controls.

There is growing empirical evidence for an association between childhood abuse (CA) and intimate partner violence (IPV) in adulthood. We tested whether revictimized survivors of severe to extreme severities of child sexual abuse (CSA) and severe severities of child physical abuse (CPA) differed from nonvictimized healthy controls in their trait preferences in intimate partners and their current mate choice. In a sample of 52 revictimized female patients with posttraumatic stress disorder (PTSD) after CSA/CPA and 52 female healthy controls, the validated Intimate Partner Preferences Questionnaire (IPPQ) was used to assess (a) the desirability of tenderness, dominance, and aggression traits in potential partners, and (b) the presence of these traits in their current intimate partners. Factors potentially associated with partner preference and mate choice, for example, chronicity of traumatic events and lower self-esteem, were explored. Our results showed that, in general, revictimized PTSD patients did not have a preference for dominant or aggressive partners. However, revictimized women displayed a significantly larger discrepancy than did healthy controls between their preferences for tenderness traits and their ratings of the presence of tenderness traits in their current partners. Our results indicated that revictimized patients had lower self-esteem values; however, these values were associated with higher demands for tenderness traits. Furthermore, our results revealed that compared with patients who experienced early-onset childhood abuse (CA), those who experienced later onset CA were more accepting of dominant traits in potential partners. Women who had experienced IPV rated their current partners to be overly dominant. A higher tolerance of dominance traits might increase the risk of IPV in a specific subgroup of abused women (women with a later onset of abuse experiences and experiences of IPV).

Attention-deficit/hyperactivity disorder associated with KChIP1 rs1541665 in Kv channels accessory proteins.

Attention-deficit/hyperactivity disorder (ADHD) is an early onset childhood neurodevelopmental disorder with high heritability. A number of genetic risk factors and environment factors have been implicated in the pathogenesis of ADHD. Genes encoding for subtypes of voltage-dependent K channels (Kv) and accessory proteins to these channels have been identified in genome-wide association studies (GWAS) of ADHD. We conducted a two-stage case–control study to investigate the associations between five key genes (KChIP4, KChIP1, DPP10, FHIT, and KCNC1) and the risk of developing ADHD. In the discovery stage comprising 256 cases and 372 controls, KChIP1 rs1541665 and FHIT rs3772475 were identified; they were further genotyped in the validation stage containing 328cases and 431 controls.KChIP1 rs1541665 showed significant association with a risk of ADHD at both stages, with CC vs TT odds ratio (OR) = 1.961, 95% confidence interval (CI) = 1.366–2.497, in combined analyses (P-FDR = 0.007). Moreover, we also found rs1541665 involvement in ADHD-I subtype (OR (95% CI) = 2.341(1.713, 3.282), and Hyperactive index score (P = 0.005) in combined samples.Intriguingly, gene-environmental interactions analysis consistently revealed the potential interactionsof rs1541665 collaboratingwith maternal stress pregnancy (Pmul = 0.021) and blood lead (Padd = 0.017) to modify ADHD risk. In conclusion, the current study provides evidence that genetic variants of Kv accessory proteins may contribute to the susceptibility of ADHD.Further studies with different ethnicitiesare warranted to produce definitive conclusions.

Mutations in RAB39B in individuals with intellectual disability, autism spectrum disorder, and macrocephaly

BackgroundAutism spectrum disorder (ASD), a developmental disorder of early childhood onset, affects males four times more frequently than females, suggesting a role for the sex chromosomes. In this study, we describe a family with ASD in which a predicted pathogenic nonsense mutation in the X-chromosome gene RAB39B segregates with ASD phenotype.MethodsClinical phenotyping, microarray, and whole genome sequencing (WGS) were performed on the five members of this family. Maternal and female sibling X inactivation ratio was calculated, and phase was investigated. Mutant-induced pluripotent stem cells engineered for an exon 2 nonsense mutation were generated and differentiated into cortical neurons for expression and pathway analyses.ResultsTwo males with an inherited RAB39B mutation both presented with macrocephaly, intellectual disability (ID), and ASD. Their female sibling with the same mutation presented with ID and a broad autism phenotype. In contrast, their transmitting mother has no neurodevelopmental diagnosis. Our investigation of phase indicated maternal preferential inactivation of the mutated allele, with no such bias observed in the female sibling. We offer the explanation that this bias in X inactivation may explain the absence of a neurocognitive phenotype in the mother. Our cellular knockout model of RAB39B revealed an impact on expression in differentiated neurons for several genes implicated in brain development and function, supported by our pathway enrichment analysis.ConclusionsPenetrance for ASD is high among males but more variable among females with RAB39B mutations. A critical role for this gene in brain development and function is demonstrated.

