Proopiomelanocortin (POMC) sequencing and developmental delay: Preliminary evidence for a SNP in the 3' UTR region of the POMC gene-Possible relevance for biological risk and self-injurious behavior.

The proopiomelanocortin (POMC) molecule has been implicated in models of self-injurious behavior (SIB) in neurodevelopmental disorders, but it has never been specifically sequenced in search of base specific polymorphisms. The empirical focus of this preliminary study was to sequence the POMC gene in 11 children (mean age = 41.8 months, range = 12-60 months; 73% male) with clinical concerns regarding global developmental delay, 5 with reported self-injury. Genomic DNA was extracted from blood samples, and the POMC gene was amplified by specific oligonucleotide primers via polymerase chain reaction. The amplified gene products were sequenced by the University of Minnesota Genomic Center, and the results were analyzed using Sequencher software. A single nucleotide polymorphism (SNP), 1130 C>T, was found in the 3' untranslated region (UTR) of two samples (one of whom had SIB). The program TargetScanHuman was used to predict the function of this mutation. Variant c.1130 C<T was predicted to be located in the target site of two microRNAs (miRNAs; hsa-mir-3715 and hsa-mir-1909), and the variant allele T may result in an increased minimum free energy for the two miRNAs. Further work with much larger samples is needed to continue the investigation of POMC's possible function as a risk factor for the development of SIB in children with developmental delay/disability. The findings presented in this study show that the SNP found in the 3' UTR could alter the binding of miRNAs to POMC 3'UTR, thus, increasing POMC expression and affecting several biological systems with high relevance to the biology of self-injury. There was a significant difference in ß-endorphin levels between SIB (M = 169.25 pg/mL) and no SIB (M = 273.5 pg/mL, SD = 15.2) cases (p < .01). Intervention implications are tied to prior observations of individual differences among SIB responders and nonresponders to treatment with the opioid antagonist naltrexone. Stratifying individuals with SIB by POMC mutation status may provide a potential tailoring-like variable to guide the selection of who is more (or less) likely to respond to opiate antagonist treatment. Currently, opioid antagonistic treatment for SIB is empiric (trial and error).

A Direct Comparison of Self-Injurious and Stereotyped Motor Behavior Between Preschool-Aged Children With and Without Developmental Delays.

OBJECTIVE: To compare the prevalence of self-injurious behavior (SIB) and stereotyped motor behavior (STY) of preschool-aged children with developmental delays (DD group) and their peers without developmental delays (TD group) using a standardized caregiver report scale. METHODS: The Repetitive Behavior Scale-Revised was completed by caregivers of children with developmental delays and their peers without developmental delays. Frequency of occurrence and severity ratings for SIB and STY were compared between groups. RESULTS: SIB and STY were reported more often and at a greater level of severity in the DD group. Older chronological age was associated with more severe STY in the DD group but not the TD group. Gender was not related to STY or SIB for either group. CONCLUSIONS: Differences in STY and SIB were evident between preschoolers with and without DD. Findings are discussed from developmental and behavioral psychology perspectives regarding the expression of repetitive behavior in developmentally at-risk pediatric populations.

Skin and self-injury: a possible link between peripheral innervation and immune function?

The aim of this preliminary case study series was to investigate epidermal innervation in pediatric patients with significant neurological impairment and self-injurious behavior. We enrolled four pediatric patients with self-injury (two males, two females; mean age 12y, range 9-14y) and used archival specimens from healthy, age-matched children with typical development for comparison purposes. Epidermal nerve fiber density, peptide content, and mast cell degranulation patterns from non-damaged skin were tested between the patients and the comparison group. The male patients with self-injury had significantly increased epidermal nerve fiber densities, increased substance P positive fiber count and extensive mast cell degranulation compared with sex- and age-matched individuals with typical development. Our case series shows for the first time altered peripheral innervation from non-damaged tissue in children with significant self-injury and developmental disability compared with a healthy comparison group. Establishing the role of peripheral nociceptive and immune modulatory neural pathways may offer new treatment avenues for this devastating neurobehavioral disorder.

