Background Dysregulation of the RAS-mitogen-activated protein kinase signalling pathway underlies RASopathies, a family of neurodevelopmental disorders associated with variable cancer predisposition. However, the prevalence and spectrum of solid tumours and the contribution of specific variants to tumour susceptibility remain poorly defined. Methods We assessed solid tumour prevalence and spectrum in the largest single-centre cohort of individuals with RASopathies (n=138), excluding neurofibromatosis type 1 and integrated these findings with a systematic literature review to evaluate tumour distribution and genotype-phenotype correlations. Results In our cohort, at least one solid tumour was identified in 10.8% of individuals with Noonan syndrome (NS), 47.8% with Costello syndrome (CS) and 7.3% with cardiofaciocutaneous syndrome (CFCS). Malignant tumours occurred in 5.4%, 30.4% and 2.4%, respectively. CS showed the highest tumour burden, frequently with multiple primary tumours, predominantly of the bladder. In NS, low-grade central nervous system (CNS) tumours were most common, particularly among individuals carrying PTPN11 variants. Tumour onset occurred with a median age of 19, 14 and 13 years in NS, CS and CFCS, respectively. Literature data analysis identified candidate variants in HRAS , PTPN11 and SOS1 genes associated with increased risk for solid tumours, which differed from mutational hotspots reported in childhood leukaemia or sporadic cancers. Conclusion Solid tumour risk in RASopathies is syndrome-dependent and genotype-dependent, with CS showing a high burden of bladder tumours and NS mainly associated with CNS tumours. These findings may support tailored surveillance strategies.

A 5-year-old child with tuberculous meningoencephalitis developed severe drug-induced hepatitis after conventional antitubercular therapy. Consequently, standard treatment was discontinued, and second-line drugs were administered in combination with high-dose corticosteroids. However, the disease continued to progress significantly. The introduction of infliximab resulted in substantial clinical and radiologic improvement, highlighting its potential role in managing refractory cases of central nervous system tuberculosis.

PURPOSE:Biallelic variants in RDH11, encoding retinol dehydrogenase 11, have been associated with a syndromic disorder, based on 4 individuals from 2 unrelated families. We aimed to profile the clinical variability, natural history and associated molecular spectrum of this condition. METHODS:In the frame of a collaborative effort, clinical and molecular data were collected using a semistructured survey. Structural modeling of RDH11 with NADH(P) was used to assess the functional impact of missense variants. RESULTS:Sixteen affected individuals from 9 unrelated families with biallelic RDH11 variants were assembled, frequently showing juvenile-onset progressive myopathy with vacuolar degeneration and prodromic asymptomatic hyperCKemia. Neurodevelopmental impairment, juvenile-onset cataract, and retinal dystrophy were confirmed as common features. Microcephaly and distinct craniofacial traits were also recurrent, whereas short stature was less frequent than previously reported. Most pathogenic variants were truncating, supporting RDH11 loss of function as the mechanism of disease. Consistently, the identified missense changes were predicted to affect RDH11 catalytic function. CONCLUSION:We refine the clinical and molecular spectra of RDH11-related disorder, reclassifying it as syndromic intellectual disability with muscular (juvenile myopathy) and ocular (retinal dystrophy) involvement. These insights are expected to improve diagnostic accuracy and patient care, guiding clinical evaluation, and genetic counseling.

UBTF codes for a nucleolar transcription factor required for transcription of rDNA genes. UBTF gain-of-function (GoF) has been identified as the cause of CONDBA syndrome, with a recurrent missense change, p.Glu210Lys occurring in most affected individuals. More recently, eight subjects with truncating variants or microdeletions involving UBTF have been associated with a distinct neurodevelopmental disorder in which developmental delay (DD) and intellectual disability (ID) co-occur with behavioral anomalies in the absence of signs of neuroregression. Here, we report on four affected individuals, including one adult subject, from a single family carrying a heterozygous UBTF splice-site variant affecting transcript processing. All subjects presented with a clinical phenotype characterized by DD/ID with behavioral problems, without signs of neuroregression. By systematically examining the clinical features in both current and previously reported cases, we identify a characteristic facial gestalt as a hallmark of the disorder, and recognize increased BMI and a hyper-nasal voice as previously underappreciated features. These data provide further evidence that UBTF haploinsufficiency causes a non-regressive form of DD/ID clinically distinct from CONDBA syndrome.