Neuropathology of childhood-onset basal ganglia degeneration caused by mutation of VAC14.

ObjectiveTo characterize the clinical features and neuropathology associated with recessive VAC14 mutations.MethodsWhole‐exome sequencing was used to identify the genetic etiology of a rapidly progressive neurological disease presenting in early childhood in two deceased siblings with distinct neuropathological features on post mortem examination.ResultsWe identified compound heterozygous variants in VAC14 in two deceased siblings with early childhood onset of severe, progressive dystonia, and neurodegeneration. Their clinical phenotype is consistent with the VAC14–related childhood‐onset, striatonigral degeneration recently described in two unrelated children. Post mortem examination demonstrated prominent vacuolation associated with degenerating neurons in the caudate nucleus, putamen, and globus pallidus, similar to previously reported ex vivo vacuoles seen in the late‐endosome/lysosome of VAC14‐deficient neurons. We identified upregulation of ubiquitinated granules within the cell cytoplasm and lysosomal‐associated membrane protein (LAMP2) around the vacuole edge to suggest a process of vacuolation of lysosomal structures associated with active autophagocytic‐associated neuronal degeneration.InterpretationOur findings reveal a distinct clinicopathological phenotype associated with recessive VAC14 mutations.

P.367 - A case of childhood onset of treatable sensory neuronopathy caused by mutations in riboflavin transporter RFVT2 presenting as pure sensory ataxia with excellent response to riboflavin – a five year follow up

Childhood onset neuronopathies are a clinically heterogeneous group of disorders. Its original description is known as Brown-Vialetto-Van Laere syndrome and characterized by motor neuronopathy with early onset of bulbar palsy, hearing loss and respiratory failure. Sensorimotor neuronopathy was described later. No treatment was available for this neurodegenerative disorder until recent discovery of riboflavin transporters RFVT3 and RFVT2. We report a case of early childhood onset of RFVT2 related disorder due to compound heterozygous mutation p.S52F and p.L339P in the SLC52A2 gene presenting as a pure sensory ataxia associated with sensorineural hearing loss, respiratory dysfunction, optic atrophy and retinitis pigmentosa. The patient is a 2-year-old girl at the onset of her condition. Initial presentation consisted of isolated sensory ataxia. Lack of clinically evident muscle weakness and electrodiagnostic studies ruled out motor neuronopathy. 3T high resolution MRI of the brain showed abnormal T2 signal in the reticulospinal tracts. There was biochemical evidence for abnormal acylcarnitine profile. A year later patient developed hearing loss, optic nerve atrophy and retinitis pigmentosa. Polysomnogram revealed central apnea with reduced O2 concentration. We followed prospectively clinical, neurophysiological and biochemical parameters starting at baseline and after initiation of therapy with high doses of riboflavin. We report overt response to high-dose of oral riboflavin therapy in our patient. The clinical and biochemical responses in our patient consistent with reports in the literature that riboflavin supplementation can ameliorate the progression of this neurodegenerative condition, particularly when initiated early in the course and can be lifesaving. In addition, this case further broadened knowledge of this rare disorder including never reported before findings of abnormal MRI, retinitis pigmentosa and detailed characterization of respiratory dysfunction.