Investigation of NRXN1 deletions: clinical and molecular characterization.

Deletions at 2p16.3 involving exons of NRXN1 are associated with susceptibility for autism and schizophrenia, and similar deletions have been identified in individuals with developmental delay and dysmorphic features. We have identified 34 probands with exonic NRXN1 deletions following referral for clinical microarray-based comparative genomic hybridization. To more firmly establish the full phenotypic spectrum associated with exonic NRXN1 deletions, we report the clinical features of 27 individuals with NRXN1 deletions, who represent 23 of these 34 families. The frequency of exonic NRXN1 deletions among our postnatally diagnosed patients (0.11%) is significantly higher than the frequency among reported controls (0.02%; P = 6.08 × 10(-7) ), supporting a role for these deletions in the development of abnormal phenotypes. Generally, most individuals with NRXN1 exonic deletions have developmental delay (particularly speech), abnormal behaviors, and mild dysmorphic features. In our cohort, autism spectrum disorders were diagnosed in 43% (10/23), and 16% (4/25) had epilepsy. The presence of NRXN1 deletions in normal parents and siblings suggests reduced penetrance and/or variable expressivity, which may be influenced by genetic, environmental, and/or stochastic factors. The pathogenicity of these deletions may also be affected by the location of the deletion within the gene. Counseling should appropriately represent this spectrum of possibilities when discussing recurrence risks or expectations for a child found to have a deletion in NRXN1.

The duplication 17p13.3 phenotype: analysis of 21 families delineates developmental, behavioral and brain abnormalities, and rare variant phenotypes.

Chromosome 17p13.3 is a gene rich region that when deleted is associated with the well-known Miller-Dieker syndrome. A recently described duplication syndrome involving this region has been associated with intellectual impairment, autism and occasional brain MRI abnormalities. We report 34 additional patients from 21 families to further delineate the clinical, neurological, behavioral, and brain imaging findings. We found a highly diverse phenotype with inter- and intrafamilial variability, especially in cognitive development. The most specific phenotype occurred in individuals with large duplications that include both the YWHAE and LIS1 genes. These patients had a relatively distinct facial phenotype and frequent structural brain abnormalities involving the corpus callosum, cerebellar vermis, and cranial base. Autism spectrum disorders were seen in a third of duplication probands, most commonly in those with duplications of YWHAE and flanking genes such as CRK. The typical neurobehavioral phenotype was usually seen in those with the larger duplications. We did not confirm the association of early overgrowth with involvement of YWHAE and CRK, or growth failure with duplications of LIS1. Older patients were often overweight. Three variant phenotypes included cleft lip/palate (CLP), split hand/foot with long bone deficiency (SHFLD), and a connective tissue phenotype resembling Marfan syndrome. The duplications in patients with clefts appear to disrupt ABR, while the SHFLD phenotype was associated with duplication of BHLHA9 as noted in two recent reports. The connective tissue phenotype did not have a convincing critical region. Our experience with this large cohort expands knowledge of this diverse duplication syndrome.

High-resolution array CGH defines critical regions and candidate genes for microcephaly, abnormalities of the corpus callosum, and seizure phenotypes in patients with microdeletions of 1q43q44.

Microdeletions of 1q43q44 result in a recognizable clinical disorder characterized by moderate to severe intellectual disability (ID) with limited or no expressive speech, characteristic facial features, hand and foot anomalies, microcephaly (MIC), abnormalities (agenesis/hypogenesis) of the corpus callosum (ACC), and seizures (SZR). Critical regions have been proposed for some of the more prominent features of this disorder such as MIC and ACC, yet conflicting data have prevented precise determination of the causative genes. In this study, the largest of pure interstitial and terminal deletions of 1q43q44 to date, we characterized 22 individuals by high-resolution oligonucleotide microarray-based comparative genomic hybridization. We propose critical regions and candidate genes for the MIC, ACC, and SZR phenotypes associated with this microdeletion syndrome. Three cases with MIC had small overlapping or intragenic deletions of AKT3, an isoform of the protein kinase B family. The deletion of only AKT3 in two cases implicates haploinsufficiency of this gene in the MIC phenotype. Likewise, based on the smallest region of overlap among the affected individuals, we suggest a critical region for ACC that contains ZNF238, a transcriptional and chromatin regulator highly expressed in the developing and adult brain. Finally, we describe a critical region for the SZR phenotype which contains three genes (FAM36A, C1ORF199, and HNRNPU). Although ~90% of cases in this study and in the literature fit these proposed models, the existence of phenotypic variability suggests other mechanisms such as variable expressivity, incomplete penetrance, position effects, or multigenic factors could account for additional complexity in some cases.

