neurodevelopmental disorders are a group of medical conditions that are commonly encountered in paediatric primary care. These disorders can include Global Developmental delay, Intellectual Disability and Autism Spectrum Disorder. These disorders often appear early in development and can co-occur with each other.4 When accompanied by other clinical features, they are referred to as syndromic NDDs. This study aims to describe the predictive value of brain MRI findings for a deep neurophenotyping assessment of a child with syndromic NDD of unknown aetiology, specifically in order to: - investigate a potential genotype-MR phenotype correlation -to estimate the prevalence of brain MRI findings, with their positive and negative predictive values - analyze brain MRI findings’ sensitivity and specificity related to syndromic NDD of unknown aetiology. A retrospective, observational study was carried out on 132 patients with a clinical diagnosis of syndromic GDD/ID and/or ASD, undergoing genetic and brain MRI examinations from July 2018 to September 2022 at the Neurological Institute Foundation Casimito Mondino in Pavia, Italy. Of the 132 patients, 28 pts were not included in the analysis due to insufficient genetic, radiological or clinical data. Clinical data were collected from clinical assessments during patient clinical care visits and are used to further divide the patients for purposes of analysis. Genomic DNA was extracted from the peripheral blood lymphocytes and was subjected to array CGH and FMR1 gene tests as first level examinations. If these proved inconclusive, further examinations were applied namely the NGS exome sequencing. 4.3. MRI EVALUATION The evaluation of brain MR imaging was conducted using either a 1.5-T or 3-T MRI machine. Following the institution's protocol, all patients underwent procedural sedation to facilitate the evaluation. The MR protocol encompassed spin echo T1-weighted images, fast spin echo T2, IR, FLAIR, and additional sequences that were employed if abnormalities were detected. Subsequently, the resulting images were reviewed by a board-certified paediatric neuroradiologist. To identify specific anomalies associated with the corpus callosum, ventricles, pituitary gland, optic pathway, cerebellum, white matter, basal ganglia, thalamus, hippocampi, and brainstem, abnormal brain MRI findings were classified into five major categories. These categories allowed for anatomical division of the findings into supratentorial, infratentorial, ventricular system, midline structures, or the sellar region. 4.4. STATISTICAL ANALYSIS Statistical analyses were performed using R 4.2.2. Descriptive statistic are performed as row counts and percentages for qualitative variables, mean and standard deviation (median and quartiles if non parametric) for quantitative variables. Radiological and clinical characteristics were compared between the groups of positive and negative results of the genetic test using the Kruskal–Wallis rank sum test for continuous variables and Pearson’s Chi-squared tests for categorical variables, as appropriate. The Bonferroni correction was used to control for multiple comparisons in post-hoc analyses. The variables resulted significant are considered as covariates in a multivariate logistic regression, together with the variables with p-values<0.1. This last group of variables are analyzed because of the interesting trend showed and the results close to the significance. Statistical significance was established at a p-value of < 0.05.
I disturbi neurosviluppo sono un gruppo di condizioni mediche comunemente riscontrate nella cura primaria pediatrica. Questi disturbi possono includere Ritardo Globale dello Sviluppo, Disabilità Intellettiva e Disturbo dello Spettro Autistico. Questi disturbi compaiono spesso precocemente nello sviluppo e possono co-occorrere tra loro. Quando accompagnati da altre caratteristiche cliniche, vengono definiti DSN sindromici. Questo studio mira a descrivere il valore predittivo delle scoperte dell'MRI cerebrale per una valutazione approfondita del neurofenotipo di un bambino con DSN sindromico di eziologia sconosciuta, in particolare per: - indagare una potenziale correlazione genotipo-fenotipo dell'MRI - stimare la prevalenza delle scoperte dell'MRI cerebrale, con i loro valori predittivi positivi e negativi - analizzare la sensibilità e la specificità delle scoperte dell'MRI cerebrale relative al DSN sindromico di eziologia sconosciuta. È stato condotto uno studio retrospettivo osservazionale su 132 pazienti con diagnosi clinica di Ritardo Globale dello Sviluppo/Disabilità Intellettiva e/o Disturbo dello Spettro Autistico sindromici, sottoposti a esami genetici e MRI cerebrale dal luglio 2018 al settembre 2022 presso la Fondazione Istituto Neurologico Casimiro Mondino di Pavia, Italia. Dei 132 pazienti, 28 non sono stati inclusi nell'analisi a causa di dati genetici, radiologici o clinici insufficienti. I dati clinici sono stati raccolti durante le visite di cura clinica dei pazienti e sono utilizzati per suddividere ulteriormente i pazienti a fini di analisi. Il DNA genomico è stato estratto dai linfociti del sangue periferico ed è stato sottoposto a esami array CGH e del gene FMR1 come esami di primo livello. Se questi esami si sono rivelati inconcludenti, sono state applicate ulteriori indagini, ovvero il sequenziamento dell'esoma NGS. 4.3. VALUTAZIONE MRI La valutazione dell'imaging cerebrale con risonanza magnetica (MRI) è stata condotta utilizzando una macchina MRI da 1,5 T o 3 T. Seguendo il protocollo dell'istituto, tutti i pazienti sono stati sottoposti a sedazione procedurale per agevolare la valutazione. Il protocollo MRI comprendeva immagini ponderate in T1 con eco di spin, eco di spin veloce T2, IR, FLAIR e sequenze aggiuntive che sono state impiegate in caso di anomalie rilevate. Successivamente, le immagini risultanti sono state valutate da un neuroradiologo pediatrico certificato. Per identificare anomalie specifiche associate al corpo calloso, ai ventricoli, alla ghiandola pituitaria, alla via ottica, al cervelletto, alla sostanza bianca, ai gangli basali, al talamo, e all'ippocampo.
