Phenotype and genotype of 87 patients with Mowat-Wilson syndrome and recommendations for care

Mowat-Wilson syndrome (MWS) is a rare intellectual disability/multiple congenital anomalies syndrome caused by heterozygous mutation of the ZEB2 gene. It is generally underestimated because its rarity and phenotypic variability sometimes make it difficult to recognize. Here, we aimed to better delineate the phenotype, natural history, and genotype-phenotype correlations of MWS.MethodsIn a collaborative study, we analyzed clinical data for 87 patients with molecularly confirmed diagnosis. We described the prevalence of all clinical aspects, including attainment of neurodevelopmental milestones, and compared the data with the various types of underlying ZEB2 pathogenic variations.ResultsAll anthropometric, somatic, and behavioral features reported here outline a variable but highly consistent phenotype. By presenting the most comprehensive evaluation of MWS to date, we define its clinical evolution occurring with age and derive suggestions for patient management. Furthermore, we observe that its severity correlates with the kind of ZEB2 variation involved, ranging from ZEB2 locus deletions, associated with severe phenotypes, to rare nonmissense intragenic mutations predicted to preserve some ZEB2 protein functionality, accompanying milder clinical presentations.ConclusionKnowledge of the phenotypic spectrum of MWS and its correlation with the genotype will improve its detection rate and the prediction of its features, thus improving patient care.GENETICS in MEDICINE advance online publication, 4 January 2018; doi:10.1038/gim.2017.221

Phenotype and genotype of 87 patients with Mowat–Wilson syndrome and recommendations for care

Purpose: Mowat–Wilson syndrome (MWS) is a rare intellectual disability/multiple congenital anomalies syndrome caused by heterozygous mutation of the ZEB2 gene. It is generally underestimated because its rarity and phenotypic variability sometimes make it difficult to recognize. Here, we aimed to better delineate the phenotype, natural history, and genotype–phenotype correlations of MWS. Methods: In a collaborative study, we analyzed clinical data for 87 patients with molecularly confirmed diagnosis. We described the prevalence of all clinical aspects, including attainment of neurodevelopmental milestones, and compared the data with the various types of underlying ZEB2 pathogenic variations. Results: All anthropometric, somatic, and behavioral features reported here outline a variable but highly consistent phenotype. By presenting the most comprehensive evaluati

Electrical status epilepticus during sleep in Mowat\ue2\u80\u93Wilson syndrome

Aim: Mowat\u2013Wilson Syndrome (MWS) is a genetic rare disease. Epilepsy is present in 70\u201375% of Patients and an age-dependent electroclinical pattern has been described. Up to date, there are studies with overnight sleep EEGs, probably because of the severe intellectual disability (ID) and hyperactivity of these Patients. Our purpose was to verify the hypothesis that MWS Patients might have electrical status epilepticus in slow wave sleep (ESES pattern). Methods: A retrospective analysis of anamnestic and electrographic data was performed on 7 consecutive MWS Patients followed between 2007 and 2016. Only Patients with at least one overnight sleep EEG were included in the study. Results: Five out of 7 Patients had overnight sleep EEG studies and were included in this study. All of them had an anterior ESES pattern with spike-and-wave index > 85%. The architecture of sleep was abnormal. An ESES related regression of cognitive and motor functions with impact on daily activities (ESES-related syndrome) was demonstrated in 3 out of 5 (60%) Patients. In two Patients marked improvement of cognitive and motor performances was observed when the epileptiform activity during sleep was successfully controlled or it was spontaneously reduced. Conclusions: The clinical significance of the ESES pattern is hard to assess in MWS Patients due to severe ID, but changing in behaviour or in motor and cognitive functions should mandate sleep EEG investigation and, if ESES is present, an appropriate treatment should be tried. Furthermore, overnight sleep EEG recordings, if regularly performed in the follow up, might help to understand if ESES pattern hampers the cognitive and communicative profile in MWS

SCN2A Pathogenic Variants and Epilepsy: Heterogeneous Clinical, Genetic and Diagnostic Features

Pathogenic variants of the SCN2A gene (MIM 182390) are associated with several epileptic syndromes ranging from benign familial neonatal-infantile seizures (BFNIS) to early infantile epileptic encephalopathy. The aim of this work was to describe clinical features among five patients with concomitant SCN2A gene variants and cryptogenic epileptic syndromes, thus expanding the SCN2A spectrum of phenotypic heterogeneity. De novo variants were identified in four patients, while one inherited variant was identified in a patient with an unaffected carrier biological father with somatic mosaicism. Two of five patients were diagnosed with a neonatal epileptic encephalopathy. The remaining three patients manifested a focal epileptic syndrome associated with autistic spectrum disorders (ASD) or with a variable degree of intellectual disability (ID), one of them displaying a hitherto unreported atypical late onset epilepsy. Overall, the pattern of clinical manifestations among these patients suggest that any observed neurological impairment may not be directly related to the severity of the electroclinical pattern, but instead likely associated with the mutation itself. Moreover, our results highlight the importance of SCN2A mutational screening in cases of ID/ASD with or without epilepsy