Background/Objectives: The advent of disease modifying therapies (DMTs) for Spinal Muscular Atrophy (SMA) has highlighted the need for reliable tools to assess bulbar function in type I individuals. The Oral and Swallowing Abilities Tool (OrSAT) was originally developed to evaluate swallowing and feeding abilities in infants with SMA type I during the first two years of life. This study aimed to assess the applicability of the OrSAT in a cohort of children with SMA type I older than 2 years. Methods: Fifty-two children with genetically confirmed SMA type I, aged 2 to 12.6 years, were included. All participants had received at least one DMT, administered either soon after diagnosis or when treatment became available. Bulbar and feeding abilities were assessed using the OrSAT and results were grouped according to clinical subtype and feeding modality. Given the small sample size of the subgroups and the ordinal nature of OrSAT scores, comparisons between groups were performed using the non-parametric Kruskal-Wallis test. Results: At follow-up, 27 children were orally fed, 19 were exclusively tube-fed, and 6 were tube-fed but were also able to eat some food by mouth. The OrSAT scores reflect a wide spectrum of bulbar function from severe to no impairment. Most children who required exclusive tube-feeding at follow-up had already been tube-fed at treatment initiation, while a small number showed improvement in swallowing abilities and the partial recovery of oral feeding during follow-up. Conclusions: Our results suggest that the OrSAT, previously used only in the first two years of life, may also be applicable in older children to describe bulbar involvement and monitor changes over time. However, further studies are needed to refine the tool for this age group and to formally validate its use in older children with SMA type I. Its use may contribute to the longitudinal assessment of swallowing abilities and support rehabilitative management.

Background Congenital anomalies are a leading cause of infant morbidity and mortality and arise from complex interactions between genetic susceptibility and prenatal environmental exposures. Increasing evidence indicates that these teratogens induce epigenetic alterations, including changes in DNA methylation, histone modifications, and non-coding RNA expression, thereby disrupting fetal gene regulation. In Italy, congenital malformations affect approximately 2-3% of live births, with environmental factors accounting for a relevant proportion of preventable cases. Methods This narrative review was structured on a literature search conducted between October and December 2025 using PubMed, Scopus, and Web of Science. Scientific publications addressing epigenetic mechanisms, teratogenic exposures, congenital anomalies, maternal health, and pediatric prevention were identified and narratively synthesized. In parallel, Italian legislation, constitutional amendments, legislative decrees, and international directives were qualitatively reviewed to examine the evolution of public health and maternal-child protection policies. Results Prenatal exposures may be responsible for altered fetal development through epigenetic mechanisms occurring during critical stages of embryogenesis. The Italian regulatory framework has progressively strengthened Public Health, occupational safety, and maternal protection measures, reducing avoidable prenatal hazards. Conclusions As leaders in Child Health, Pediatricians are uniquely positioned to identify modifiable prenatal risk factors, counsel families, and promote evidence-based clinical strategies, translating scientific advances into preventive action to reduce the burden of congenital diseases.

PURPOSE:Biallelic variants in the minor spliceosomal gene RNU4ATAC were successively identified in Taybi-Linder/Microcephalic osteodysplastic primordial dwarfism type I, Roifman, and Lowry-Wood syndromes, which are characterized by variable microcephaly, short stature, neurodevelopmental impairment, skeletal dysplasia, and immunodeficiency. Two-thirds of the reported individuals present with Taybi-Linder syndrome, the first-described and most severe form. METHODS:We collected clinical and molecular data from individuals with biallelic RNU4ATAC variants through various French and European networks and clinics to refine the phenotypic spectrum of RNU4ATAC-opathies. RESULTS:We enrolled 69 participants and identified 18 new pathogenic variants. We report a significant proportion of attenuated or atypical presentations, novel rare symptoms, and, unexpectedly, a broad spectrum of autoimmune or inflammatory manifestations, affecting nearly half of the participants. Integrating our data with the 109 published cases, we propose a novel classification based on the main manifestations, immunodeficiency, and microcephalic primordial dwarfism. Using computer-assisted facial analysis, we also demonstrated the existence of a specific dysmorphic pattern in RNU4ATAC-opathies that is distinct among some sub-syndromes. CONCLUSION:We present a large cohort of individuals with RNU4ATAC-opathies and expand the phenotypic spectrum to paucisymptomatic forms, indicating that these diseases are likely to remain underdiagnosed.