Rasch analysis of items from two self-report measures of motor function: determination of item difficulty and relationships with children's ability levels.

AIM: The aim of this article was to determine item measurement properties of a set of items selected from the Gillette Functional Assessment Questionnaire (FAQ) and the Pediatric Outcome Data Collection Instrument (PODCI) using Rasch analysis, and to explore relationships between the FAQ/PODCI combined set of items, FAQ walking scale level, Gross Motor Function Classification System (GMFCS) levels, and the Gait Deviation Index on a common measurement scale. METHOD: Rasch analysis was performed on data from a retrospective chart review of parent-reported FAQ and PODCI data from 485 individuals (273 males; 212 females; mean age 9 y 10 mo, SD 3 y 10 mo) who underwent first-time three-dimensional gait analysis. Of the 485 individuals, 289 had a diagnosis of cerebral palsy (104 GMFCS level I, 97 GMFCS level II, 69 GMFCS level III, and 19 GMFCS level IV). Rasch-based person abilities and item difficulties based on subgroups defined by the FAQ walking scale level, Gait Deviation Index, and the GMFCS level were compared. RESULTS: The FAQ/PODCI item set demonstrated necessary Rasch characteristics to support its use as a combined measurement scale. Item groupings at similar difficulty levels were consistent with the mean person abilities of subgroups based on FAQ walking scale level, Gait Deviation Index, and GMFCS level. INTERPRETATION: Rasch-derived person ability scores from the FAQ/PODCI combined item set are consistent with clinical measures. Rasch analysis provides insights that may improve interpretation of the difficulty of motor functions for children with disabilities.

Microdeletion of Xq28 involving the AFF2 (FMR2) gene in two unrelated males with developmental delay.

Fragile X E (FRAXE) is an X-linked form of intellectual disability characterized by mild to moderate cognitive impairment, speech delay, hyperactivity, and autistic behavior. The folate-sensitive fragile site FRAXE is located in Xq28 approximately 600 kb distal to the fragile X syndrome fragile site (FRAXA) and harbors an unstable GCC (CCG) triplet repeat adjacent to a CpG island in the 5' untranslated region of the AFF2 (FMR2) gene. The disorder results from amplification and methylation of the GCC repeat and resultant silencing of AFF2. Although chromosome abnormalities that disrupt AFF2 have been reported in two individuals with mild-moderate intellectual disability, microdeletions of Xq28 that delete only AFF2 have not been described as a potential cause of FRAXE-intellectual disability. We performed clinical and molecular characterization of two males with 240 and 499 kb deletions, respectively, at Xq28, both of which encompassed only one gene, AFF2. The 240 kb deletion in Patient 1 was intragenic and lead to the loss of 5' exons 2-4 of AFF2; the 499 kb deletion in Patient 2 removed the 5' exons 1-2 of AFF2 including approximately 350 kb upstream of the gene. Both individuals had developmental and speech delay, and one had mild dysmorphism. We predict disruption of AFF2 in these two patients is likely the cause of their overlapping phenotypes.

Deletions and duplications of developmental pathway genes in 5q31 contribute to abnormal phenotypes.

