Piero Pavone

Self-limited focal epilepsies in childhood (SELFEs), formerly referred to as “benign epilepsies in childhood”, constitute a heterogeneous group of epileptic conditions with onset predominantly in the neonatal, infantile, and childhood periods. A defining feature of these syndromes is that seizures arise without underlying structural, metabolic, or other demonstrable cerebral pathology, and the overall clinical trajectory is expected to be favorable, with seizures resolving spontaneously over time. Current nosological frameworks divide SELFEs into two broad categories according to age at onset: (a) neonatal and infantile forms, encompassing self-limited familial and non-familial neonatal, neonatal-infantile, and infantile epilepsies, genetic epilepsy with febrile seizures plus (GEFS+), and myoclonic epilepsy of infancy (MEI); and (b) childhood-onset forms, including self-limited epilepsy with centrotemporal spikes (SeLECTS), self-limited epilepsy with autonomic seizures (SeLEAS), childhood occipital visual epilepsy (COVE), and photosensitive occipital lobe epilepsy (POLE). Despite their historically “benign” label, there is no general agreement to include GEFS + and MEI among the group of SELFEs as both these conditions have been not classified as focal epilepsy in general. Accumulating evidence shows that a subset of affected children subsequently develop additional seizure types, cognitive deterioration, and behavioral or neuropsychiatric difficulties—outcomes that the word “benign” does not adequately communicate. Advances in molecular genetics have identified pathogenic variants affecting ion channels, synaptic transmission, and neuronal excitability, reshaping current understanding of disease mechanisms and phenotypic variability across these syndromes. This review highlights clinically relevant challenges in the diagnosis and management of SELFEs, critically examines emerging genotype–phenotype correlations, and provides evidence-based recommendations for antiseizure medication initiation and withdrawal tailored to individual syndrome characteristics and risk profiles.

Background: Moyamoya disease (MMD) refers to an isolated, usually bilateral vasculopathy of undetermined origin characterized by a chronic and progressive stenosis at the terminal end of the internal carotid artery, followed by collateralization of the cerebral vasculature at the base of the skull. Moyamoya syndrome (MMS) refers to the same Moyamoya angiographic findings when the anomaly is found in association to various inherited or acquired conditions. We report herewith the clinical and neuroradiological evaluation conducted on six children presenting with MMD and MMS together with a wide revision of the literature. Method: The medical records of patients with age < 18 years, admitted to the Pediatric Clinic of Catania University and the Pediatric Unit of the Cannizzaro Hospital Catania, Italy between 2006 and 2023 were analyzed. The children here reported were selected according to the results of neuroradiological investigations related to the Magnetic Resonance Imaging (MRI) diagnostic criteria for MMD 2021 Revised Version. Results: Six children with MMD were selected for this study: four children with genetic disorders including Neurofibromatosis type 1, Down syndrome, Marfan syndrome, partial chromosomal duplications: two observed during neuroradiological investigations for mycoplasma meningoencephalitis and for traumatic brain injury. Sex, age at diagnosis, type of vascular complications, presenting symptoms and signs, treatment, and short time clinical and neurological follow-up was reported. Conclusions: This study shows that MMD is a disorder presenting with a wide, heterogeneous clinical expression frequently associated with underlying congenital and acquired manifestations.

Background/Objectives: Cutaneous hypopigmentation is a common clinical sign observed in a variety of disorders. It may be congenital or acquired, localized or diffuse, and can range from benign to being associated with systemic conditions, including those affecting the central nervous system. Recognition of the key clinical features associated with each disorder is essential for accurate diagnosis and for differentiating one condition from another. Methods: PubMed, Embase, and Scopus databases were used to prepare a systematic review. Search terms were: “congenital”, “cutaneous”, “localized”, “diffuse”, “hypopigmentation” and “neurological disorders/signs”. The focus was on congenital cutaneous hypopigmentation, distinguishing between localized and diffuse presentations, with emphasis on neurological involvement. Peer-reviewed articles, case series, and original studies with neurological manifestations of the disease were reviewed. Cutaneous hypopigmentation disorders associated with diffuse cerebral involvement include syndromes such as Chediak–Higashi, Griscelli, Elejalde, Cross, Tietz albinism-deafness, Prader–Willi, Angelman, and several congenital metabolic disorders. In contrast, the ‘localized’ group comprises syndromes such as Waardenburg, Incontinentia pigmenti, and the phacomatoses, including hypomelanosis of Ito and tuberous sclerosis complex. Results: Overlapping phenotypes and genetic heterogeneity lead to diagnostic challenges and potential errors suggesting multiple specialists. The main clinical features of each disorder are discussed, with particular attention paid to neurological signs. A practical flowchart is provided to help distinguish between ‘diffuse’ and ‘localized’ forms with neurological involvement. Conclusions: Early identification of cutaneous features, followed by comprehensive clinical and instrumental evaluation, enables timely and accurate diagnosis, ultimately improving the clinical outcomes for affected children.

