CHARGE syndrome (CS) is a rare genetic disease causing multiple anatomical defects and sensory impairment. Visual function is usually reported by caregivers and has never been described with a structured behavioral assessment. Our primary objective was to describe ocular abnormalities, visual function and genotype–ocular-phenotype correlation in CS. A prospective monocentric cohort study was performed on 14 children with CS carrying pathogenic CHD7 variants. All children underwent ophthalmological evaluation and structured behavioral assessment of visual function. The VISIOCHARGE questionnaire was administered to parents. Colobomas were present in 93% of patients. Genotype–phenotype correlation documented mitigated features in a subset of patients with intronic pathogenic variants predicted to affect transcript processing, and severe features in patients with frameshift/nonsense variants predicting protein truncation at the N-terminus. Abnormal visual function was present in all subjects, with different degrees of impairment. A significant correlation was found between visual function and age at assessment (p-value = 0.025). The present data are the first to characterize visual function in CS patients. They suggest that hypomorphic variants might be associated with milder features, and that visual function appears to be related to age. While studies with larger cohorts are required for confirmation, our data indicate that experience appears to influence everyday use of visual function more than ocular abnormalities do.

Objective Growth differentiation factor 15 (GDF15) has been associated with food intake and weight regulation in response to metabolic stress. In animal models, it has been noted that it may play a role in the progression of non-alcoholic fatty liver disease (NAFLD), the leading cause of chronic liver disease in children. Design In the current study, we explored the association of circulating plasma concentrations of GDF15 with NAFLD in youth with overweight/obesity, and whether changes in plasma concentrations in GDF15 parallel the changes in intrahepatic fat content (HFF%) over time. Methods Plasma GDF15 concentrations were measured by ELISA in 175 youth with overweight/obesity who underwent an oral glucose tolerance test (OGTT) and magnetic resonance imaging (MRI) to assess intrahepatic, visceral, and subcutaneous fat. Baseline fasting GDF15 concentrations were measured in twenty-two overweight/obese youth who progressed (n = 11) or regressed (n = 11) in HFF% by more than 30% of original over a 2-year period. Results Youth with NAFLD had significantly higher plasma concentrations of GDF15 than those without NAFLD, independent of age, sex, ethnicity, BMI z-score (BMIz), and visceral fat (P = 0.002). During the OGTT, there was a decline in plasma GDF15 concentrations from 0 to 60 min, but GDF15 concentrations returned to basal levels by the end of the study. There was a statistically significant association between change in HFF% and change in GDF15 (P = 0.008; r2 = 0.288) over ~2 years of follow-up. Conclusions These data suggest that plasma GDF15 concentrations change with change in intrahepatic fat content in youth with overweight/obesity and may serve as a biomarker for NAFLD in children.

To date, the feeding and oral-motor abilities of patients with CHARGE syndrome (CS) have not been longitudinally assessed. This study aims to investigate the level of these abilities at different ages and evaluate how they evolve during growth. We retrospectively analysed oral-motor features of 16 patients with molecularly confirmed CS (age range 4–21 years old; mean 11 years; SD 6 years; median 10 years). Nearly 100% of CS new-borns had weak sucking at birth, and half of them demonstrated poor coordination between breathing and swallowing. Over time, the percentages of children with tube feeding dependence (60% at birth) faced a slow but steady decrease (from 33% at 6 months, 25% at 12 months, to 13% at school age) in tandem with the decreasing risk of aspiration. The ability of eating foods requiring chewing was achieved at school age, after the acquisition of an adequate oral sensory processing. A mature chewing pattern with a variety of food textures was not achieved by more than half of patients, including those requiring artificial enteral nutrition. Most patients started prolonged oral-motor treatments with speech language therapists in early childhood.Conclusions: Although feeding and swallowing disorders are constant features in CS patients, a slow and gradual development of feeding abilities occurs in most cases. Rehabilitation plays a key role in overcoming structural and functional difficulties and attaining appropriate eating skills. What is Known:• Feeding problems and swallowing dysfunction have been noted in CHARGE syndrome.• The involvement of multiple factors, including structural problems in the mouth, throat, or esophagus, and neurological impairment, make feeding a complicated task in CHARGE individuals. What is New:• Dysphagia gradually improves in most CHARGE children over time, though with a wide interindividual variability.• The percentages of children with tube feeding dependence decrease over time from 60% at birth to 33% at 6 months and 13% at school age.