The Predictive Value of Deep Neuro-phenotyping with brain MRI in Syndromic Neurodevelopmental Disorders: results on a cohort of 132 patients
ABDELGHANI, RANIM
2022/2023
Abstract
neurodevelopmental disorders are a group of medical conditions that are commonly encountered in paediatric primary care. These disorders can include Global Developmental delay, Intellectual Disability and Autism Spectrum Disorder. These disorders often appear early in development and can co-occur with each other.4 When accompanied by other clinical features, they are referred to as syndromic NDDs. This study aims to describe the predictive value of brain MRI findings for a deep neurophenotyping assessment of a child with syndromic NDD of unknown aetiology, specifically in order to: - investigate a potential genotype-MR phenotype correlation -to estimate the prevalence of brain MRI findings, with their positive and negative predictive values - analyze brain MRI findings’ sensitivity and specificity related to syndromic NDD of unknown aetiology. A retrospective, observational study was carried out on 132 patients with a clinical diagnosis of syndromic GDD/ID and/or ASD, undergoing genetic and brain MRI examinations from July 2018 to September 2022 at the Neurological Institute Foundation Casimito Mondino in Pavia, Italy. Of the 132 patients, 28 pts were not included in the analysis due to insufficient genetic, radiological or clinical data. Clinical data were collected from clinical assessments during patient clinical care visits and are used to further divide the patients for purposes of analysis. Genomic DNA was extracted from the peripheral blood lymphocytes and was subjected to array CGH and FMR1 gene tests as first level examinations. If these proved inconclusive, further examinations were applied namely the NGS exome sequencing. 4.3. MRI EVALUATION The evaluation of brain MR imaging was conducted using either a 1.5-T or 3-T MRI machine. Following the institution's protocol, all patients underwent procedural sedation to facilitate the evaluation. The MR protocol encompassed spin echo T1-weighted images, fast spin echo T2, IR, FLAIR, and additional sequences that were employed if abnormalities were detected. Subsequently, the resulting images were reviewed by a board-certified paediatric neuroradiologist. To identify specific anomalies associated with the corpus callosum, ventricles, pituitary gland, optic pathway, cerebellum, white matter, basal ganglia, thalamus, hippocampi, and brainstem, abnormal brain MRI findings were classified into five major categories. These categories allowed for anatomical division of the findings into supratentorial, infratentorial, ventricular system, midline structures, or the sellar region. 4.4. STATISTICAL ANALYSIS Statistical analyses were performed using R 4.2.2. Descriptive statistic are performed as row counts and percentages for qualitative variables, mean and standard deviation (median and quartiles if non parametric) for quantitative variables. Radiological and clinical characteristics were compared between the groups of positive and negative results of the genetic test using the Kruskal–Wallis rank sum test for continuous variables and Pearson’s Chi-squared tests for categorical variables, as appropriate. The Bonferroni correction was used to control for multiple comparisons in post-hoc analyses. The variables resulted significant are considered as covariates in a multivariate logistic regression, together with the variables with p-values<0.1. This last group of variables are analyzed because of the interesting trend showed and the results close to the significance. Statistical significance was established at a p-value of < 0.05.È consentito all'utente scaricare e condividere i documenti disponibili a testo pieno in UNITESI UNIPV nel rispetto della licenza Creative Commons del tipo CC BY NC ND.
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https://hdl.handle.net/20.500.14239/16047