Although copy number changes of 5q31 have been rarely reported, deletions have been associated with some common characteristics, such as short stature, failure to thrive, developmental delay (DD)/intellectual disability (ID), club feet, dislocated hips, and dysmorphic features. We report on three individuals with deletions and two individuals with duplications at 5q31, ranging from 3.6 Mb to 8.1 Mb and 830 kb to 3.4 Mb in size, respectively. All five copy number changes are apparently de novo and involve several genes that are important in developmental pathways, including PITX1, SMAD5, and WNT8A. The individuals with deletions have characteristic features including DD, short stature, club feet, cleft or high palate, dysmorphic features, and skeletal anomalies. Haploinsufficiency of PITX1, a transcription factor important for limb development, is likely the cause for the club feet, skeletal anomalies, and cleft/high palate, while additional genes, including SMAD5 and WNT8A, may also contribute to additional phenotypic features. Two patients with deletions also presented with corneal anomalies. To identify a causative gene for the corneal anomalies, we sequenced candidate genes in a family with apparent autosomal dominant keratoconus with suggestive linkage to 5q31, but no mutations in candidate genes were found. The duplications are smaller than the deletions, and the patients with duplications have nonspecific features. Although development is likely affected by increased dosage of the genes in the region, the developmental disruption appears less severe than that seen with deletion.

Self-injury among a community cohort of young children at risk for intellectual and developmental disabilities.

OBJECTIVE: To identify risk factors for self-injurious behavior in young children with developmental delay and to determine whether that group is also more likely to exhibit other challenging behaviors. STUDY DESIGN: A retrospective chart review of 196 children < 6 years of age referred for comprehensive neurodevelopmental evaluations. We analyzed child developmental level, receptive and expressive communication level, mobility, visual and auditory impairment, and co-morbid diagnoses of cerebral palsy, seizure disorders, and autism. RESULTS: Sixty-three children (32%; mean age = 42.7 mo, 63% male) were reported to engage in self-injurious behavior at the time of the evaluation. Children with and without self-injurious behavior did not differ on overall developmental level, expressive or receptive language level, mobility status or sensory functioning, or in rates of identification with cerebral palsy, seizure disorders, or autism. However, the self-injurious behavior group was rated significantly higher by parents on destructive behavior, hurting others, and unusual habits. CONCLUSIONS: Although self-injurious behavior was reported to occur in 32% of the cohort, the modal frequency was monthly/weekly and the severity was low. No significant differences were found for risk markers reported for adults, adolescents, and older children with intellectual and developmental disabilities. However, self-injurious behavior was comorbid with other behavior problems in this sample.

Parents' reports predict abnormal investigations in global developmental delay.

AIMS: To identify symptoms reported by parents that predict abnormal laboratory investigations in preschoolers with global developmental delay (GDD). METHODS: A cross-sectional descriptive study of 81 boys and 38 girls, with a mean age of 43.5 months (SD = 13.4), with global developmental delay. All parents/guardians completed the following: (1) a semistructured interview about their child and family; (2) the Child Development Inventory (CDI); (3) the Possible Problems Checklist (PPC); and (4) the Child Behavior Checklist 1(1/2)-5 (CBCL). RESULTS: There were 61 abnormal results: MRI 37 (31%); high-resolution chromosomes 8 (7%); fragile X molecular testing 4 (3%); and microarray comparative genomic hybridization 12 (10%). A total of 47 children had abnormal tests (40%): none, 72 (60%); one, 36 (30%); two, 8 (7%); three, (3%). Younger children with more developmental delays are more likely to have abnormal tests. They are clumsy, more passive, and less disobedience. They had lower total, externalizing, and internalizing problems scores. The odds of finding an abnormal investigation are increasingly greater as parent's report of language comprehension and social development ratios increase, and decrease in likelihood for every increase in the expressive language and fine motor ratios. INTERPRETATION: Parent's reports predict abnormal tests and indicate quantifiable differences requiring investigation.

The effects of methylphenidate on the classroom behavior of elementary school-age children with cerebral palsy: a preliminary observational analysis.