Background: Cerebral echinococcosis is a rare, potentially serious parasitic disease in children, that can lead to intracranial hypertension, focal neurological deficits, seizures, and severe complications. We conducted a systematic review and meta-analysis on diagnostic, therapeutic approaches, and outcomes in pediatric cerebral echinococcosis. Methods: A systematic search was performed on PubMed, Scopus, and Web of Science, selecting English studies on children (0–18 years). Studies describing clinical, imaging, surgical, pharmacological, and outcome data were eligible. Statistical analyses (Fisher’s exact and chi-square tests) were performed in R. Results: A total of 100 studies with 462 pediatric patients met the inclusion criteria. High-resolution imaging has largely replaced invasive diagnostics; MRI-based diagnosis correlated with better outcomes. Headaches, vomiting, papilledema, seizures, and hemiparesis were common. Surgical cysts’ removal remained the main therapy. Additional treatment with albendazole was associated with a higher probability of good outcome (p < 0.001). A greater number of cyst localizations was significantly associated with a worse prognosis (p < 0.001). Overall mortality was 8.9%, while approximately 2/3 of patients achieved a good outcome. Conclusions: Advances in non-invasive imaging, refinement of surgical technique, and targeted antiparasitic therapy improved outcomes. Nevertheless, heterogeneous reporting and the prevailing paucity of evidence limit definitive recommendations. Prospective multicenter studies are needed to refine treatment and develop pediatric-specific guidelines.

Choledochal cysts are rare cystic dilatations of the bile ducts, which are commonly found in children. We report two young patients affected by this anomaly. The clinical symptoms of the patients were minimal: mild pain localized in the upper-right quadrant and a serum increase in transaminases. Both of the patients were affected by type I choledochal cysts (B and A, respectively, according to the Todani classification). The diagnosis was made using abdominal ultrasound and then confirmed by MRI. We wish to emphasize the relevant contribution of ultrasound as an easy, reliable, rapid, low-cost modality for the diagnosis of choledochal cysts

Spinal muscular atrophies are a group of genetically and clinically heterogeneous neuromuscular disorders characterized by progressive loss of lower motor neurons, muscle weakness, and atrophy. Approximately 95% of spinal muscular atrophy cases are associated with a deletion of exons 7 and 8 in the survival motor neuron 1 ( SMN1 ) gene, resulting in insufficient levels of SMN protein. The remaining 5% of cases involve mutations in approximately 30 different genes, collectively referred to as non–SMN-related spinal muscular atrophies. These variants often present with distinct clinical features beyond typical spinal muscular atrophy symptoms, including arthrogryposis, extraocular movement abnormalities, brainstem signs, or cardiomyopathy. This review aims to provide an updated genetic landscape of non–SMN-linked spinal muscular atrophy phenotypes and propose a diagnostic protocol to assist clinicians in cases where SMN1 gene sequencing yields no conclusive findings.

Background/Objectives: Child abuse is a pervasive global issue with significant implications for the physical, emotional, and psychological well-being of victims. This review highlights the clinical, molecular, and therapeutic dimensions of child abuse, emphasizing its long-term impact and the need for interdisciplinary approaches. Early exposure to abuse activates the hypothalamic-pituitary-adrenal (HPA) axis, leading to chronic cortisol release and subsequent neuroplastic changes in brain regions such as the hippocampus, amygdala, and prefrontal cortex. These molecular alterations, including epigenetic modifications and inflammatory responses, contribute to the heightened risk of psychiatric disorders and chronic illnesses in survivors. Clinically, child abuse presents with diverse manifestations ranging from physical injuries to psychological and developmental disorders, making timely diagnosis challenging. Methods: A multidisciplinary approach involving thorough clinical evaluation, detailed histories, and collaboration with child protection services is essential for accurate diagnosis and effective intervention. Results: Recent advances in molecular biology have identified biomarkers, such as stress-related hormones and epigenetic changes, which provide novel insights into the physiological impact of abuse and potential targets for therapeutic intervention. Current treatment strategies prioritize the child’s safety, psychological well-being, and prevention of further abuse. Trauma-focused cognitive behavioral therapy and family-centered interventions are pivotal in promoting recovery and resilience. Conclusions: Emerging research focuses on integrating molecular findings with clinical practice, utilizing digital health tools, and leveraging big data to develop predictive models and personalized treatments. Interdisciplinary collaboration remains crucial to translating research into policy and practice, ultimately aiming to mitigate the impact of child abuse and improve outcomes for survivors.