021 Clinical and genetic characteristics of cutaneous melanoma with clinical history of early childhood onset

021 Clinical and genetic characteristics of cutaneous melanoma with clinical history of early childhood onset

Association of ADHD and Executive Functioning With Childhood Depression

Objective: Despite its association with increased severity and treatment resistance, relatively little is known about the correlates of early-onset childhood depression. ADHD and executive functioning (EF) are each related to depression. Given their covariation, we tested the independent association of ADHD dimensions (i.e., inattention, hyperactivity) and EF with childhood depression using structural equation modeling to identify potential targets for intervention. Method: Participants were 225 five- to 10-year-old children (68% male) with (n = 117) and without (n = 108) ADHD. Youth completed laboratory assessments of EF, and parent, teacher, and youth reports of depression were gathered. Results: With control of EF and anxiety, across informants, inattention, but not hyperactivity, was positively related to child depression. EF was positively associated with depression according to parent ratings only. Conclusion: We consider the association of inattention and EF with childhood depression, including implications for intervention and prevention from a developmental psychopathology framework.

Twenty‐year follow‐up using a postal survey of childhood vitiligo treated with narrowband ultraviolet B phototherapy

Vitiligo is a depigmenting skin disorder with an estimated prevalence of 1%.(1) Childhood-onset vitiligo occurs in approximately a third of all cases.(2) Early-onset childhood vitiligo tends to be a more extensive and progressive type of vitiligo.(3) Narrowband ultraviolet-B (NB-UVB) phototherapy is an effective treatment option in active vitiligo and leads to >75% repigmentation in 14-75% of childhood cases.(4,5) Unfortunately, no evidence is available whether this repigmentation is long-lasting. To date, no data are available on the long-term efficacy and safety of NB-UVB in childhood vitiligo. This article is protected by copyright. All rights reserved

Current status of biological treatment options in Autism Spectrum Disorder.

Autism Spectrum Disorders (ASDs) are characterised by deficits in social communication and restricted and repetitive behaviours. With an onset in early childhood, ASDs are thought to be heterogeneous, both genetically and clinically. This has led to the notion that "autism" is "autisms", however, there has been limited progress in understanding the different subgroups and the unique pathogenesis that would then allow targeted intervention. Although existing treatments are mainly symptom focussed, research is beginning to unravel the underlying genetic and molecular pathways, structural and functional neuronal circuitry involvement and the associated neurochemicals. This paper will review selected biological models with regard to pharmacological targets while also covering some of the non-pharmacological treatments such as neuro-stimulation.

MPV17 hepatocerebral mitochondrial DNA depletion syndrome presenting as acute flaccid paralysis – A case report

Mutations in human MPV17 have been reported in patients with severe mitochondrial DNA (mtDNA) depletion manifesting as early childhood onset failure to thrive, hypoglycemia, encephalopathy and progressive liver failure. We describe an 11 year old girl, born to consanguineous parents, who presented with rapidly progressive weakness of all 4 limbs with symmetrical proximal and distal weakness, gastrointestinal disease and leukoencephalopathy. Genetic analysis of the patient revealed a homozygous pathogenic mutation c.121C>T (p.R41W) in the MPV17 gene. Further, screening for this mutation in the parents revealed the presence of heterozygous mutation in both the parents, suggesting the recessive nature of the disease.

Concordance of bioactive vs. total immunoreactive serum leptin levels in children with severe early onset obesity.

ContextLeptin secreted from adipose tissue signals peripheral energy status to the brain. Monogenic leptin deficiency results in severe early onset obesity with hyperphagia. Recently, a similar phenotype of inactivating leptin mutations but with preserved immunoreactivity and hence normal circulating immunoreactive leptin has been reported.ObjectiveWe aimed to evaluate the proportion of bioactive leptin serum levels (compared to immunoreactive leptin) as a biomarker for the screening of leptin gene mutations causing monogenic obesity. Furthermore, we aimed to compare the immunoreactive and bioactive leptin levels associations with parameters of insulin resistance and insulin secretion in obese children and adolescents.Patients and methodsWe measured bioactive and immunoreactive leptin levels by enzyme-linked immunosorbent assays in fasting serum samples of 70 children with severe (BMI SDS >3) non-syndromic obesity with onset <3 years of life from our Leipzig childhood obesity cohort (n = 1204). Sanger sequencing of the leptin gene was performed in probands with proportion of bioactive/immunoreactive leptin <90%.ResultsThe mean levels of bioactive and immunoreactive leptin were almost identical (41.1±25.2 vs. 41.1±25.4ng/mL). In three probands with the lowest bioactive leptin proportion (<90%) we did not identify mutations in the leptin gene. Compared to immunoreactive leptin, bioactive leptin showed similar and slightly better statistical associations with indices of insulin resistance in correlation and multivariate analyses.ConclusionIn our sample selected for severe early onset childhood obesity, we did not identify leptin gene mutations leading to decreased proportion of bioactive leptin.Nevertheless, the bioactive leptin levels were stronger associated with selected insulin secretion/resistance indices than the immunoreactive leptin levels.