High- and low-dose methylphenidate administration was evaluated prospectively for 3 elementary school-age children with cerebral palsy, cognitive impairments, and attention-deficit hyperactivity disorder (ADHD) symptoms using single-case, randomized, double-blind, placebo-controlled designs. An observational time sampling protocol was used to directly measure and quantify classroom behavior. Summary level analysis showed that (1) low-dose (0.3 mg/kg/dose) administration was associated with clinically significant (>50%) reductions in stereotyped and disruptive behavior relative to baseline and placebo conditions, (2) high-dose (0.5 mg/kg/dose) administration was associated with exacerbated amounts of stereotyped and disruptive behavior, and (3) no changes were directly observed for task-related behavior at either dose. Results are discussed with respect to previous research with methylphenidate administration and cerebral palsy, and the suggestion is made that further work using larger, randomly selected study samples with complementary measures of behavior and performance appears warranted.

Language proficiency, development, and behavioral difficulties in toddlers.

The aim of this cross-sectional descriptive study was to explore the relation of language proficiency, behavioral difficulties, and development in infants and toddlers. Surveyed were 118 parents/caregivers of preschool children (76 boys, 42 girls). The children were a mean age of 27 months (range, 18-35 months), and 32 (27.1%) had no language delay, 8 (6.8%) had expressive delay, 14 (11.9%) had receptive delay, and 64 (54.2%) had mixed receptive-expressive delay. Children with expressive delay were more likely to have social-emotional problems. Those with receptive delay were more likely to have pervasive developmental problems. Children with receptive-expressive delay were more substantially delayed in all developmental domains; they were more withdrawn and more likely to have pervasive developmental problems. When parents of toddlers report problems, especially behavior problems, a search for delayed language is warranted as these children may be at risk for future social and emotional problems.

A Case-Controlled Investigation of Tactile Reactivity in Young Children With and Without Global Developmental Delay.

Assessing tactile function among children with intellectual, motor, and communication impairments remains a clinical challenge. A case control design was used to test whether children with global developmental delays (GDD; n = 20) would be more/less reactive to a modified quantitative sensory test (mQST) compared to controls (n = 20). Reactivity was indexed by blinded behavioral coding across vocal, facial, and gross motor responses during the mQST. On average the children with GDD were significantly more reactive than controls to most tactile sensory modalities including light touch (p = .034), pin prick (p = .008), cool (p = .039), pressure (p = .037), and repeated von Frey (p = .003). The results suggest the mQST approach was feasible and highlights the GDD sample was more reactive than controls to a range of stimuli.

Parent's reports predict their child's developmental problems.

To document parental reports about their child's delayed development, 180 consecutive parents/guardians of children, ages ranging from 16 to 70 months, were surveyed. Parents reported a mean of 8.28 (SD 4.55) problems. Symptoms most reported were not talking well (79.5%), poor speech (59.8%), immaturity (58.0%), understands poorly (55.4%), bowel/bladder problems (50.9%), seldom plays with others (47.3%), attention (46.4%), eating (43.8%), clumsy-gross motor (40.2%), and clumsy-fine motor (40.2%). There was an association between delayed development and symptoms about eating, bowel-bladder, clumsy fine-motor, not talking well, understands poorly, immature, and seldom plays with others (p<0.05). The presence of language symptoms increased the odds of delayed development by 2.25. Relevant symptoms differed by developmental domains and different groups of items predicted specific delays. Parent reports indicated quantifiable difficulties requiring detailed assessments.

Peripheral Innervation in Children With Global Developmental Delay: Biomarker for Risk for Self-Injurious Behavior?

The relation between somatosensory mechanisms and self-injury among children with neurologic impairments associated with developmental delay is not well understood. We evaluated the feasibility of procuring skin biopsies to examine epidermal nerve fiber density and reported self-injury. Following informed parental consent, epidermal skin biopsies were obtained from a distal leg site with no pre-existing skin damage from 11 children with global developmental delay (55% male; mean age = 36.8 months, 17-63 months). Visual microscopic examination and quantitative analyses showed extremely high epidermal nerve fiber density values for some children. Children with reported self-injury (5/11) had significantly (P < .02) greater density values (138.8, standard deviation = 45.5) than children without self-injury (80.5, standard deviation = 17.5). Results from this novel immunohistologic analysis of skin in very young children with neurodevelopmental delays suggest it may be a useful tool to study peripheral innervation as a possible sensory risk factor for self-injury.

Single-case experimental designs: applications in developmental-behavioral pediatrics.