The transition from pediatric to adult healthcare is a critical phase for persons with Down syndrome (DS). The InterRAI Child and Youth Mental Health – Developmental Disabilities (ChYMH-DD) and the InterRAI Intellectual Disability (ID) are validated tools for pediatric and adult populations, respectively. this study aimed to facilitate more coordinated care planning and a consistent understanding of functioning across developmental stages of persons with Down syndrome. This study included 186 participants (aged 5–35 years) with a DS diagnosis. Each participant was assessed using the age-appropriate InterRAI instrument for individuals with intellectual and developmental disabilities. The transition to adulthood is associated with an increased complexity of mood, behaviour and symptom burden, as well as a decline in engagement with preventive healthcare after childhood. This proof-of-concept study demonstrated the feasibility of applying InterRAI multidimensional assessment instruments across the transition from pediatric to adult care in individuals with DS. The observed patterns—gains in autonomy and communication alongside increasing behavioral, emotional, and medical challenges—underscore the need for structured, lifespan-oriented approaches to care.

BACKGROUND:Necrotizing pneumonia (NP) represents a severe and potentially life-threatening complication of community-acquired pneumonia in children, characterized by progressive lung parenchymal necrosis, cavity formation and significant respiratory compromise. Despite advances in pediatric critical care, NP continue to pose substantial challenges in terms of early recognition, optimal management strategies and prediction of intensive care requirements. OBJECTIVES:This multicenter observational study aimed to comprehensively analyze the clinical characteristics, microbiological patterns, radiological features and management strategies of pediatric NP requiring intensive care admission, with particular focus on identifying predictive factors for disease severity and resource utilization. METHODS:We conducted a retrospective analysis of all children admitted with radiologically confirmed NP to Italian pediatric intensive care units (PICUs) between January 2018 and December 2022. Comprehensive data collection included demographics, clinical presentation, laboratory findings, microbiological results, radiological patterns, therapeutic interventions, complications and outcomes. Statistical analysis was performed to identify associations between clinical variables and outcomes. RESULTS:Among 76 children (median age 45 months, interquartile range: 19-84), Streptococcus pneumoniae was identified in 38 patients (52.8%), followed by Staphylococcus aureus in 18 (23.7%), including 12 Panton-Valentine leukocidin-positive strains (16.7%). Mechanical ventilation was required in 44 patients (57.9%), chest drainage in 58 (76.3%) and video-assisted thoracoscopic surgery in 11 (14.5%). Comorbidities were present in 23 patients (30.3%). Mean PICU stay was 8.9 ± 8.8 days with zero mortality. Independent predictors of prolonged PICU stay included age <24 months [odds ratio (OR) 2.8, 95% confidence interval (CI): 1.2-6.5], comorbidities (OR 3.2, 95% CI: 1.4-7.3) and bilateral involvement (OR 3.8, 95% CI: 1.5-9.6). CONCLUSIONS:Pediatric NP remains a challenging clinical entity requiring multidisciplinary management and significant intensive care resources. Early recognition of severity predictors, prompt microbiological diagnosis and individualized therapeutic approaches are essential for optimizing outcomes. Our findings support the need for standardized protocols and further prospective studies to refine management strategies for this severe condition. CLINICAL TRIAL REGISTRATION:Not applicable (observational study).

