Get Your Molar Tooth Right: Joubert Syndrome Misdiagnosis Unmasked by Whole-Exome Sequencing.

Joubert syndrome (JS) is a recessively inherited ciliopathy, characterized by a specific cerebellar and brainstem malformation recognizable on brain imaging as the "molar tooth sign" (MTS). Clinical signs include hypotonia, developmental delay, breathing abnormalities, and ocular motor apraxia. Older patients develop ataxia, intellectual impairment, and variable organ involvement. JS is genetically heterogeneous, with over 40 ciliary genes overall accounting for 65-75% cases. Thus, in recent years, the genetic diagnosis of JS has been based on the analysis of next-generation sequencing targeted gene panels. Since clinical features are unspecific and undistinguishable from other neurodevelopmental syndromes, the recognition of the MTS is crucial to address the patient to the appropriate genetic testing. However, the MTS is not always properly diagnosed, resulting either in false negative diagnoses (patients with the MTS not addressed to JS genetic testing) or in false positive diagnoses (patients with a different brain malformation wrongly addressed to JS genetic testing). Here, we present six cases referred for JS genetic testing based on inappropriate recognition of MTS. While the analysis of JS-related genes was negative, whole-exome sequencing (WES) disclosed pathogenic variants in other genes causative of distinct brain malformative conditions with partial clinical and neuroradiological overlap with JS. Reassessment of brain MRIs from five patients by a panel of expert pediatric neuroradiologists blinded to the genetic diagnosis excluded the MTS in all cases but one, which raised conflicting interpretations. This study highlights that the diagnostic yield of NGS-based targeted panels is strictly related to the accuracy of the diagnostic referral based on clinical and imaging assessment and that WES has an advantage over targeted panel analysis when the diagnostic suspicion is not straightforward.

The International Classification of Functioning, Disability and Health-Children and Youth as a framework for the management of spinal muscular atrophy in the era of gene therapy: a proof-of-concept study.

BACKGROUND: Management of spinal muscular atrophy (SMA) has progressed enormously and reached unprecedented levels with nusinersen gene therapy. We are finally able to counter the progression of this devastating genetic disease, contributing to the definition of new trajectories in its natural history and the identification of new SMA phenotypes post-gene therapy. The aim of this paper was to use the The International Classification of Functioning, Disability and Health-Children and Youth as a framework for the management of spinal muscular atrophy in the era of gene therapy: a proof-of-concept study (ICF-CY) as a comprehensive documentation tool to better understand and improve care provided to a child with SMA and to illustrate its use in a multidisciplinary perspective with a proof-of-concept study. CASE REPORT: An SMA child under gene therapy receiving a rehabilitation program. Clinical and functional outcome measures assessed at all levels of the ICF-CY, including impairment by Hammersmith Infant Neurological Examination, activity by Hammersmith Functional Motor Scale and Functional Independence Measure for Children, and participation by Pediatric Quality of Life Inventory™ - PedsQL™ and Neuromuscular Module™ as well as by parent report. Treatment outcomes were assessed at two main time points: at T0: prior to administration of nusinersen, and T1: immediately before the first administration of maintenance doses, 6 months after the first administration of nusinersen. A significant clinical improvement was seen on all domains between T0 and T1. The patient improved especially in motor skills and motor disability severity. The HRQOL showed a substantial improvement, too. ICF-CY codes were used to document change in body functions or structures, performance of activities or participation in social roles both in terms of gradient and hierarchy of change. This proof-of-concept study is the first attempt to explore SMA in a comprehensive manner from the perspective of the ICF-CY using a selected set of codes. These codes define essential child dimensions that can make up an ICF-CY core set, as identified by a trained multidisciplinary team, to guide assessment, treatment and rehabilitation. CLINICAL REHABILITATION IMPACT: Although limited to a single patient, this study makes nonetheless a strong point: we suggest using the ICF-CY as an essential tool in SMA management at a time when gene therapy with nusinersen is changing the phenotypes of activity and functioning in these children.

A systematic review of coping strategies in parents of children with attention deficit hyperactivity disorder (ADHD).

BACKGROUND: Parents of children with attention deficit hyperactivity disorder (ADHD) use several coping strategies to deal with ADHD symptoms impacting family life. AIM: The aim of this systematic review was to summarize the coping strategies used by parents of children with ADHD, identify which tools are most frequently used to measure coping strategies, and examine factors influencing parental coping. METHOD: According to PRISMA guidelines, we searched for articles indexed in PubMed, EBSCOhost, Scopus, and Web of Science using a combination of expressions including "coping" AND "ADHD" OR "attention-deficit/hyperactivity disorder" AND "parent" OR "parenting" OR "caregiver". RESULTS: Fourteen empirical studies were identified as relevant to our research. Many different types of tools are used to assess coping strategies. We found that parents of ADHD children used more avoidant-focused coping strategies than parents of typical children. Mothers of ADHD children sought significantly more support and used more indirect means than mothers of typically developing (TD) children. CONCLUSIONS: This review underlines the importance of further exploring coping mechanisms of parents of children with ADHD in order to promote positive coping strategies for parents of children with ADHD, and to help such parents to identify people who can support them.