This article discusses single-case experimental designs (SCEDs) and their relevance to developmental-behavioral pediatrics. Information concerning SCEDs have not been described in the Journal of Developmental and Behavioral Pediatrics, despite its relevance to the field. General issues related to the underlying logic and applications of SCEDs are reviewed with examples selected from the literature to illustrate the strengths and weaknesses of different design strategies. It is suggested that SCEDs can be a useful alternative to traditional between-group designs for clinical and evaluation research because the unit of the analysis is the individual; therefore the feedback to clinicians and families is direct about the effectiveness of a behavioral intervention or medication for that individual. In the field of developmental-behavioral pediatrics, SCEDs can be especially useful in the management of vague symptoms or poorly defined diseases to improve the confidence in a treatment decision for an individual patient. This report is intended to facilitate the understanding and use of single-case methodology so that clinicians are aware that flexible, true experiential designs exist to fill the gap in knowledge and also "do the best for my patient."

Seizures and pain uncertainty associated with parenting stress and Rett syndrome.

Data were collected parenting stress, adaptive behavior, pain, and health issues from the caregivers of 35 girls and women with Rett syndrome (mean age = 20.3). A majority (60%) of parents reported stress in the clinical range on at least 1 subscale of the Parenting Stress Index-Short Form. Seizures and uncertainty about their daughter's gastrointestinal pain experience were significantly associated with higher levels of parenting stress. No other child factors (adaptive behavior, age, residential status) were significantly related to parenting stress. Factors related to chronic health concerns (seizures, ambiguous pain presentation) may be important when considering family stress issues in relation to general outcomes for girls with Rett syndrome and related developmental disorders.

Refining analyses of copy number variation identifies specific genes associated with developmental delay.

Copy number variants (CNVs) are associated with many neurocognitive disorders; however, these events are typically large, and the underlying causative genes are unclear. We created an expanded CNV morbidity map from 29,085 children with developmental delay in comparison to 19,584 healthy controls, identifying 70 significant CNVs. We resequenced 26 candidate genes in 4,716 additional cases with developmental delay or autism and 2,193 controls. An integrated analysis of CNV and single-nucleotide variant (SNV) data pinpointed 10 genes enriched for putative loss of function. Follow-up of a subset of affected individuals identified new clinical subtypes of pediatric disease and the genes responsible for disease-associated CNVs. These genetic changes include haploinsufficiency of SETBP1 associated with intellectual disability and loss of expressive language and truncations of ZMYND11 in individuals with autism, aggression and complex neuropsychiatric features. This combined CNV and SNV approach facilitates the rapid discovery of new syndromes and genes involved in neuropsychiatric disease despite extensive genetic heterogeneity.

Parent-reported pain in Rett syndrome.

OBJECTIVES: Clinical reports suggest that patients with Rett syndrome (RTT) live with significant chronic health issues as well as severe motor and communication impairments. Consequently, patients with RTT may be at risk for living with pain but not having it recognized. The purpose of this preliminary study was to document parent reported estimates of pain frequency, pain communication, and pain source. METHODS: Caregivers of 44 patients with clinically diagnosed RTT (mean RTT age = 21.5, SD = 13.5) completed a health survey about their daughter that contained a number of items specific to pain from the Non-Communicating Children's Pain Checklist - Revised SURVEY RESULTS: Among survey responders, 24% reported that their child had experienced pain on 8 or more days (> 1 week) in the previous 30 days. The most frequent form of pain communication was facial expression (85%) and vocalization (82%, eg, moan, cry). The most commonly reported pain source was gastro-intestinal (66%). Pain frequency was significantly (P<0.05) correlated with age (0.41), number of pain sources (0.72), and number of health problems (0.45); and the number pain sources was significantly (P<0.05) correlated with number of health problems (0.67). DISCUSSION: These preliminary results suggest that pain is a problem for a significant subgroup of patients with RTT. Almost one quarter of respondents indicated their daughters experience over a week of pain per month. The frequent health and communication issues associated with RTT suggest an increased risk that pain may be overlooked or discounted in this vulnerable population.