A narrow spectrum of heterozygous variants in RNU4-2, encoding the small nuclear RNA (snRNA) U4, underlies ReNU syndrome, a neurodevelopmental disorder (NDD) characterized by moderate to severe developmental delay (DD), intellectual disability (ID), a distinctive facial gestalt, and multisystem involvement. Pathogenic variants have primarily been reported within an 18-nt critical region contributing to stabilizing the U4/U6 snRNA duplex and proper spliceosome assembly. By combining whole genome sequencing reanalysis and targeted direct sequencing in 190 molecularly unexplained NDD cases, we report on five affected individuals carrying pathogenic/putative pathogenic RNU4-2 variants (2.6%). Three individuals harbored the recurrent pathogenic n.64_65insT variant, while two were heterozygous for private/rare maternally inherited variants (n.30 A > T and n.43_44insT) within the 5’ Stem-loop region. Deep clinical phenotyping confirmed a homogeneous constellation of features in all individuals, with global DD, ID, brain malformations, and a recognizable facial gestalt representing core findings. Based on structural homology models and available cryo-EM data, n.30 A > T and n.43_44insT were predicted to disrupt key intra- and inter-molecular interactions critical for spliceosome function. Our findings expand the mutational spectrum of ReNU syndrome, and confirm the 5’ Stem-loop as a second mutational hotspot in RNU4-2. We propose that a more complex genetics likely underlies the inheritance of a subset of disease-causing RNU4-2 variants from an apparently unaffected parent. We anticipate a relatively high proportion of pathogenic RNU4-2 variants among individuals with unclassified NDD despite extensive genomic testing, and propose a set of facial gestalt core features as a clinical screening tool to prioritize patients for RNU4-2 analysis.

Background: Perceptual analysis has highlighted that the voice characteristics of patients with rare congenital genetic syndromes differ from those of normophonic subjects. In this paper, we describe the voice phenotype, also called the phonotype, of patients with Crisponi/cold-induced sweating syndrome type 1 (CS/CISS1). Methods: We conducted an observational study at the Department of Life Sciences and Public Health, Rome. Thirteen patients were included in this study (five males; mean age: 16 years; SD: 10.63 years; median age: 12 years; age range: 6–44 years), and five were adults (38%). We prospectively recorded and analyzed acoustical features of three corner vowels [a], [i], and [u]. For perceptual analysis, the GIRBAS (grade, instability, roughness, breathiness, asthenia, and strain) scale was utilized. Acoustic analysis was performed through BioVoice software. Results: We found that CS/CISS1 patients share a common phonotype characterized by articulation disorders and hyper-rhinophonia. Conclusions: This study contributes to delineating the voice of CS/CISS1 syndrome. The phonotype can represent one of the earliest indicators for detecting rare congenital conditions, enabling specialists to reduce diagnosis time and better define a spectrum of rare and ultra-rare diseases.

Background/Objectives: Heterozygous variants in the heterogeneous nuclear ribonucleoprotein C gene (HNRNPC) have recently been reported to cause intellectual developmental disorder-74 (MRD74), a neurodevelopmental disorder with no recurrent diagnostic handles. Affected individuals show variable, non-specific, and subtle dysmorphic features. The degree of developmental delay (DD)/intellectual disability (ID) is also wide, ranging from mild to severe. The mutational spectrum is relatively broad with exon deletions and splice site and frameshift variants distributed along the entire length of the gene leading to HNRNPC loss of function. Only two missense changes located within the RNA-binding motif (RBM) and adjacent linker region of the more abundant isoform (Arg64Trp and Arg99Gln) have been described. Notably, the Arg99Gln amino acid substitution was reported in a subject presenting with a more complex and unique clinical phenotype characterized by distinctive facial features, DD/ID, cochlear aplasia, and bilateral colobomatous microphthalmia, suggesting the possible occurrence of phenotypic heterogeneity. Results: Here, we report the second individual carrying the Arg99Gln change in HNRNPC and having clinical features with a significant overlap with the peculiar phenotype of the previously described subject, supporting the occurrence of a genotype–phenotype correlation. Conclusions: Due to the concomitant occurrence of ocular and cochlear involvement as recognizable diagnostic handles, we propose that the HNRNPCArg99Gln-related phenotype should be considered as a potential differential diagnosis in subjects with ID and major signs of CHARGE syndrome not fulfilling the minimum criteria for a clinical diagnosis.

