Respiratory and gastrointestinal dysfunctions associated with auriculo-condylar syndrome and a homozygous PLCB4 loss-of-function mutation.

Auriculo-Condylar Syndrome (ACS) is a craniofacial malformation syndrome characterized by external ear anomalies, hypoplasia of the mandibular condyle, temporomandibular joint abnormalities, micrognathia, and microstomia. Glossoptosis, masticatory abnormalities, orthodontic problems, and malocclusion occur in a majority of affected subjects. The clinical diagnosis is usually suggested by the pathognomonic ear appearance ("question mark ear"), consisting of a variable degree of clefting between the helix and earlobe. The genetic mechanisms underlying ACS have recently been identified. Both autosomal dominant and recessive inheritance of mutations in phospholipase C, beta 4 (PLCB4) and endothelin 1 (EDN1) have been reported along with autosomal dominant mutations in guanine nucleotide-binding protein (G protein) α inhibiting activity polypeptide 3 (GNAI3). We report 6 years of follow-up of a child with a clinical phenotype consistent with ACS due to a homozygous frameshift mutation in PLCB4. The baby presented feeding difficulties associated with failure to thrive and a complex sleep-related respiratory disorder, characterized by central and obstructive apnoeas. Our observations of this case further delineate the phenotype of ACS associated with autosomal recessive PLCB4 loss-of-function mutations, underscoring gastrointestinal dysfunction and severe sleep-related breathing abnormalities as additional features when compared to patients with heterozygous mutations with a presumed dominant negative effect. © 2016 Wiley Periodicals, Inc.

Behavioral profile in RASopathies.

Here, we describe neurobehavioral features in patients with RASopathies (i.e., Noonan syndrome, LEOPARD syndrome, Costello syndrome, and cardiofaciocutaneous syndrome), developmental disorders caused by mutations in genes coding transducers participating in the RAS-MAPK signaling cascade. Parents of 70 individuals with a RASopathy were asked to fill out the following questionnaires: Child Behavior Checklist (CBCL), Social Communication Questionnaire version lifetime (SCQ-L), and Modified Checklist for Autism in toddlers (M-CHAT). Data analysis indicated high rates of internalizing (37%) and externalizing problems (31%) on CBCL. Scores over the cut-off were documented in 64% of patients with cardiofaciocutaneous syndrome, 44% with Costello syndrome, and 12% with Noonan syndrome on SCQ-L/M-CHAT. Our findings indicate that mutations promoting dysregulation of the RAS-MAPK cascade mark an increased psychopathological risk and highlight that autistic-like behavior could be underdiagnosed in patients with RASopathies.

Recognition Memory in Noonan Syndrome.

Noonan syndrome (NS) and the clinically related NS with multiple lentiginous (NMLS) are genetic conditions characterized by upregulated RAS mitogen activated protein kinase (RAS-MAPK) signaling, which is known to impact hippocampus-dependent memory formation and consolidation. The aim of the present study was to provide a detailed characterization of the recognition memory of children and adolescents with NS/NMLS. We compared 18 children and adolescents affected by NS and NMLS with 22 typically developing (TD) children, matched for chronological age and non-verbal Intelligence Quotient (IQ), in two different experimental paradigms, to assess familiarity and recollection: a Process Dissociation Procedure (PDP) and a Task Dissociation Procedure (TDP). Differences in verbal skills between groups, as well as chronological age, were considered in the analysis. Participants with NS and NSML showed reduced recollection in the PDP and impaired associative recognition in the TDP, compared to controls. These results indicate poor recollection in the recognition memory of participants with NS and NSML, which cannot be explained by intellectual disability or language deficits. These results provide evidence of the role of mutations impacting RAS-MAPK signaling in the disruption of hippocampal memory formation and consolidation.

Visual and visuoperceptual function in children with Panayiotopoulos syndrome.

PURPOSE: The aim of this study was to assess behavioral aspects of visual function and visuoperceptual abilities in patients with Panayiotopoulos syndrome (PS), and their possible associations with clinical and electroencephalography (EEG) findings in order to establish the possible effect of interictal paroxysmal activity on visual performance. METHODS: The cohort included 28 patients (14 male and 14 female) of ages ranging between 4 and 15 years. All patients underwent serial videopolygraphic studies and a detailed battery of tests assessing visual abilities, including assessment of acuity, stereopsis, visual fields, and visuoperceptual abilities; tests included the Movement Assessment Battery for Children, the Visuo Motor Integration tests, and evaluation of motion and form coherence threshold. RESULTS: On the assessment of visual function, only 4 of the 28 (15%) had abnormal crowding acuity and one had abnormal stereopsis. On the visuoperceptual assessment, one patient had abnormal results on the Visuo Motor Integration tests, and one on the Movement Assessment Battery for Children, whereas 4 (15%) had abnormal results for form coherence threshold and one for motion threshold. DISCUSSION: Our results suggest that, although most of our patients had focal or diffuse EEG abnormalities involving the occipital regions, abnormalities of visual and visuoperceptual function were relatively uncommon. Age at onset of seizure <5 years and EEG activation to eye closure and during sleep can be considered as factors that slightly increased the risk for developing visual abnormalities. Their presence, however, was not always associated with abnormal visual findings.

Psychopathological features in Noonan syndrome.

