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Background: Crisponi/cold-induced sweating syndrome (CS/CISS) is a rare autosomal recessive disorder characterized by severe neonatal manifestations including paroxysmal muscle contractions, tendency for hyperthermia, and feeding and swallowing difficulties with high neonatal mortality. Pathogenic variants in the Cytokine Receptor-Like Factor 1 (CRLF1) gene have been associated with CS/CISS. These variants result in a loss of function of the encoded protein, which disrupts the formation of a functional heterodimer with Cardiotrophin-Like Cytokine Factor 1 (CLCF1). This complex is essential for the development of autonomic and sensory nervous systems, as well as for bone remodeling. We report two patients affected by CS harboring pathogenic variants in the CRLF1 gene. Methods—case reports: The first patient was diagnosed postnatally, presenting with non-epileptic paroxysmal events characterized by opisthotonus and orofacial contractions. He survived beyond infancy, later developing scoliosis and persistent episodes of hyperthermia. In the second patient, a prenatal ultrasound at 20 weeks of gestation revealed bilateral camptodactyly, also referred to as the ‘horn’s sign’, raising early suspicion of CS. The diagnosis was subsequently confirmed both clinically and genetically. After birth, the infant developed severe dysphagia, apnea, and paroxysmal events not associated with epileptiform activity on EEG. Sanger sequencing identified a homozygous c.708_709delinsT frameshift variant in the CRLF1 gene. The patient died at 30 days of age due to respiratory failure. Results and conclusions: With this manuscript, we aim to further delineate the phenotypic spectrum of this rare condition and propose the ‘horn’s sign’ as a targeted prenatal marker for early diagnosis in populations with known founder mutations or familial risk factors.

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.

PurposePhelan–McDermid syndrome is a rare genetic disorder caused by Shank3 protein deficiency, resulting from rearrangements of chromosome 22q13.3 in the region containing the SHANK3 gene. Shank proteins serve as pivotal scaffolding proteins in the postsynaptic density of excitatory synapses in the mammalian brain. Clinical features of Phelan–McDermid syndrome include global developmental delay, hypotonia, impaired language, dysmorphic features, sleep disturbances, and epileptic seizures. Brain magnetic resonance imaging (MRI) findings are typically limited and nonspecific. To our knowledge, no previous report has described an evolving unilateral thalamic focal lesion, its biopsy, and concomitant white matter changes as demonstrated by diffusion tensor imaging (DTI).MethodsA 7-year clinical and MRI follow-up was conducted. At age 5, the patient exhibited emerging symptoms, including attention deficit and language impairment, prompting an array-comparative genomic hybridization analysis. MRI examinations included standard morphological sequences as well as advanced techniques such as DTI, spectroscopy, dynamic contrast enhancement, and dynamic susceptibility contrast perfusion imaging. A biopsy of the lesion was performed, and fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) of various brain structures were analyzed.ResultsMagnetic resonance spectroscopy revealed alterations in the ratios of choline/creatine, myo-inositol/creatine, and N-acetylaspartate/creatine in the evolving right thalamic lesion. Significant differences in DTI parameters were observed only in the right posterior thalamic radiation. Histopathological analysis of the biopsy did not demonstrate any malignant cellular elements.ConclusionsIn Phelan–McDermid syndrome, a unilateral, evolving focal thalamic lesion has not been previously described. Effective management of this condition necessitates comprehensive data collection to gain unique insights into this complex and rare syndrome.

The paper discusses some issues which confront the interpreter of the opening lines of the Prognosticon, and dwells especially upon the interpretation of δοϰέει μοι and of προλέγων. It argues, first, that the former conveys not a mere opinion but rather a strongly upheld conviction which is to be demonstrated, and that the formula is typical of ‘scientific’ texts of the 5th cent. B.C.; second, that the meaning of the verb προλέγειν, and the value of προ- with verbs of saying, should be compared rather with older texts, from Homer to Herodotus, than with other works of the Corpus Hippocraticum, and that the closest parallel is perhaps that of προ-φήτηϲ, as suggested by J. Wackernagel. Here the prefix προ- indicates a statement made openly in front of an audience. It is also argued that προ- in connection with verbs of saying in Homer, esp. in Od. I 37, may not have not the sense of prediction.

The Aldine edition of Galen, awaited for more than 25 years, was perhaps the most risky enterprise in the whole history of the publishing house, and it almost brought Aldus' heirs to bankruptcy. Although the editors were among the most renowned specialists of the time, the edition was harshly criticized by one former friend and collaborator of Aldus, Desiderius Erasmus of Rotterdam. Why? Was the edition so bad, were the manuscripts on which the edition was based responsible for its quality? Or were there other reasons for Erasmus' complaint? This paper tries to give some hints in order to answer such questions, arguing that the role of Erasmus in the assessment of the value of the edition should take us into Aldus' house in the period of the late fifteenth and early sixteenth century, and into the political and religious debate of the time.

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.

Recurrent headaches, encompassing migraine and tension-type headaches, represent prevalent conditions affecting individuals across different age groups, exerting a substantial influence on daily functioning and quality of life. Headaches serve as common manifestations of underlying health issues. Among these, celiac disease, an autoimmune disorder activated by gluten consumption, has emerged as a noteworthy concern. Recent research indicates a correlation between celiac disease and heightened susceptibility to headaches, particularly migraines. Celiac disease (CD) is an immune-mediated systemic, widespread disorder presenting a heterogeneous constellation of symptoms with a relatively easy diagnosis and therapy. Among signs and symptoms exhibited in celiac disease patients, headache is one of the most common neurological issues addressed among both adults and children. Headache disorders and CD are highly prevalent in the general population; for this reason, any causal association between these conditions and the role of a gluten-free diet (GFD) has been debated. The aim of this manuscript is to review the current scientific literature regarding the potential association between CD and headaches and the beneficial effects of a GFD. Among the various authors, in our opinion, the current state of the evidence suggests a significant role for the early screening of CD during the initial diagnosis of recurrent headaches, either in adults or children.

Behçet’s Disease (BD), also recognized as Behçet Syndrome, manifests uniquely in pediatric populations as Pediatric Behçet’s Disease (PBD), characterized by multisystemic inflammatory symptoms including recurrent oral and genital aphthae, and diverse ocular, vascular, and neurological involvements. This review elucidates the prevalence, burden, and management strategies of headaches in children with PBD, focusing on both primary headaches, such as migraine and tension-type headaches, and secondary headaches linked to systemic disease manifestations. It explores the pathophysiological underpinnings specific to PBD-related headaches and discusses the intricate relationship between systemic inflammatory processes and neurological symptoms. By examining the literature from 2004 to 2024, this study highlights the high frequency of headache in PBD patients, underscoring its diagnostic and clinical significance. We aim to provide a detailed understanding of headache management in PBD, emphasizing tailored therapeutic strategies that address the unique challenges faced by this patient population. This review also underscores the importance of comprehensive clinical evaluations to optimize outcomes and mitigate long-term sequelae, proposing that awareness and understanding of headache in PBD can significantly enhance both diagnosis and management.