Coping, stress and negative psychological outcomes in parents of children admitted to a pediatric neurorehabilitation care unit.

BACKGROUND: Parents' attitudes and psychological adjustment during their child's hospitalization in a pediatric neurorehabilitation care unit are key aspects for the child's adherence to care and the impact of the disease. AIM: The aim of this study was to examine the relationship between parenting stress, coping style, and negative psychological outcomes in families of children admitted for the first time to a pediatric neurorehabilitation care unit. DESIGN: This is an observational study. SETTING: Pediatric neurorehabilitation care unit. POPULATION: One hundred twenty-four parents of children diagnosed with neurodevelopmental or neurological conditions. METHODS: Parents completed standardized questionnaires assessing parenting stress, coping style, anxiety and depressive symptoms. RESULTS: We found that parents of children with neurodevelopmental conditions showed more emotion-focused coping strategies (P=0.016) and depressive symptoms (P=0.01) compared with parents of children with neurological conditions. Hierarchical regression analyses showed that emotion- and avoidance-oriented coping style and socioeconomic status are crucial factors in the adjustment process of parents of children with neurodevelopmental conditions. By contrast, parenting stress and child difficulties were the most significant predictors of negative psychological outcomes in parents with neurological conditions. CONCLUSIONS: This study sought to develop more understanding of the relationship among parenting stress, coping, and anxiety or depressive symptoms in parent of children hospitalized in a pediatric neurorehabilitation care unit. We suggest that examining parents may increase our understanding of the interplay between child and parent functioning in families with children admitted for the first time to a pediatric neurorehabilitation care unit. CLINICAL REHABILITATION IMPACT: Identify these predictors might help professionals to develop screening procedures to identify parent at high risk for anxiety or depression, and to conduct early interventions to reduce uncertainty and maladaptive coping strategies that may influences rehabilitation process.

Motor competency and social communication skills in preschool children with autism spectrum disorder.

This study aimed to investigate the association between motor competency and social communication in children with Autism Spectrum Disorder (ASD) compared with children with Intellectual Disabilities (ID) and typically developing (TD) children. Motor competency, ASD symptoms, and nonverbal Intelligent Quotient (IQ) were investigated through the following tests: Movement Assessment Battery for Children, second edition (MABC-2), Social Communication Questionnaire (SCQ), Autism Classification System of Functioning: Social Communication (ACSF:SC) and Leiter International Performances Scale Revised (Leiter-R). The ASD + ID and ID groups had lower MABC-2-manual dexterity mean scores, MABC-2-aiming and catching mean scores, MABC-2-static and dynamic balance mean scores and MABC-2-TTS compared with the TD group (P < 0.05). In addition, the ASD + ID group had lower MABC-2-aiming and catching mean scores compared with the ID group. In the ASD + ID group, we found a significant negative correlation (P < 0.001) between MABC-2-aiming and catching scores with SCQ scores, nonverbal IQ and ACSF:SC levels. Our findings provide new insight into the common neuropsychological mechanisms underlying social communication and motor deficits in ASD. Multiple deficits in motor functioning may be present in ASD and ID, however deficits involving the ability to integrate motor and social cues are somewhat specific to ASD. Autism Res 2018, 11: 893-902. © 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: This study highlighted the specificity of motor impairment in ASD comparing performances on a frequently used measure of motor impairment between clinical groups (ASD + ID and ID) and a non-clinical group. While previous research has suggested that multiple deficits in motor functioning may be present in ASD, our findings suggest that deficits in tasks involving the ability to integrate visual and motor cues (aiming and catching task) are somewhat specific to ASD.

Social communication in children with autism spectrum disorder (asd): Correlation between DSM-5 and autism classification system of functioning-social communication (ACSF:SC).

