New Insights into the Neuropsychological Profile and Intellectual Quotient Variability in Joubert Syndrome Compared to Other Congenital Cerebellar Malformations.

The neuropsychological characteristics of the cerebellar cognitive affective syndrome (CCAS) in congenital, non-progressive malformations of the cerebellum have been scarcely investigated, and even less is known for Joubert syndrome (JS), an inherited, non-progressive cerebellar ataxia characterized by the so-called molar tooth sign. The few studies on this topic reported inconsistent results about intellectual functioning and specific neuropsychological impairments. The aim of this research is to examine the neuropsychological profile of JS compared to other congenital cerebellar malformations (CM), considering individual variability of intellectual quotient (IQ) in the two groups. Fourteen patients with JS and 15 patients with CM aged 6-25 years were tested through a comprehensive, standardized neuropsychological battery. Their scores in the neuropsychological domains were inspected through descriptive analysis and compared by mean of MANOVA and ANOVA models, then replicated inserting IQ as covariate. The two groups showed a largely overlapping neuropsychological profile, consistent with CCAS. However, the JS group showed worse performance in visual-spatial memory compared to CM patients, although this difference was mitigated when considering IQ. These findings highlight a divergence between JS and other CM in visual-spatial memory, which might suggest a critical role of the cerebellum in recalling task-relevant memories and might inform rehabilitative interventions.

Resolution of severe neurobehavioral difficulties in an individual with Primrose syndrome with sertraline.

Primrose syndrome (PS) is a rare genetic disease characterized by developmental delay, intellectual disability, sensorineural hearing loss, and dysmorphic features. PS is caused by de novo pathogenic variants in the ZBTB20 gene, which encodes a transcription factor modulating neurogenesis. We describe resolution with sertraline of neurobehavioral difficulties in a 17-year-old Hispanic male with PS with de novo heterozygous c.1916G > A (p.C639Y) variant of ZBTB20. Neurobehavioral difficulties included aggression towards self and others, irritability, tearfulness, and mood liability that did not respond to behavioral interventions or aripiprazole. Treatment with sertraline, a medication indicated for psychiatric disorders including anxiety and depression, led to the resolution of neurobehavioral difficulties after 2 weeks of initiation of medication. The treatment course suggests that selective serotonin reuptake inhibitors, such as sertraline, may be a useful tool for neurobehavioral difficulties in PS over antipsychotics that are accompanied by complex side effect profiles, and suggest that anxiety is the primary cause of the neurobehavioral difficulties in this patient.

Neural and behavioral measures suggest that cognitive and affective functioning interactions mediate risk for psychosis-proneness symptoms in youth with chromosome 22q11.2 deletion syndrome.

Behavioral components of chromosome 22q11.2 deletion syndrome (22q), caused by the most common human microdeletion, include cognitive and adaptive functioning impairments, heightened anxiety, and an elevated risk of schizophrenia. We investigated how interactions between executive function and the largely overlooked factor of emotion regulation might relate to the incidence of symptoms of psychotic thinking in youth with 22q. We measured neural activity with event-related potentials (ERPs) in variants of an inhibitory function (Go/No-Go) experimental paradigm that presented affective or non-affective stimuli. The study replicated inhibition impairments in the 22q group that were amplified in the presence of stimuli with negative, more than positive affective salience. Importantly, the anterior N2 conflict monitoring ERP significantly increased when youth with 22q viewed angry and happy facial expressions, unlike the typically developing participants. This suggests that youth with 22q may require greater conflict monitoring resources when controlling their behavior in response to highly salient social signals. This evidence of both behavioral and neurophysiological differences in affectively influenced inhibitory function suggests that frequently anxious youth with 22q may struggle more with cognitive control in emotionally charged social settings, which could influence their risk of developing symptoms of psychosis.

Caregiver-reported clinical characteristics and the burden associated with Kabuki syndrome.

