Background/Objectives: ZNF711(Zinc finger protein 711) encodes a zinc finger protein of currently undefined function, located on the X chromosome. Current knowledge includes a limited number of case reports where this gene has been exclusively associated with X-linked intellectual disability (XLID). As far as we are aware, we report the first cases of epilepsy associated with this particular variant. Our aim is to further delineate the phenotypic spectrum of ZNF711 gene pathogenic variants, adding clinical features to this rare condition, following a genotype-first approach. Case presentation: We describe the familiar case of two male siblings presenting with moderate intellectual disability (ID), language delay, and motor stereotypies. Additionally, they experienced generalized tonic–clonic seizures (GTCSs) and myoclonic seizures with interictal electroencephalographic abnormalities. Both children underwent various genetic testing and counselling, including an extended next-generation sequencing (NGS) panel, revealing a hemizygous c.657C > G pathogenic variant in the ZNF711 gene from maternal inheritance. Conclusions: This case expands the clinical range of ZNF711 variants by highlighting epilepsy as a potential comorbidity and suggesting other possible causal candidates for generalized epilepsy. Moreover, it emphasizes the need for further research into the phenotypic spectrum associated with this variant.

White–Sutton syndrome (WSS), associated with POGZ gene mutations, is a rare genetic disorder characterized by a spectrum of phenotypic features, including intellectual disabilities, developmental delays, and epilepsy. A case report described a female patient diagnosed with WSS who experienced seizures resistant to conventional antiseizure medications. Despite various therapeutic attempts, including valproate, topiramate, levetiracetam, clobazam, rufinamide, and vigabatrin, the patient's seizures persisted. After initiating an off-label treatment with cannabidiol (CBD), the patient achieved complete remission from seizures. Following significant clinical improvement, CBD therapy was discontinued by the parents against medical advice, leading to seizure recurrence. Upon reinstatement of CBD, the patient once again experienced successful seizure control. This report emphasizes the need for further investigation into the off-label use of CBD, as an adjunctive therapy in pediatric individuals with drug-resistant epilepsy associated with WSS. Although CBD shows promise in other epileptic syndromes, this case highlights its potential effectiveness in this specific condition. This manuscript aims to contribute to the understanding of WSS and advocate for further research into novel treatments, particularly the role of CBD in managing epilepsy within this complex clinical context.

Background/Objectives: Ischemic arterial stroke (AIS) is a cerebrovascular event that can occur acutely within the first hours or days of life, presenting as a neurological emergency. To date, clearly defined genetic risk factors for AIS have not been established, although certain genes involved in cerebrovascular regulation mechanisms are suspected to play a role. The Interferon Regulatory Factor 6 (IRF6) gene is a transcription factor involved in craniofacial and epidermal development. Recently, pathogenic variants of IRF6 have been implicated in the cytoprotective pathway of ischemic cerebrovascular disease. The aim of this manuscript is to further support the already-reported association between IRF6 and AIS. Materials and Methods: Genetic counseling and exome sequencing analysis were conducted for diagnostic purposes. Results: We report the case of a female newborn with palatoschisis, cleft palate, sensorineural deafness, facial dysmorphisms, and cutaneous defects who suffered an ischemic stroke in the territory of the left middle cerebral artery on day 1 of life. Family and pregnancy histories revealed no identifiable risk factors, and coagulation studies were normal. Exome sequencing identified a de novo c.1124T>C (p.Phe375Ser) variant in the IRF6 gene. The child developed right spastic hemiplegia and began motor rehabilitation therapy. Recently, a genome-wide association study (GWAS) using m6A-SNPs identified a statistical association between AIS and a single nucleotide polymorphism (SNP) that influences the expression of the IRF6 gene as an expression quantitative trait locus (eQTL). Conclusions: To our knowledge, this is the first report of neonatal ischemic stroke in a child carrying a de novo IRF6 pathogenic variant, further supporting its potential role as a genetic factor influencing cerebrovascular events. Further studies are needed to elucidate the precise relationship between IRF6 and AIS.

Background/objectives: Malan syndrome (MALNS) is a rare overgrowth disorder caused by pathogenic Nuclear Factor I × ( NFIX ) gene variants, and characterized by postnatal overgrowth, macrocephaly, developmental delay, intellectual disability and distinctive facial features. Chiari type I malformation (CMI), a condition where the cerebellar tonsils extend below the foramen magnum, has been observed in some patients with MALNS, although the exact relationship between these disorders remains unclear. The objective of this case report is to describe a novel NFIX variant in a patient with MALNS and associated CMI. This case adds to the literature on NFIX variants in patients with CMI and underscores the potential benefit of early genetic testing for diagnosis and management. Case presentation: We describe a patient with clinical features consistent with MALNS, including macrocephaly, developmental delay, and typical craniofacial features. Brain Magnetic Resonance Imaging (MRI) revealed the presence of CMI. Genetic testing identified a novel heterozygous variant in NFIX , not previously described in the literature. Conclusion: This case contributes to the clinical and molecular characterization of MALNS by linking a previously unreported NFIX variant to CMI. The case underlines the importance to take into account MALNS in patients presenting with overgrowth and CMI. Furthermore, we report a novel variant to improve diagnostic accuracy and genotype-phenotype correlation. Indeed, timely molecular diagnosis is essential to differentiate among overgrowth syndromes and to establish appropriate long-term clinical follow-up.

Oxidative stress is a central mechanism linking placental dysfunction, fetal injury, and neonatal disease, supporting the concept of a perinatal oxidative stress continuum that begins during abnormal placentation and may persist after birth. This narrative review explores the biological rationale and current experimental and clinical evidence for melatonin as a potential multitarget intervention across this continuum. Melatonin combines direct antioxidant activity with mitochondrial protection, anti-inflammatory and anti-apoptotic effects, and modulation of endogenous antioxidant defenses and redox homeostasis. Evidence from placental, fetal, and neonatal studies suggests potential protective effects in pregnancy complications and in neonatal conditions characterized by oxidative injury, including hypoxic–ischemic encephalopathy, bronchopulmonary dysplasia, necrotizing enterocolitis, neonatal sepsis, and retinopathy of prematurity. The review was informed by a non-systematic search of PubMed/MEDLINE, Scopus, Web of Science and Cochrane Library for relevant literature published up to 2026, including preclinical and clinical studies, systematic reviews, and relevant clinical trial registrations. Overall, although preclinical evidence is encouraging and early clinical studies suggest potential safety and biological activity, translation into clinical practice remains limited by heterogeneous study designs, dosing and timing regimens, and the lack of adequately powered randomized trials. Further research is needed to establish optimal dosing, timing, patient selection, pharmacokinetic–pharmacodynamic relationships, and long-term safety and efficacy.