In clinical practice, cutaneous disorders associated with neurologic involvement are relatively common, as both cutaneous and systems often originate from similar or synchronous embryonic mechanisms. Cutaneous hypopigmentation includes a wide range of disorders that can be categorized congenital and acquired based on the onset, and as localized and generalized types, depending on their skin distribution. Although cutaneous hypopigmentation may appear as a benign clinical manifestation, its association with neurologic or others systemic involvement can indicate more severe underlying disorders. This literature review focuses on congenital localized types of cutaneous hypopigmentation that are classically linked to neurologic impairment. Four congenital disorders were highlighted for their characteristic presentation of localized cutaneous hypopigmentation and neurologic involvement: Waardenburg syndrome, incontinentia pigmenti, hypomelanosis of Ito, and tuberous sclerosis complex. Clinical and genetic findings for these conditions were reviewed and updated, with an emphasis on the cutaneous manifestations, associated systemic anomalies, and neurologic involvement. Established diagnostic criteria and emerging trends in therapeutic approaches were also explored. Promising results, particularly the use of mammalian target of rapamycin (mTOR) in the treatment of tuberous sclerosis complex, highlight the potential for improved outcomes. Early diagnosis, rapid treatment, and innovative therapies may play a crucial role in positively altering the clinical course of these disorders.

Polydactyly and syndactyly, which are commonly encountered congenital limb deformities, rarely occur together and are linked with significant genetic mutations. This report sheds light on a unique co-presentation involving mutations in both the GLI3 and TBX5 genes, offering a deeper understanding of the genetic interactions that may influence limb development. This case report is important to increase our knowledge on genetic bases of limb malformations. We report the case of an 8-month-old boy, born to non-consanguineous parents, presenting with both polydactyly and syndactyly in his limbs, in particular, complete syndactyly between the third to fifth fingers and post-axial polydactyly of the feet. His father showed a similar phenotype. Genetic testing identified a pathogenic heterozygous variant in the GLI3 gene (c .3762 T > A, p.(Tyr1254 *)) and a variant of uncertain significance in the TBX5 gene (c .1063 C>T, p.(Arg355Cys)). This case highlights the complex nature of diagnosing and managing congenital limb deformities driven by genetic factors. It underscores the critical importance of comprehensive genetic testing in determining the etiology of limb malformations. The GLI3 variant, classified according to ACMG guidelines as a class IV mutation, likely results in a truncated protein due to a premature stop codon, confirmed by family segregation analysis indicating its paternal origin, suggesting autosomal dominant inheritance. Notably, the TBX5 gene variant, often associated with Holt-Oram syndrome—which is characterized by only hand skeletal anomalies and early-onset atrial fibrillation—suggests a risk of developing cardiac issues that are not currently present but may emerge as the child grows. This potential for evolving clinical manifestations necessitates vigilant long-term monitoring and may influence future medical management and therapeutic approaches.

Epileptic and developmental encephalopathies (EDEs) are a group of severe, genetically various neurological conditions characterized by early-onset seizures and developmental impairments. Recent advances in molecular genetics and diagnostic tools have led to the development of precision therapies, aiming to address the deep causes of these disorders. Examples, such as pyridoxine for pyridoxine-dependent epilepsy and the ketogenic diet for GLUT1 deficiency syndrome illustrate the potential of presumed tailored treatments. However, challenges persist, as current therapies often fail to fully mitigate neurodevelopmental impairments. Moreover, traditional phenotype-based management strategies, while effective for seizure control, do not address the root causes of these disorders, underscoring the limitations of existing approaches. This article explores the evolving landscape of precision medicine in EDEs, emphasizing the importance of genetic insights in therapy design and the need for a multidisciplinary approach. It also highlights the barriers to widespread implementation, including diagnostic delays, accessibility, and a lack of robust clinical evidence. To fully realize the potential of precision therapies, comprehensive genetic integration, innovation in treatment, and global collaboration are essential. The future of EDE management lies in therapies that not only control symptoms but also correct genetic and molecular defects, offering a more effective, individualized approach to care.