Kabuki syndrome is a genetic disorder that can affect multiple body systems and manifest as congenital abnormalities and both developmental and socio-emotional delays. The condition is largely unknown by most primary care physicians and has no available treatment other than symptomatic management. This research sought to obtain caregiver-reported data about the experience of living with and caring for someone with Kabuki syndrome to fill a gap in the available literature. Fifty-seven caregivers participated in an online survey and reported that Kabuki syndrome affected their children in a wide variety of ways, including a high frequency of visits to various healthcare professionals. Caregivers reported their child experienced problems with hearing, eating, eyes, mouth, immune system, anxiety, depression, autism, teeth, joints, seizures, kidneys, and heart. Caregivers also described the challenges of caring for someone with Kabuki syndrome, including an impact on emotional well-being and the ability to work outside the home. This unique research characterizes the caregiver experience of living with and caring for someone with Kabuki syndrome, both through observed manifestations of Kabuki syndrome in their own children and their experience managing their treatment. Additional research is needed to investigate the patient experience of living with Kabuki syndrome.

The Impact of Congenital Esophageal Atresia on the Family Functioning.

PURPOSE: Most of the research in the field of esophageal atresia (EA) is focused on diagnostic problems and surgery. There is scarce literature addressing the impact of EA on the lives of families of patients. The aim of this paper is to investigate whether the presence of underlying associated malformations, disease-specific feeding problems and prematurity would have a significant influence on the family of a child after surgical repair of EA. DESIGN AND METHODS: The study sample consisted of 73 participants who were parents of children after surgery of EA. The impact of EA on families was assessed using an Authors-Designed Questionnaire (ADQ) to collect medical and sociodemographic background data as well as standardized questionnaire: the PedsQL™ Family Impact Module (PedsQL-FIM). RESULTS: The presence of cardiac impairment significantly (p = 0.037) affects the functioning of the family in the emotional domain. The coexistence of skeletal impairment seems to have the greatest impact on the functioning of the family, three statistically significant correlations have been demonstrated: (p = 0.021) - in the social domain, (p = 0.009) - in the cognitive domain and (p = 0.023) - in the domain of communication. The families of patients with tracheoesophageal fistula (TEF) had the statistically lower (p < 0.05) score of functioning in the emotional domain than those with children without TEF. CONCLUSION: Feeding problems and the presence of associated anomalies significantly affect the functioning of the family of the child with EA.

Speech and language in bilateral perisylvian polymicrogyria: a systematic review.

AIM: We aimed to systematically review the speech production, language, and oral function phenotype of bilateral perisylvian polymicrogyria (BPP), and examine the correlation between the topography of polymicrogyria and the severity of speech, language, and oral functional impairment. METHOD: A systematic search of MEDLINE, Embase, and PubMed databases was completed on 26th October 2017 using Medical Subject Heading terms synonymous with BPP and speech, language, or oral motor impairment. In total, 2411 papers were identified and 48 met inclusion criteria. RESULTS: Expressive and receptive language impairment and oral structural and functional deficits are frequent in BPP. Expressive deficits are frequently more severe than receptive. Only one study used formal assessments to demonstrate the presence of speech disorder, namely dysarthria. Seven studies reported an association between diffuse BPP and more severe language impairment. INTERPRETATION: Findings confirmed that language deficits are common in BPP, though assessment of the specific speech phenotype is limited. The paucity of high quality studies detailing the specific communication phenotype of BPP highlights the need for further investigation. Improving understanding of this phenotype will inform the development of targeted therapies and lead to better long-term outcomes. WHAT THIS PAPER ADDS: Speech, language, and oral functional impairments are common in individuals with bilateral perisylvian polymicrogyria. Posterior polymicrogyria is associated with a less severe language impairment than anterior polymicrogyria. Deeper investigation of speech is needed to understand implicated networks in this malformation.

Joubert syndrome: neuroimaging findings in 110 patients in correlation with cognitive function and genetic cause.