Variable phenotype expression in a family segregating microdeletions of the NRXN1 and MBD5 autism spectrum disorder susceptibility genes

Autism spectrum disorder is a developmental condition of early childhood onset, which impacts socio-communicative functioning and is principally genetic in etiology. Currently, more than 50 genomic loci are deemed to be associated with susceptibility to autism spectrum disorder, showing de novo and inherited unbalanced copy number variants and smaller insertions and deletions (indels), more complex structural variants, as well as single-nucleotide variants deemed of pathological significance. However, the phenotypes associated with many of these genes are variable, and penetrance is largely unelaborated in clinical descriptions. This case report describes a family harboring two copy number variant microdeletions, which affect regions of NRXN1 and MBD5—each well-established in association with risk of autism spectrum disorder and other neurodevelopmental disorders. Although each copy number variant would likely be categorized as pathologically significant, both genomic alterations are transmitted in this family from an unaffected father to the proband, and shared by an unaffected sibling. This family case illustrates the importance of recognizing that phenotype can vary among exon overlapping variants of the same gene, and the need to evaluate penetrance of such variants in order to properly inform on risks.

SLC6A1 gene involvement in susceptibility to attention-deficit/hyperactivity disorder: A case-control study and gene-environment interaction

Attention-deficit/hyperactivity disorder (ADHD) is an early onset childhood neurodevelopmental disorder with an estimated heritability of approximately 76%. We conducted a case-control study to explore the role of the SLC6A1 gene in ADHD. The genotypes of eight variants were determined using Sequenom MassARRAY technology. The participants in the study were 302 children with ADHD and 411 controls. ADHD symptoms were assessed using the Conners Parent Symptom Questionnaire. In our study, rs2944366 was consistently shown to be associated with the ADHD risk in the dominant model (odds ratio [OR]=0.554, 95% confidence interval [CI]=0.404–0.760), and nominally associated with Hyperactive index score (P=0.027). In addition, rs1170695 has been found to be associated with the ADHD risk in the addictive model (OR=1.457, 95%CI=1.173–1.809), while rs9990174 was associated with the Hyperactive index score (P=0.010). Intriguingly, gene-environmental interactions analysis consistently revealed the potential interactions of rs1170695 with blood lead (Pmul=0.044) to modify the ADHD risk. Expression quantitative trait loci analysis suggested that these positive single nucleotide polymorphisms (SNPs) may mediate SLC6A1 gene expression. Therefore, our results suggest that selected SLC6A1 gene variants may have a significant effect on the ADHD risk.

Motor Stereotypies: A Pathophysiological Review.

Motor stereotypies are common, repetitive, rhythmic movements with typical onset in early childhood. While most often described in children with autism spectrum disorder (ASD) and intellectual disability (ID), stereotypies can also present without developmental delay and persist into adulthood. Stereotypies are often disruptive and harmful, both physically and socially, and effective evidence-based treatments are lacking. This can be attributed, in part, to our incomplete knowledge of the underlying biological and environmental risk. Several studies implicate various neurotransmitters, brain circuits, anatomical loci, and pre- and post-natal environmental influences in stereotypy onset and symptom severity. However, there are few points of convergence among a relatively small number of studies, indicating that more research is needed to confirm the underlying bases of risk. Of particular note is the lack of published genetic studies of stereotypies, despite evidence for Mendelian inheritance patterns in some families. Focusing future studies on typically-developing children with primary motor stereotypies may be a useful approach to minimize potential biological, environmental, and genetic heterogeneity that could theoretically hinder consistent findings. Ultimately, a deeper understanding of the underlying biology and risk factors for motor stereotypies will lead us closer to more effective targeted therapies that will alleviate suffering in affected children.