Growth differentiation factor 15 (GDF15) has been associated with many important biological functions, such as food intake and weight regulation in response to metabolic stress. In animal models, it has also been noted that it may play a role in the progression of nonalcoholic fatty liver disease (NAFLD), the leading cause of chronic liver disease in children. Nevertheless, the exact role of GDF15 in liver disease has yet to be elucidated. We aimed to explore the association of GDF15 with NAFLD in obese youth, and whether GDF15 changes similarly with changes in hepatic fat content (HFF%) over time. Fasting plasma GDF15 levels were measured by ELISA in obese youth with (89) and without (95) NAFLD. Additionally, fasting GDF15 levels were measured in 22 obese youth who progressed (11) or regressed (11) in HFF% by more than 30% over a two-year period. Abdominal MRI was performed on all subjects to quantify HFF%. For the first time, we describe a novel association between GDF15 and NAFLD in obese youth. Figure 1A shows a statistically significant difference in fasting GDF15 levels (p<0.0001) between three groups stratified by degree of HFF%. Figure 1B shows a statistically significant association between change in HFF% and change in GDF15 (p=0.01; r2=0.29). These data suggest that GDF15 levels change with change in intrahepatic fat content in obese youth and may serve as a biomarker for NAFLD in children. Disclosure B. Galuppo: None. C. Agazzi: None. B. Pierpont: None. S. Samuels: None. E. Tarabra: None. S. Caprio: None. N. Santoro: None.

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<b><i>Introduction:</i></b> The X-chromosomal <i>USP9X</i> gene encodes a deubiquitylating enzyme involved in protein turnover and TGF-β signaling during fetal and neuronal development. <i>USP9X</i> variants in females are primarily associated with complete loss-of-function (LOF) alleles, leading to neurodevelopmental delay and intellectual disability, as well as a wide range of congenital anomalies. In contrast, <i>USP9X</i> missense variants in males often result in partial rather than complete LOF, specifically affecting neuronal migration and development. <i>USP9X</i> variants in males are associated with intellectual disability, behavioral disorders, global developmental delay, speech delay, and structural CNS defects. Facial dysmorphisms are found in almost all patients. <b><i>Case Presentation:</i></b> We report the case of an Italian boy presenting dysmorphism, intellectual disability, structural brain anomalies, and congenital heart disease. Using next-generation sequencing analysis, we identified a hemizygous de novo variant in the <i>USP9X</i> gene (c.5470A&#x3e;G, p.Met1824Val) that was never reported in the literature. <b><i>Conclusion:</i></b> We provide an overview of the available literature on <i>USP9X</i> variants in males, in order to further expand the genotypic and phenotypic landscape of male-restricted X-linked mental retardation syndrome. Our findings confirm the involvement of <i>USP9X</i> variants in neuronal development and corroborate the possible association between the novel <i>USP9X</i> variant and congenital heart malformation.

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Background Down syndrome is a genetic disorder caused by trisomy of chromosome 21 and characterized by an increased risk of multiorgan involvement. In Down syndrome children, functional constipation and lower urinary tract infections have been described, together with higher risk for incontinence and delayed sphincter control. At present, to our knowledge, no clear association between Down syndrome, Bladder Bowel Dysfunction and neural tube defects has been previously described. Case presentation We describe two female patients with Down syndrome presenting Bladder Bowel Dysfunction in association with neural tube defects, who both underwent personalized multidisciplinary intervention and pelvic floor rehabilitation, with good clinical outcomes. Conclusion At present, no screening program has been established in order to rule out neural tube defects or neurogenic urinary anomalies in Down syndrome patients presenting bowel and/or bladder dysfunction. In our opinion, presence of spinal abnormalities, despite rare, may be contribute to urinary symptoms and should be ruled out in patients presenting progressive or persistent Bladder Bowel Dysfunction. Early diagnosis and management of spinal cord defects associated with neurogenic urinary dysfunction may allow to prevent possible complications.