BACKGROUND: Joubert syndrome is a clinically and genetically heterogeneous ciliopathy. Neuroimaging findings have not been systematically evaluated in a large cohort of patients with Joubert syndrome in correlation with molecular genetic cause and cognitive function. METHODS: Brain MRI of 110 patients with Joubert syndrome was included in this study. A comprehensive evaluation of brain MRI studies for infratentorial and supratentorial morphological abnormalities was performed. Genetic cause was identified by whole-exome sequencing, and cognitive functions were assessed with age-appropriate neurocognitive tests in a subset of patients. RESULTS: The cerebellar hemispheres were enlarged in 18% of the patients, mimicking macrocerebellum. The posterior fossa was enlarged in 42% of the patients, resembling Dandy-Walker malformation. Abnormalities of the brainstem, such as protuberance at the ventral contour of the midbrain, were present in 66% of the patients. Abnormalities of the supratentorial brain were present in approximately one-third of the patients, most commonly malrotation of the hippocampi. Mild ventriculomegaly, which typically did not require shunting, was present in 23% of the patients. No correlation between neuroimaging findings and molecular genetic cause was apparent. A novel predictor of outcome was identified; the more severe the degree of vermis hypoplasia, the worse the neurodevelopmental outcome was. CONCLUSIONS: The spectrum of neuroimaging findings in Joubert syndrome is wide. Neuroimaging does not predict the genetic cause, but may predict the neurodevelopmental outcome. A high degree of vermis hypoplasia correlates with worse neurodevelopmental outcome. This finding is important for prognostic counselling in Joubert syndrome.

Mullerian dysgenesis: a critical review of the literature.

PURPOSE: To present an update of the genetic, clinical, diagnostic, and therapeutic aspects of Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome. METHODS: Studies were considered eligible if they have evaluated patients with MRKH syndrome. Eligible articles were identified by a search of MEDLINE bibliographical database from 1950 to August 2016. A purely descriptive approach was adopted concerning all outcomes examined by the individual studies. RESULTS: MRKH syndrome is defined as congenital aplasia of the upper vagina and impairment of uterine development in normal 46XX females. Accounting for 1:4500 women, MRKH is the second most common cause of primary amenorrhea following gonadal dysgenesis. Potential association of MRKH syndrome to specific genes has been the focus of recent research. Null-association results of HOXA genes and Wnt5a, Wnt7a, and Wnt9a have been reported, while point mutations of the WNT4 gene point mutations have been associated with an MRKH-like syndrome characterized by Mullerian duct regression and hyperandrogenism. Ultrasound and Magnetic Resonance Imaging (MRI) are the main techniques to establish an accurate diagnosis of the syndrome. Several non-surgical and surgical procedures have been reported for the creation of a functional neovagina; in general, non-surgical treatment should be the first initially pursued. Along with psychological support, recent developments in assisted reproductive technologies of IVF techniques and the availability of gestational surrogacy, as well as the recent breakthrough of successful uterus transplantation, enable women with MRKH syndrome to attain their own genetic child. CONCLUSION(S): MRKH syndrome is a medical modality with important social, legal, and ethical projections that require a multi-disciplinary approach.

Power-Up: Exploration and Play in a Novel Modified Ride-On Car for Standing.

PURPOSE: The purpose of this study was to compare the physical activity and play behaviors of preschoolers without disabilities and 1 preschooler with physical disability. METHODS: Participants were 42 preschoolers without disabilities and 1 preschooler with physical disability (Child A). Child A used either crutches or a modified ride-on car while in the gymnasium and playground. RESULTS: In the gymnasium, Child A engaged in less solitary play and more parallel play while using the modified ride-on car compared with crutches. On the playground, Child A engaged in more sitting and less running while using crutches compared with preschoolers without disabilities. On the playground, Child A engaged in more peer interaction and less teacher interaction when using the modified ride-on car compared with crutches. CONCLUSIONS: For children with disabilities who may use assistive devices, clinicians, families, and teachers are encouraged to embrace a "right device, right time, right place" approach.