ZNHIT3 is defective in PEHO syndrome, a severe encephalopathy with cerebellar granule neuron loss.

Progressive encephalopathy with oedema, hypsarrhythmia, and optic atrophy (PEHO) syndrome is an early childhood onset, severe autosomal recessive encephalopathy characterized by extreme cerebellar atrophy due to almost total granule neuron loss. By combining homozygosity mapping in Finnish families with Sanger sequencing of positional candidate genes and with exome sequencing a homozygous missense substitution of leucine for serine at codon 31 in ZNHIT3 was identified as the primary cause of PEHO syndrome. ZNHIT3 encodes a nuclear zinc finger protein previously implicated in transcriptional regulation and in small nucleolar ribonucleoprotein particle assembly and thus possibly to pre-ribosomal RNA processing. The identified mutation affects a highly conserved amino acid residue in the zinc finger domain of ZNHIT3. Both knockdown and genome editing of znhit3 in zebrafish embryos recapitulate the patients' cerebellar defects, microcephaly and oedema. These phenotypes are rescued by wild-type, but not mutant human ZNHIT3 mRNA, suggesting that the patient missense substitution causes disease through a loss-of-function mechanism. Transfection of cell lines with ZNHIT3 expression vectors showed that the PEHO syndrome mutant protein is unstable. Immunohistochemical analysis of mouse cerebellar tissue demonstrated ZNHIT3 to be expressed in proliferating granule cell precursors, in proliferating and post-mitotic granule cells, and in Purkinje cells. Knockdown of Znhit3 in cultured mouse granule neurons and ex vivo cerebellar slices indicate that ZNHIT3 is indispensable for granule neuron survival and migration, consistent with the zebrafish findings and patient neuropathology. These results suggest that loss-of-function of a nuclear regulator protein underlies PEHO syndrome and imply that establishment of its spatiotemporal interaction targets will be the basis for developing therapeutic approaches and for improved understanding of cerebellar development.

Seizures in Children With Cerebral Palsy and White Matter Injury.

The goal of this study was to describe the prevalence, syndromes, and evolution of seizure disorders in children with cerebral palsy (CP) due to white matter injury (WMI). For this population-based cohort study, brain MRI scans and medical records were reviewed in children in the Victorian Cerebral Palsy Register born between 1999 and 2006 recorded as having WMI. Children were excluded if they had features of an undiagnosed syndrome, associated cortical malformation or injury, or no medical contact in the preceding year. Included were 166 children with CP and isolated WMI due to presumed vascular insufficiency or hemorrhage; 87 were born preterm. Seizure and CP details were obtained from medical records and interviews, and EEG recordings were reviewed. Forty-one children (25%) had seizures beyond the neonatal period. Four children had West syndrome, which resolved with treatment. Thirteen children had febrile seizures that they outgrew. Thirty children had focal epilepsy with seizure manifestations and EEG discharges typical of early-onset childhood occipital epilepsy or childhood epilepsy with centrotemporal spikes; 23 have outgrown these seizures. Two children had idiopathic generalized epilepsy; it was ongoing in 1 child. Fourteen children had evolution from 1 epileptic syndrome to another. At last follow-up (median age, 12.7 years; minimum age, 9.7 years), 80% had not had a seizure for >2 years. The electroclinical features of seizure disorders associated with CP and WMI are those of the age-limited, epileptic syndromes of childhood, with favorable outcome in the majority. The findings have important implications for counseling and drug treatment.

Benign mitochondrial myopathy with exercise intolerance in a large multigeneration family due to a homoplasmic m.3250T>C mutation in MTTL1.