The aim of this study was to classify children with Autism Spectrum Disorder (ASD) according to Autism Classification System of Functioning: Social Communication (ACSF:SC) criteria, in order to investigate the association between social communication ability, ASD severity, adaptive functioning, cognitive abilities and psychoeducational profile. The severity of social communication impairment was specified through Diagnostic and Statistical Manual of Mental Disorders-5th edition (DSM-5) and ACSF:SC tool. The ADOS-2, Vineland-II and PEP-3 were administered to all participants. We found a positive correlation between DSM-5 levels and ACSF:SC-Typical Performance (r = 0.35; P = 0.007) and ACSF:SC-Capacity (r = 0.31; P = 0.01) levels. Children included in the five levels of ACSF:SC (Typical Performance and Capacity) showed statistically significant differences in ADOS-2 (Social Affect), Vineland-II (Communication and Socialization), and PEP-3 (Communication, motor skills, maladaptive behavior) scores. The results of this study indicate that ACSF:SC provide a better understanding of functional profile of children with ASD based on the social communication abilities. Children with greater severity of social communication showed more difficulty in adaptive behavior and psychoeducational profiles. In conclusion, the ACSF:SC could help clinicians and therapists not only to understand the strength and weakness of preschool children with ASD but also to devise specific treatment in order to promote their social integration. Autism Res 2017. © 2017 International Society for Autism Research, Wiley Periodicals, Inc. Autism Res 2017, 10: 1249-1258. © 2017 International Society for Autism Research, Wiley Periodicals, Inc.

Psychopathology in children and adolescents with primary headaches: categorical and dimensional approaches.

BACKGROUND: Recurrent headache is common in childhood, but there is not a great amount of data on the associations between headaches and psychopathology in children. OBJECTIVE: The aim of this study is to examine the relationships between primary headaches and psychopathology in children, using both the categorical and dimensional assessment. METHODS: The sample consisted of 70 patients with primary headache compared to a matched sample of 50 healthy children. Psychiatric comorbidity was defined according to the diagnostic criteria of the Diagnostic and Statistical Manual of Disorders. Child psychopathology outcomes were assessed using child- and parent-reported standardized instruments. RESULTS: Internalizing and externalizing problems were significantly represented among children with headaches compared to the control group, respectively 63% and 27%, without significant differences between migraine and tension-type headache children. Moreover, a total of 26% of the children with a headache reported psychiatric comorbidity such as anxiety and mood disorders. CONCLUSION: The dimensional approach improves accuracy in the recognition of emotional and behavioral problems compared to the categorical approach; however, the use of both of these approaches could be useful for clinical practice, treatment and research.

Familial liability, obstetric complications and childhood development abnormalities in early onset schizophrenia: a case control study.

BACKGROUND: Genetic and environmental risk factors and gene-environment interactions are linked to higher likelihood of developing schizophrenia in accordance with the neurodevelopmental model of disease; little is known about risk factors and early development in early-onset schizophrenia (EOS) and very early-onset schizophrenia (VEOS). METHODS: We present a case-control study of a sample of 21 patients with EOS/VEOS and a control group of 21 patients with migraine, recruited from the Child Neuropsychiatry Unit, Department of Neurologic and Psychiatric Science, University of Bari, Italy. The aim was to assess the statistical association between VEOS/EOS and family history for psychiatric disorders, obstetric complications and childhood developmental abnormalities using 2 × 2 tables and a Chi Squared or Fisher test. RESULTS: The results show a statistical association between EOS/VEOS and schizophrenia and related disorders (P = 0.02) and personality disorders (P = 0.003) in relatives, and between EOS/VEOS and developmental abnormalities of early relational skills (P = 0.008) and learning (P = 0.04); there is not a statistically relevant difference between cases and controls (P > 0.05) for any obstetric complications (pre, peri and postpartum). CONCLUSIONS: This study confirms the significant role of familial liability but not of obstetric complications in the pathogenesis of VEOS/EOS; the association between childhood developmental abnormalities and EOS/VEOS supports the neurodevelopmental model of disease.

Electrophysiological study in 2 children with transient hypohidrosis induced by topiramate.

OBJECTIVE: Hypohidrosis, often associated with hyperthermia, has been reported, mostly in children, as a rare and reversible adverse effect of topiramate, an anticonvulsant drug with a broad spectrum of antiepileptic activity. The aim of our study is to detect a possible skin innervation involvement as the mechanism underlying hypohidrosis in children treated with topiramate. METHODS: A neurophysiological study has been performed on 2 children who have developed hypohidrosis under topiramate treatment. Electrophysiological data have been recorded during topiramate treatment and compared with a control group. Sympathetic skin responses have been recorded during topiramate assumption and after its discontinuation. RESULTS: In our 2 cases with hypohidrosis related to topiramate, electrophysiological study showed normal function of both beta and delta sensory fibers and absent sympathetic skin responses that recovered to normal after topiramate discontinuation. CONCLUSIONS: Our findings confirm that topiramate might induce a transitory specific carbonic anhydrase block at the level of sweat glands, without involvement of peripheral nervous system.