From Wolf-Hirschhorn syndrome to NSD2 haploinsufficiency: a shifting paradigm through the description of a new case and a review of the literature.

BACKGROUND: Wolf-Hirschhorn syndrome (WHS) is a well-defined disorder, whose core phenotype encompasses growth restriction, facial gestalt, intellectual disability and seizures. Nevertheless, great phenotypic variability exists due to the variable extent of the responsible 4p deletion. In addition, exome sequencing analyses, recently identified two genes, namely NSD2 and NELFA, whose loss-of-function variants contribute to a clinical spectrum consistent with atypical or partial WHS. The observation of patients exhibiting clinical features resembling WHS, with only mild developmental delay and without the typical dysmorphic features, carrying microdeletions sparing NSD2, has lead to the hypothesis that NSD2 is responsible for the intellectual disability and the facial gestalt of WHS. While presenting some of the typical findings of WHS (intellectual disability, facial gestalt, microcephaly, growth restriction and congenital heart defects), NSD2-deleted children tend to display a milder spectrum of skeletal abnormalities, usually consisting of clinodactyly, and do not exhibit seizures. We describe the clinical picture of a child with WHS due to a de novo mutation of NSD2 and discuss the clinical and diagnostic implications. CASE PRESENTATION: A 6-year-old boy was evaluated for a history of intrauterine growth restriction, low birth weight, neonatal hypotonia, and psychomotor delay. No episodes of seizure were reported. At physical examination, he displayed marphanoid habitus, muscle hypotrophy and facial dysmorphisms consisting in high frontal hairline, upslanting palpebral fissures and full lips with bifid ugula. Cryptorchidism, shawl scrotum, mild clinodactyly of the right little finger and bilateral syndactyly of the II and III toes with sandal gap were also noted. The radiographic essay demonstrated delayed bone age and echocardiography showed mild mitral prolapse. Whole genome sequencing analysis revealed a heterozygous de novo variant of NSD2 (c.2523delG). CONCLUSIONS: Full WHS phenotype likely arises from the cumulative effect of the combined haploinsufficiency of several causative genes mapping within the 4p16.3 region, as a contiguous genes syndrome, with slightly different phenotypes depending on the specific genes involved in the deletion. When evaluating children with pictures resembling WHS, in absence of seizures, clinicians should consider this differential diagnosis.

Prevalence of children witnessed violence in a pediatric emergency department.

Witnessed violence is a form of child abuse with detrimental effects on child wellbeing and development, whose recognition relies on the assessment of their mother exposure to intimate partner violence (IPV). The aim of this study was to assess the frequency of witnessed violence in a population of children attending a pediatric emergency department (ED) in Italy, by searching for IPV in their mother, and to define the characteristics of the mother-child dyads. An observational cross-sectional study was conducted from February 2020 to January 2021. Participating mothers were provided a questionnaire, which included the Woman Abuse Screening Tool (WAST) and additional questions about their baseline data and health. Descriptive analysis was reported as frequency and percentage for the categorical variables and median and interquartile range (IQR) for quantitative variables. Mothers and children screened positive and negative for IPV and witnessed violence, respectively, were compared by the chi-square test or the exact Fisher test for categorical variables, and by the Wilcoxon-Mann-Whitney test for continuous variables. Out of 212 participating mothers, ninety-three (43.9%) displayed a positive WAST. Mothers tested positive were mainly Italian (71%, p 0.003), had a lower level of education (median age at school dropout 19, p 0.0002), and a higher frequency of unemployment (p 0.001) and poor personal health status (8.6%, p 0.001). The children of mothers tested positive showed a higher occurrence of abnormal psychological-emotional state (38.7%, p 0.002) and sleep disturbances (26.9%, p 0.04). CONCLUSION: IPV was common in a population of mothers seeking care for their children in a pediatric ED. WHAT IS KNOWN: • Witnessed violence is a form of child abuse, usually inferred by their mothers' exposure to IPV. The latter is suffered by one in three women worldwide. WHAT IS NEW: • This study shows a 43.9% prevalence of IPV among mothers attending an Italian pediatric ED. • Positive mother-child dyads displayed a higher frequency of poor mothers' health status and children's abnormal emotional state and sleep disturbances.

ADHD symptoms and school impairment history in parents of ADHD children are a fundamental diagnostic and therapeutic clue.

BACKGROUND: Attention Deficit and Hyperactivity Disorder (ADHD) is a multi-factorial condition, with inheritance playing a major role. Recognizing parents' ADHD represents a clue not only for an earlier diagnosis of the disease in their children, but also to optimize psycho-educational therapy outcomes, by addressing the impairment of parenting related to untreated ADHD. This study aimed to assess the frequency of features suggestive of ADHD during childhood among parents of affected children, and the presence of school and emotional impairment. METHODS: We administered the Wender Utah Rating Scale-25, a self-assessment tool for the retrospective identification of symptoms consistent with ADHD during childhood, to a cohort of 120 parents of 60 children with ADHD, and to a consistent number of "controls". RESULTS: The WURS-25 proved positive in 49.1% of fathers and 30.0% of mothers of ADHD patients, compared to 1.7% of fathers and 1.7% of mothers of non-ADHD patients (p < 0.0001). The questions addressing learning and emotional impairment provided significantly higher scores in parents with an overall positive test compared to those with negative test (p < 0.0001). CONCLUSIONS: This study demonstrates a remarkably high rate of symptoms consistent with ADHD during childhood in parents of affected children. Physicians should be aware that this is a relevant anamnestic clue and, given the relevance of parents' role in the management of children with ADHD, an important issue to address in order to optimize patients' treatment.