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).

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.

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.

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.

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.

Developmental and behavior problems predict parenting stress in young children with global delay.

To identify parent-reported symptoms that predict parenting stress in preschoolers with global developmental delay, 201 parents/guardians of 142 boys and 59 girls with global delay, mean age 39.1 months (range, 18 to 63 months) were studied retrospectively. Parents completed the following: (a) a semistructured interview; (b) the Child Development Inventory, (c) Child Behavior Checklist 1½-5, and the (d) Parenting Stress Index-Short Form. Forty-two percent of parents described clinically significant parenting stress (≥ 85th percentile). The Parenting Stress Index-Short Form subscales Difficult Child and Parent-Child Dysfunctional Interactions were elevated. Parental stress increased with higher gross motor development and decreased as social and fine-motor ratios increased. Furthermore, stress increased when parents reported higher levels on the Emotionally Reactive and Withdrawn scale scores and when parents reported Pervasive Developmental and Oppositional Defiant Problems. In mobile children with global delay, behavior problems predict parenting stress.

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.

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.

Attention problems and parent-rated behavior and stress in young children at risk for developmental delay.

The aim of this article is to characterize the neurobehavior of young children at risk for developmental delay and attention problems. Two hundred and eighty-one children, ages 18 to 70 months, were evaluated. All parents/guardians completed the Child Development Inventory, Child Behavior Checklist for Ages 1½ to 5, Inventory for Client and Agency Planning, and Parenting Stress Index-Short Form. All children had significant delays (developmental ratios <.70). A Mann-Whitney U test compared those with and without attention problems (T score >70). A 2-tailed P value of <.05 indicated statistical significance. Children with attention problems were more likely to have withdrawn behavior, sleep problems, and aggressive behavior. All had severe problem behaviors, and their families experienced significant stress. Attention problems and other serious problem behaviors occur frequently in young children at risk for developmental delay. Parental stress warrants prompt intervention for their children and positive supports for them.

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 principle of double effect, genetic testing, and global developmental delay.

Well-intended efforts to diagnose a child's developmental delay may have unintended negative consequences for a child and his family. Consequently, clinicians may feel caught in a moral dilemma: between doing the good they seek and avoiding the harm they foresee. The dilemma is that when investigating global developmental delay it is not possible to avoid all the anticipated negative outcomes of genetic testing and concurrently fulfill our obligations to do the good from which these harmful effects result. It is imperative to recognize dilemmas especially where the moral questions or relevant facts are not as clear cut as in ethics textbooks and to bring their moral questions into a structured dialogue with the patient and his or her family. A modified principle of double effect is a useful method for deliberating about these moral cases. Three case examples illustrate the utility of the principle of double effect when investigating global developmental delay.

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.

Parent evaluation of spasticity treatment in cerebral palsy using botulinum toxin type A.

OBJECTIVE: To assess parent ratings of treatment acceptability associated with botulinum toxin type A (BTX-A) injection for spasticity in children with cerebral palsy (CP). DESIGN: A single-point survey design across a sequentially recruited cohort, using a standardized evaluation measure. SETTING: Regional specialty health care center medical clinic and pain research program. PARTICIPANTS: Fifty-nine parents of children with CP receiving BTX-A injection for spasticity. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: The Treatment Evaluation Inventory. RESULTS: Overall, parent ratings of treatment acceptability ranged from moderate to high. There were no significant differences for caregiver ratings in relation to characteristics of the raters (age, sex, marital status) or of the children (age, sex, mental retardation, severity of disability) characteristics. CONCLUSIONS: These findings indicate that on average, parents of children with CP consider BTX-A treatment for the management of spasticity to be an acceptable form of treatment.

Parental report of pain and associated limitations in ambulatory children with cerebral palsy.

OBJECTIVE: To document parental reports about pain in children with cerebral palsy (CP). DESIGN: A cross-sectional descriptive study. SETTING: Motion analysis laboratory. PARTICIPANTS: Seventy-seven ambulatory children with CP (44 boys, 33 girls; age range, 3-17y) presenting as consecutive assessments. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Parents completed (1) a semistructured interview, (2) the Pediatric Outcome Data Collection Instrument (PODCI), (3) the Child Behavior Checklist (CBCL), (4) the Behavior Rating Inventory of Executive Functioning (BRIEF), and (5) Gillette Functional Assessment Questionnaire. Two dichotomous PODCI pain and comfort questions were estimates of pain frequency and impact. RESULTS: Sixty-one percent reported "pain over the last week," and 33% reported "pain interfered with normal activities." Pain did not differ by topographic classification. Girls had more pain. "Pain that interfered with normal activities" was associated with limitations in activities of daily living and physical education. Social problems and attention problems on the CBCL and the initiate scale on the BRIEF were associated with pain that interfered with activity. CONCLUSIONS: Pain in children with CP is frequent and associated with behavioral and social consequences. Sex is a risk factor; girls experience more pain. Intervention strategies that successfully support transition into adulthood are needed.

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.

Health professional student attitudes towards people with disability.

OBJECTIVE: To investigate health professional student attitudes toward people with disability. It was hypothesized that attitude and comfort would differ by discipline. Further, it was hypothesized that factors such as gender and background in disability would influence these attitudes and their ease in dealing with difficult encounters in rehabilitation. DESIGN: A cross-sectional survey design. SETTING: University of South Dakota (USD) PARTICIPANTS: Three hundred and thirty-eight students were surveyed. MAIN OUTCOME MEASURES: (a) Attitude Toward Disabled Persons (ATDP) scale; (b) Scale of Attitudes Toward Disabled Persons (SADP); (c) Rehabilitation Situations Inventory (RSI). RESULTS: There were differences among student groups on the attitude scales and factor scores. All students' attitudes were less positive than SADP norms and nursing students held the least positive opinions. There were no attitudinal differences by gender. Those with a background in disability held more positive attitudes. Years of experience and hours per week employed predicted comfort with challenging rehabilitation situations. Inconsiderate treatment by staff, inappropriate sexual overtures and aggressive behaviour by patients were stated to be most challenging. CONCLUSION: Health professional students hold less positive attitudes than SADP norms. Nursing undergraduate students were at greater risk of holding negative attitudes. Work experience was important for comfort with challenging rehabilitation situations. Specific educational experiences are needed to promote more positive attitudes.

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."