INTRODUCTION: Noonan syndrome (NS) is an autosomal dominant disorder characterized by short stature, skeletal and haematological/lymphatic defects, distinctive facies, cryptorchidism, and a wide spectrum of congenital heart defects. Recurrent features also include variable cognitive deficits and behavioural problems. Recent research has been focused on the assessment of prevalence, age of onset and characterization of psychiatric features in this disorder. Herein, we evaluated the prevalence of attention deficit and hyperactivity disorder (ADHD), anxiety and depressive symptoms and syndromes in a cohort of individuals with clinical and molecular diagnosis of NS. METHODS: The Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children Present and Lifetime version (K-SADS PL) has been used for the assessment of psychiatric disorders according to Diagnostic and Statistical Manual of Mental Disorders (DSM-IV). Multidimensional Anxiety Scale for Children (MASC) and the Children's Depression Inventory (CDI) have been assessed for the evaluation of anxiety and depressive symptoms and syndromes, whereas Conners Teacher and Parent Rating Scales-long version (CRS-R) have been used to evaluate ADHD. RESULTS: The study included 27 individuals (67% males) with an average age of 10.4 years (range 6-18 years) receiving molecular diagnosis of NS or a clinically related condition, evaluated and treated at the Neuropsychiatric Unit of Children's Hospital Bambino Gesù and at the Center for Rare Diseases of Fondazione Policlinico Universitario Agostino Gemelli, in Rome. Twenty individuals showed mutations in PTPN11, five in SOS1 and two in SHOC2. The mean IQ was 94 (Standard Deviation = 17, min = 56, max = 130). Seventy percent of the individuals (n = 19; 95% Confidence Interval = 52-85%) showed ADHD features, with six individuals reaching DSM-IV-TR criteria for ADHD disorder, and thirteen showing subsyndromal traits. Symptoms or syndrome of anxiety were present in 37% of the cohort (n = 10; 95% Confidence Interval = 19-56%), with two individuals showing anxiety disorder and eight cases exhibiting subsyndromal traits. CONCLUSION: Our results show individuals with NS do present a very high risk to develop psychiatric disorders or symptoms during paediatric age. Based on these findings, preschool assessment of inattentive, hyperactivity/impulsivity and anxiety/depressive symptoms is recommended in order to plan a personalized treatment for psychological/psychiatric issues in affected individuals. Dedicated prospective studies are required to confirm the present data and better characterize the psychopathological profile in NS.

Surgery of children with frontal lobe lesional epilepsy: neuropsychological study.

AIM OF THE STUDY: was to provide new data about the evolution of neuropsychological findings in patients with lesional frontal lobe epilepsy (FLE) operated on with lesion excision. PATIENTS AND METHODS: Twelve patients with lesional FLE underwent full clinical examination including neurological, neuropsychological and developmental assessments, high-resolution magnetic resonance imaging (MRI), ictal and interictal prolonged EEG monitoring and evaluation of seizure semeiology before and after surgery. The mean follow-up duration was 2 years and 10 months (range=14 months-7 years). Another group of lesional temporal lobe epilepsy, matched for the age at surgery and side of surgery, was likewise studied in order to compare neuropsychological patterns and to try to find out specific features in frontal lobe epilepsy evolution. RESULTS: All patients resulted seizure free at outcome except one belonging to Engel's class II. Before surgery general intelligence was similar in FLE as well as in TLE group. Executive functions and motor coordination were frequently affected in FLE whereas patients with TLE often presented with deficits in naming, visual memory and visuo-spatial attention. After surgery there was a frequent decline of IQ in FLE group together with a slight deterioration, especially of executive functions in some patients. An improvement of behaviour was often observed in both groups. CONCLUSIONS: As already reported in literature, neuropsychological pre-surgical data confirms the involvement of attention and executive functions in lesional FLE. No significant neuropsychological improvement was produced by surgery that determined in some cases a slight decline of general intelligence and specific frontal abilities. Yet, generally behaviour improved and seizures were controlled.

Early visual assessment in preterm infants with and without brain lesions: correlation with visual and neurodevelopmental outcome at 12 months.

BACKGROUND: Several studies have reported the development of various aspects of visual function in infancy and early childhood in both preterm and term-born infants, but only a few studies have focused on the predictive power of neonatal visual findings in infants with brain lesions. AIMS: To explore visual findings at term age, and at 3 and 12 months corrected age in preterm infants (gestational age <33 weeks) with and without brain lesions; to compare the assessment at term age and at 12 months; and to assess the relationship between visual findings and neurodevelopmental outcome at 12 months. STUDY DESIGN: Cranial ultrasound scans (US) were classified in normal, mild or major abnormalities. One-hundred and forty-five infants were assessed with age specific tests for visual function at term age, and at 3 and 12 months. Neurodevelopmental assessment (Griffiths' Scales) was performed at 12 months. RESULTS: A good correlation was found between early and late visual assessment and neurodevelopment outcome. Of the 121 infants with normal neonatal visual assessment, 119 were also normal at 12 months and 116 had normal developmental quotient. Of the 24 infants with abnormal neonatal visual assessment, 12 were also abnormal at 12 months. All the false positives had normalised by 3 months. Of the 35 infants with major US abnormalities, 20 had normal and 15 abnormal scores on the neonatal assessment. At 1 year 17 had normal and 18 abnormal scores. CONCLUSION: A normal visual assessment at term age is a good predictor of normal visual and neurodevelopmental outcome at 12 months. An abnormal visual examination in the neonatal period was a less reliable prognostic indicator, infant should be reassessed at 3 months.