Most mitochondrial disorders with onset in early childhood are progressive and involve multiple organs. The m.3250T>C mutation in MTTL1 has previously been described in a few individuals with a possibly riboflavin-responsive myopathy and an association with sudden infant death syndrome was suspected. We describe a large family with this mutation and evaluate the effect of riboflavin treatment. Medical data were collected with the help of a standardized data collection form. Sanger sequencing was used to screen for variants in mitochondrial DNA and the proportion of the mutation was analyzed in different tissues. Biochemical and muscle morphological investigations of muscle tissue were performed in two individuals. The effect of riboflavin treatment was evaluated in two individuals. Thirteen family members experienced exercise intolerance with fatigue and weakness. Inheritance was maternal with 100% penetrance. The course was either static or showed improvement over time. There was no evidence of other organ involvement except for a possible mild transient cardiac enlargement in one child. Muscle investigations showed isolated complex I deficiency and mitochondrial proliferation. The level of m.3250T>C was apparently 100%, i.e. homoplasmic, in all examined tissues. Riboflavin treatment showed no effect in any treated family member and there have been no cases of sudden infant death in this family. This study illustrates the importance of considering mitochondrial disorders in the work-up of individuals with exercise intolerance and provides a better understanding of the phenotype associated with the m.3250T>C mutation in MTTL1.

The clinico-epidemiological profile of atopic dermatitis in residential schoolchildren: A study from South Chhattisgarh, India

Introduction: Atopic dermatitis is a chronic, inflammatory, relapsing skin disorder with early age of onset in infancy and early childhood. Objective: The present study was conducted to study the clinico-epidemiological profile of atopic dermatitis among children of residential schools of naxal-infested South Chhattisgarh. Materials and Methods: Ninety children (4.6%) of atopic dermatitis were pooled out from a previous study by the same authors on 1943 children of eight residential schools. The various clinico-epidemiological factors were studied and analyzed using relevant statistical tools. Results: Out of ninety children having atopic dermatitis, boys:girls ratio was 1:1.73. The mean age of onset was 2.14 ± 0.52 years, and the mean duration of illness was 1.71 ± 0.38 years. The personal history of atopy was present in 34 (37.8%) children whereas a family history of atopy was seen in 47 (52.2%) children. Among clinical presentation, chronic type (n = 56, 62.2%) was most common, followed by subacute (n = 24, 26.2%) and acute (n = 10. 11.1%). Flexor (n = 42, 46.7%) was the most common site affected followed by extensor and face (n = 24, 26.7%) each. Mild severity was seen in 76 (84.4%) children followed by moderate severity (n = 12, 13.4%) and severe (n = 2, 2.2%) children. Sweating (n = 53, 58.9%) was the most common aggravating factor followed by seasonal (n = 51, 56.7%), wool (n = 24, 26.7%), stress (n = 15, 16.7%), dust (n = 10, 11.1%), physical exercise (n = 8, 8.9%), and food (n = 2, 2.2%). Conclusions: Atopic dermatitis of chronic type with mild in severity is more common in community.

MC4R Mutation in Early-onset Severe Childhood Obesity—Genotype–phenotype Correlation

Melanocortin-4 receptor (MC4R; OMIM#155541) encodes a 332-amino acids protein possessing typical G-protein-coupled receptors’ (GPCRs) structural design having three intact and functional domains, mutations which lead to the most recurrent type of monogenic obesity. Methods: We report here a case of a 5-year-old boy from Iraq who presented to the clinic for evaluation of progressive weight gain since he was 6 months of age. There were no symptoms of hypothalamic dysfunction except increase in appetite. His height was 120 cm (97th centile of the Centers for Disease Control and Prevention [CDC] growth chart, mid parental height was 50th centile), weight was 57 kg (&gt;97th centile on CDC chart) and body mass index was 39.6 kg/m2 (&gt;97th centile on CDC chart). A monogenic cause of obesity was strongly suspected in view of early onset severe childhood obesity. Results: Mutation screening of MC4R revealed a homozygous isoleucine by arginie at codon 69 (I69R) mutation in the patient, while his father was heterozygous for this mutation. Conclusion: We describe a monogenic form of obesity with characteristic presentation due to I69R MC4R mutation inherited as an autosomal recessive condition. The finding is different from previous reports which have documented this mutation to be inherited in a dominant manner. The findings of the present study reiterate the complex nature of obesity with possible involvement of modifier genes and/or genetic heterogeneity in its causation.