DDX17 is an RNA helicase shown to be involved in critical processes during the early phases of neuronal differentiation. Globally, we compiled a case series of 11 patients with neurodevelopmental phenotypes harbouring de novo monoallelic variants in DDX17. All 11 patients in our case series had a neurodevelopmental phenotype, whereby intellectual disability, delayed speech and language, and motor delay predominated. We performed in utero cortical electroporation in the brain of developing mice, assessing axon complexity and outgrowth of electroporated neurons, comparing wild-type and Ddx17 knockdown. We then undertook ex vivo cortical electroporation on neuronal progenitors to quantitatively assess axonal development at a single cell resolution. Mosaic ddx17 crispants and heterozygous knockouts in Xenopus tropicalis were generated for assessment of morphology, behavioural assays and neuronal outgrowth measurements. We further undertook transcriptomic analysis of neuroblastoma SH-SY5Y cells, to identify differentially expressed genes in DDX17-KD cells compared to controls. Knockdown of Ddx17 in electroporated mouse neurons in vivo showed delayed neuronal migration as well as decreased cortical axon complexity. Mouse primary cortical neurons revealed reduced axon outgrowth upon knockdown of Ddx17 in vitro. The axon outgrowth phenotype was replicated in crispant ddx17 tadpoles and in heterozygotes. Heterozygous tadpoles had clear neurodevelopmental defects and showed an impaired neurobehavioral phenotype. Transcriptomic analysis identified a statistically significant number of differentially expressed genes involved in neurodevelopmental processes in DDX17-KD cells compared to control cells. We have identified potential neurodevelopment disease-causing variants in a gene not previously associated with genetic disease, DDX17. We provide evidence for the role of the gene in neurodevelopment in both mammalian and non-mammalian species and in controlling the expression of key neurodevelopment genes.

In this study we applied the ‘floppy module’, originally developed for newborns with hypotonia, to older infants in order to establish the range of findings in both low-risk infants and in those with hypotonia due to different etiologies. Data were collected from 413 assessments obtained in 159 low-risk infants assessed at different ages between the age of 3 and 24 months. The distribution of findings in the low-risk infants was similar to the data previously obtained in low-risk newborns, with all assessments having optimal findings (column 3) on all items. The only item with a small number of findings outside column 3 was tendon reflexes. The module was also applied to a cohort of 57 infants with hypotonia older than 3 months in order to identify individual items that may be useful in differential diagnosis. Items assessing antigravity movements were the most sensitive to identify neuromuscular disorders. Dysmorphic features and other organ involvement were most suggestive of genetic disorder, while seizures were a reliable indicator of CNS involvement. Conclusion: Our findings suggest that the neonatal floppy module can be reliably administered also in infants from the age of 3 months. The pilot application of the module in infants with hypotonia from the age of 3 months also suggested that the module could be used to help the clinician in the differential diagnosis of infants with hypotonia.

BACKGROUND:Hereditary Hemorrhagic Telangiectasia (HHT) is a rare, hereditary, autosomal dominant vascular disease, characterized by visceral arteriovenous malformations (AVMs), mucocutaneous telangiectasias and epistaxis. While symptomatic medical and surgical therapies are used in the management of pediatric patients, data comparing phenotypic presentation between genetically related individuals (e.g., parent-child pairs) remain limited. AIMS AND METHODS:We conducted a single-center retrospective study involving pediatric patients with genetically confirmed HHT and their affected parents at Fondazione Policlinico Universitario A. Gemelli IRCCS in Rome, Italy. The aim of our study was to assess genotype-phenotype correlation and intrafamilial HHT-phenotypic variability. Clinical, laboratory, imaging, and therapeutic data were collected between May 2022 and May 2023. Variables including presence of AVMs, epistaxis, telangiectasias, anemia, and need for interventions were compared between children and their parents. RESULTS:The study included 11 children (mean age 11.8 years) and 9 adults (mean age 47 years), all exhibiting ENG or ACVRL1 variants. While epistaxis was common in both cohorts (91% in children vs. 100% in adults), mucocutaneous telangiectasias and AVMs were more prevalent in adults. AVMs were more frequently detected in adults, especially among ENG carriers. Notably, phenotype concordance between parent-child pairs with the same mutation was observed in only 3 up to 9 families (33.3%), with substantial intrafamilial variability in AVM distribution and disease severity. CONCLUSIONS:Our findings confirm the variable expressivity of HHT, even among first-degree relatives sharing the same pathogenic variant. No consistent overlap was observed between parent and child phenotypes, reinforcing the need for individualized pediatric screening and follow-up. Early genetic testing remains essential to prevent complications and guide appropriate management.