Cognitive competence at the onset of West syndrome: correlation with EEG patterns and visual function

The aim of this study was to evaluate cognitive development at the onset of West syndrome (WS) with regard to electroencephalogram (EEG) patterns and visual function. Twenty-five patients (14 males, 11 females) at the onset of spasms (T0) in WS and 2 months later (T1) underwent a full clinical evaluation, including neuroimaging, cognitive assessment, video-EEG, and visual function. Mean age of the patients at spasm onset was 5.9 months (SD 2.5; range 2 to 13mo). Cognitive development, assessed with Griffiths Mental Development Scales (GMDS), was generally impaired at T0 and was significantly related to visual function (p<0.001) at both T0 and T1. In general, there was a specific major impairment in the eye-hand coordination scale of the GMDS which tended to disappear after 2 months in less severe cases. At the onset of spasms, sleep EEG organization seemed to be better related to cognitive abilities than awake hypsarrhythmia. These results support a close link between visual function and cognitive competence in WS and provide additional information to improve the understanding of possible mechanisms underlying cognitive impairment

Neurodevelopmental evolution of West syndrome: A 2-year prospective study

Objective: The aim of this study was to evaluate the epileptic and developmental evolution in infants with West syndrome. Methods: A prospective study of 21 infants was performed, with a follow-up at 2 years. Serial assessment included long-term EEG monitoring, visual and auditory evaluation and assessment of neurodevelopment. Results: Neurosensory and developmental impairments at the spasm onset were transitory in seven cases, including four cryptogenic forms. in all other cases, there was a progressive worsening in neurosensory and developmental impairments. The epileptic evolution was generally better: in 11 of the 16 infants without seizures at outcome, spasms had already disappeared by 2 months after disease onset. Statistic analysis of results showed a correlation between neurosensory impairment and development throughout the whole follow-up. in addition, visual function at T1 resulted significant predictor of developmental outcome. Among the epileptic features, disorganization of slow sleep was an unfavorable prognostic factor. Conclusion: Some forms of West syndrome are confirmed to have a benign evolution: among them there are not only cryptogenic cases but also symptomatic ones without significant neurodevelopmental impairment. Abnormalities of sleep organization, expression of the pervasive epileptic disorder, seem to play a role in determining a developmental deterioration. Neurosensory impairment since the onset of the disease could be a relevant cause of the developmental disorder. (C) 2007 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved

Intraoperative radiotherapy for locally advanced prostate cancer: The experience of the European institute of oncology

INTRODUCTION AND OBJECTIVE: To present the technique adopted for intraoperative radiotherapy (IORT) for locally advanced prostate cancer. METHODS: Between June 2005 and February 2007, 24 patients (pts) with non-metastatic prostate cancer were treated with IORT before prostatectomy as part of their surgical procedure. Median DJHZDV\HDUVUDQJH7HQSWVZHUHFODVVL\ubfHGDV 7FSWVDV\u9577KHPHGLDQL36$ZDVQJPODQGWKH median bioptic Gleason Score was 7. According to NCCN 2007, risk group distribution was as follows: intermediate risk 2 pts (8.33%) and high risk 22 pts (91.67%). A total of 11 pts (45.83%) were treated with neoadjuvant hormones. Immediately before IORT prostate dimensions and rectum depth were measured with intraoperative ultrasound. IORT was delivered by a mobile linear accelerator in the operating room. The prescribed dose was 12 Gy at the 90% isodose. In vivo dosimetry was performed. Three months later, postoperative external beam radiotherapy (EBRT) of 45-50,4 Gy in 25-28 fractions was prescribed to the prostatic bed alone and whole pelvis in case of pT3-4 pN0 and pN1, respectively. RESULTS: According to the MSKCC nomograms, the mean SUHRSHUDWLYHSUREDELOLW\RIRUJDQFRQ\ubfQHGGLVHDVHH[WUDFDSVXODUGLVHDVH and lymph node involvement were 8%, 40% and 25% respectively. 3RVWRSHUDWLYHKLVWRORJLFDO\ubfQGLQJVZHUHDVIROORZVPHGLDQ*6UDQJH 6-9), pT2 7 pts (29,2%), pT3 14 pts (58,3), pT4 3 (12,5%), pN0 12 pts, S1SWV2UJDQFRQ\ubfQHGGLVHDVHS7S15ZDVGLDJQRVHGLQ pts (16.6%) and no further radiation treatment was prescribed. Based RQWKHGH\ubfQLWLYHKLVWRORJLFDOUHSRUWVSRVWRSHUDWLYHSHOYLFDQGSURVWDWLF bed EBRT is planned in 12 and 8 pts, respectively. After a median follow up of 9.2 months (range 3.3-15.7) only 1 patient had evidence of biochemical relapse. No patients had major acute rectal toxicity. No acute urinary toxicity was observed in 6 patients, 17 patients had G1 toxicity. No increased risk of urinary incontinence was recorded. CONCLUSIONS: IORT delivered before prostatectomy appeared a feasible and safe approach for prostate cancer, showing a satisfactory dose coverage to the prostate bed with relatively low rectal wall dose. Longer follow-up is needed to evaluate late toxicity and clinical control