Associations between neurodevelopmental genes, neuroanatomy, and ultra high risk symptoms of psychosis in 22q11.2 deletion syndrome.

22q11.2 deletion syndrome is a neurogenetic disorder resulting in the deletion of over 40 genes. Up to 40% of individuals with 22q11.2DS develop schizophrenia, though little is known about the underlying mechanisms. We hypothesized that allelic variation in functional polymorphisms in seven genes unique to the deleted region would affect lobar brain volumes, which would predict risk for psychosis in youth with 22q11.2DS. Participants included 56 individuals (30 males) with 22q11.2DS. Anatomic MR images were collected and processed using Freesurfer. Participants were genotyped for 10 SNPs in the COMT, DGCR8, GNB1L, PIK4CA, PRODH, RTN4R, and ZDHHC8 genes. All subjects were assessed for ultra high risk symptoms of psychosis. Allelic variation of the rs701428 SNP of RTN4R was significantly associated with volumetric differences in gray matter of the lingual gyrus and cuneus of the occipital lobe. Moreover, occipital gray matter volumes were robustly associated with ultra high risk symptoms of psychosis in the presence of the G allele of rs701428. Our results suggest that RTN4R, a relatively under-studied gene at the 22q11 locus, constitutes a susceptibility gene for psychosis in individuals with this syndrome through its alteration of the architecture of the brain. © 2017 Wiley Periodicals, Inc.

Cognitive, adaptive, and behavioral features in Joubert syndrome.

Joubert syndrome (JS) is a recessive neurodevelopmental disorder characterized by a distinctive cerebellar and brainstem malformation recognizable on brain imaging, the so-called molar tooth sign. The full spectrum of cognitive and behavioral phenotypes typical of JS is still far from being elucidated. The aim of this multicentric study was to define the clinical phenotype and neurobehavioral features of a large cohort of subjects with a neuroradiologically confirmed diagnosis of JS. Fifty-four patients aged 10 months to 29 years were enrolled. Each patient underwent a neurological evaluation as well as psychiatric and neuropsychological assessments. Global cognitive functioning was remarkably variable with Full IQ/General Quotient ranging from 32 to 129. Communication skills appeared relatively preserved with respect to both Daily Living and Socialization abilities. The motor domain was the area of greatest vulnerability, with a negative impact on personal care, social, and academic skills. Most children did not show maladaptive behaviors consistent with a psychiatric diagnosis but approximately 40% of them presented emotional and behavioral problems. We conclude that intellectual disability remains a hallmark but cannot be considered a mandatory diagnostic criterion of JS. Despite the high variability in the phenotypic spectrum and the extent of multiorgan involvement, nearly one quarter of JS patients had a favorable long-term outcome with borderline cognitive deficit or even normal cognition. Most of JS population also showed relatively preserved communication skills and overall discrete behavioral functioning in everyday life, independently from the presence and/or level of intellectual disability. © 2016 Wiley Periodicals, Inc.

Neurogenetic Aspects of Hyperphosphatasia in Mabry Syndrome.

An autosomal recessive syndrome of hyperphosphatasia (elevated circulating alkaline phosphatase (AP), seizures and neurologic deficits) was first described by Mabry and colleagues in 1970. Over the ensuing four decades, few cases were reported. In 2010, however, new families were identified and the syndromic nature of the disorder confirmed. Shortly thereafter, next generation sequencing was used to characterize causative defects in the glycosyl phosphatidylinositol (GPI) biosynthetic pathway, based partly on our understanding of how AP is anchored by GPI to the plasma membrane. Whether the seizures and cognitive defects seen in Mabry syndrome patients are attributable in part to the constant hyperphosphatasia is not known, as there are more than 250 other proteins dependent on GPI for their anchoring to the plasma membrane. However, Mabry syndrome may provide a new window on AP function in growth and development.