BACKGROUND:Achondroplasia is the most common form of disproportionate short stature and can lead to serious medical complications, including foramen magnum and spinal stenosis. Until 2021, there were no precision treatments available, and in some countries, elective surgery was considered a standard approach to increase height, improve body proportions, enhance functionality, and correct deformities in a selected group of patients. Recently, C-type natriuretic peptide (CNP) has been explored as a potential treatment, aiming to counteract the molecular activity driven by FGFR3. Although post-market and real-world data on the drug are still limited, many questions remain about the potential for combining pharmacological and surgical therapies and how this might influence patient outcomes. Concerns have also been raised regarding the potential impact of drugs on bone healing. However, anecdotal evidence from orthopaedic practice suggests that the two ossification processes do not interfere with one another. The aim of this study was to describe the first real-world case series in which vosoritide treatment was integrated with limb surgery in children and adolescents with achondroplasia. RESULTS:Sixteen paediatric patients with molecular confirmation of achondroplasia were included in the study. All patients underwent combined vosoritide therapy and limb surgeries (13 for lower limb lengthening and 3 for varus correction through epiphysiodesis).The complementary roles of vosoritide therapy and surgery were highlighted, with treatment outcomes aligning closely with expectations. CONCLUSION:This report provides the first clinical description of the combination of precision therapy with limb surgery in a relatively large multicentre cohort of paediatric patients with achondroplasia. These findings support continued exploration of the integration of different therapeutic approaches.

Costello syndrome (CS) is an ultra-rare condition belonging to the RASopathies, a group of disorders characterized by aberrant RAS/MAPK pathway signaling, which is involved in ocular development and in some eye pathologies. However, only a few studies assessing the ophthalmic features of individuals with CS are available. In this article, we describe the main ophthalmic anomalies and MRI findings in a large cohort of CS patients and compare our data with theliterature. 21 individuals with CS were enrolled and performedvisual acuity and refractive error assessment, intraocular pressure (IOP) evaluation, ocular motility examination, anterior segment inspection, fundus examination, macular optical coherence and corneal tomography, and brain MRI with the measurement of optic nerve thickness. A high prevalence of refractive errors was observed (90%), amblyopia, with best-corrected visual acuity below 20/40 in at least one eye in all assessed cases. Strabismus was also described in the present cohort (95%), with exotropia, esotropia, and hypertropia equally present. Moreover, 66.7% of our patients presented nystagmus. OCT was normal in all cases performed (6). Eighteen individuals underwent brain MRI, and 63% of them showed an altered optic nerve thickness. We described for the first time to date bilateral optic nerve thickness reduction assessed through MRI in CS. Moreover, in our cohort, we detect a high prevalence of amblyopia, refractive errors, and nystagmus across all ages. These findings support the implementation of an early ophthalmologic assessment and management in patients with CS to prevent deterioration of visual functions; therefore, improving overall quality of life.

Copy number variants (CNV) are a major cause of neurodevelopmental disorders. Novel CNV syndromes may still be unrecognized. We report a 9q34.11 microduplication syndrome characterized by neurodevelopmental impairment and recurrent facial anomalies. Following the identification of a de novo 9q34.11 microduplication involving the SET and SPTAN1 genes in an 11-year-old girl with speech delay, intellectual disability, and behavioral abnormalities, we identified 13 additional patients with overlapping duplications. Besides the neurodevelopmental disorder, clinical features observed among affected individuals included recurrent dysmorphic features, such as midface hypoplasia and thin lips. The minimal region of overlap among these cases contained the SET gene, suggesting that its triplosensitivity may play a role in the observed phenotypes.