Behavioral phenotype in Costello syndrome with atypical mutation: a case report.

Costello syndrome (CS) is a rare genetic disorder caused, in the majority of cases, by germline missense HRAS mutations affecting Gly(12) promoting enhanced signaling through the MAPK and PI3K-AKT signaling cascades. In general, the cognitive profile in CS is characterized by intellectual disability ranging from mild to severe impairment. The first published descriptions of behavior in CS children underlined the presence of irritability and shyness at younger ages with sociable personality and good empathic skills after 4-5 years of age, however some recent studies have reported autistic traits. We report on a 7-year-old boy heterozygous for a rare duplication of codon 37 (p.E37dup) in HRAS, manifesting impaired social interaction and non-verbal communication and with circumscribed interests. These additional features improve phenotype delineation in individuals with rare HRAS mutations, facilitating the development of specific behavioral treatments which could lead to improvement in cases of autism spectrum disorder.

Care pathways in childhood neurodevelopmental disorders: Toward greater awareness of KBG syndrome among pediatricians.

INTRODUCTION: KBG syndrome is an autosomal dominant, polymalformative genetic syndrome that is mainly associated with neurodevelopmental and learning disorders, intellectual disability, behavioral disorders, and epilepsy as well as characteristic dysmorphic features, short stature, and ENT (ear, nose, and throat) abnormalities. However, the diagnostic pathway of these individuals is an element that has not been broadly evaluated. The main aim of this study was therefore to characterize the diagnostic pathway for these individuals, by assessing the different healthcare professionals involved and the main referral elements. METHOD: This was a multicenter, retrospective, descriptive study. A cohort of 30 individuals with KBG syndrome who were followed up at Poitiers University Hospital and Bordeaux University Hospital we recruited. RESULTS: Pediatricians were the main healthcare professionals who referred individuals for genetic consultation, and the main reason for referral was an assessment of learning delays or intellectual disability, in association with other abnormalities. CONCLUSION: Pediatricians play a crucial role in the diagnostic guidance of individuals with KBG syndrome, and the main reason for referral remains the assessment of a learning delay or intellectual disability. Healthcare professionals must therefore remain attentive to the child's development and the various anomalies associated with it, in particular characteristic dysmorphic features, behavioral disorders, and statural growth.

Overgrowth syndromes.

PURPOSE OF REVIEW: Human growth ensues from a complex interplay of physiological factors, in the wider setting of varying genetic traits and environmental influences. Intensive research in these divergent areas, and particularly in the field of genetics, continues to clarify the molecular basis of disorders which result in overgrowth, and it is therefore timely to provide a review of these findings. RECENT FINDINGS: This article provides an overview of the factors which regulate growth, followed by a discussion of the more commonly encountered overgrowth syndromes and their genetic basis as it is understood at the current time. There is also an added focus on recently discovered genetic associations in some conditions, such as Weaver, Perlman and Proteus syndromes. SUMMARY: New discoveries continue to be made regarding the genetic basis for many overgrowth syndromes and the development of a much needed molecular classification system for overgrowth may become possible as the interlinking functions of these genes on growth are unravelled. As there exists a wide spectrum of syndromes, disorders resulting in overgrowth can represent a diagnostic and therapeutic challenge, from those causing prenatal overgrowth with a poor prognosis to less severe genetic aberrations which are identified in later childhood or adult life.

Description of children with 45,X/46,XY karyotype.

We hypothesized that because 45,X/46,XY (X/XY) children share a cell line with Turner syndrome (TS), they also share co-morbidities described in TS. In addition, the presence of the Y chromosome in brain and in other body tissues would influence their function. On the basis of our findings, we aimed to establish optimal procedures for clinical evaluation, management, and follow-up of these children. Sixteen X/XY children were evaluated and managed at a single institution as part of standard clinical care as established at the time between 1969 and 2009. In January of 2005, we started retrospective record review of all X/XY children in combination with cohort follow-up (of those who had not reached adult height) until August of 2009. The study included review of clinical presentation, clinical characteristics, diagnostic measures, radiologic studies, karyotype studies, psycho-endocrinology evaluation, and growth-promoting treatments. There was no specific intervention. Phenotype reflected cell line distribution. The presence of 45,X cell line explains how X/XY children have abnormalities similar to girls with TS, while presence of Y chromosome explains why they have tomboyish behavior. In conclusion, these children require clinical evaluation similar to that performed in female children with TS, including cardiovascular, renal, endocrine, growth and development, autoimmune, psychological, and educational evaluation. Specific management needs to be tailored to the presence of Y chromosomal material.

Microduplication 22q11.2: a description of the clinical, developmental and behavioral characteristics during childhood.

Microduplication 22q11.2 is a recently discovered genomic disorder. So far, targeted research on the cognitive and behavioral characteristics of individuals with this microduplication is limited. Therefore, 11 Flemish children (3-13 years old) with a microduplication 22q 1.2 were investigated in order to describe their clinical, developmental and behavioral characteristics. We measured their general intelligence, visual-motor capacities, attention, behavioral problems and characteristics of autism. In addition, there was an interview with the parents on developmental history and we reviewed available information from other specialists. The results show that the cognitive and behavioral phenotype of the children with microduplication 22q.11.2 is very wide and heterogeneous. Some of the children have a cognitively nearly normal development whereas others are more severely affected. All children had some degree of developmental delay and some of them have an intellectual disability. The most common clinical features include congenital malformations such as heart defects and cleft lip, feeding problems, hearing impairment and facial dysmorphism. The most common non-medical problems are learning difficulties, motor impairment, attention deficits, social problems and behavioral problems. There is no correlation between the size of the duplication and the phenotype.

X-linked Aarskog syndrome: report on a novel FGD1 gene mutation. Executive dysfunction as part of the behavioural phenotype.

Aarskog-Scott syndrome [OMIM 100050] is a predominantly X-linked disorder that is phenotypically characterized by short stature, craniofacial dysmorphisms, brachydactyly and urogenital abnormalities. The level of intelligence shows a great variability and no specific behavioural phenotype has been described so far. In about 20 percent ofAarskog families, a mutation in the FGD1 gene located in Xp11.21 can be identified. In the present study, four affected males from the fourth generation of a large Dutch family (published in 1983 by Van de Vooren et al. (41)) are described. A novel FGD1 missense mutation (R402W) at position 1204 (1204C>T) was demonstrated. In the patients, the level of intelligence varied between normal and severely disabled. Their behavioural profile showed, among others, elements of attention deficit hyperactivity disorder, primarily reflected by impaired executive attentional processes that may be sensitive to systematic training.

Sexual delusion in a case of vaginal aplasia after surgical operation for neovagina.

The Mayer-Rokitansky-Kuster-Hauser (MRKH) is a syndrome of unknown etiology characterized by congenital aplasia of the uterus and the upper part (2/3) of the vagina in women showing normal development of secondary sexual characteristics. We report the case of a patient with vaginal aplasia and schizophrenia presenting with sexual delusion. To the authors' knowledge this is the first case to provide evidence of coexistence between MRKH and sexual delusion in a schizophrenic patient. The core of the patient's delirium was that she was having sexual intercourse with an eminent person through the big toe of her right foot. We approached this case using a neurological and a psychodynamic hypothesis. The neurological hypothesis suggests that the "deactivation" of the patient's genitalia led to an expansion of the adjacent big toe cortical area. The psychodynamic hypothesis supports that the sexual function and pleasure was partially expelled from the body image and was stored in a non sexual part of the body (i.e., big toe). Clinicians should be aware of this association and offer patients with MRKH psychological or/and psychiatric evaluation.