Search Results (1,012)

Background: Subacute sclerosing panencephalitis (SSPE) is a chronic, progressive disease of the central nervous system (CNS) caused by persistent infection at this level with the wild measles virus. Its incidence is negatively correlated with measles vaccination coverage. The pathogenesis isn’t fully understood, but infection before the age of 2 is an important risk factor. Methods: This is a retrospective observational study conducted at the Louis Turcanu Emergency Children’s Hospital in Timisoara, Romania, based on the analysis of the medical records of patients diagnosed with SSPE between January 2021 and December 2025. We analyzed demographic and epidemiological factors, clinical and paraclinical findings, management, and outcomes. Results: Seven children were diagnosed during the study period, with a mean age of 8.4 years (range 7–11 years). Six of them had contracted measles during their first year of life, and one at the age of four. The mean latency period was 7.1 years (range 4–9 years). On admission, all patients presented symptoms consistent with clinical stage II, with periodic slow wave discharges on electroencephalogram (EEG). The initial brain Magnetic Resonance Imaging (MRI) was normal in two cases, while revealing varied abnormalities in all others. Despite complex treatment with isoprinosine and anticonvulsants, progressive cognitive and neurological deterioration continued in all patients. Conclusions: SSPE is a rare but serious, debilitating disease despite its complex, multidisciplinary care. Following a 10-year SSPE-free period, the reappearance of these pediatric cases constitutes a public health alert, unequivocally demonstrating the importance of measles vaccination. Full article

Dermatomyositis (DM) is a rare, autoimmune inflammatory myopathy characterized by a heterogeneous clinical course and complex etiopathogenesis. Although classically defined by the coexistence of muscle inflammation and distinctive skin lesions, DM frequently presents as a systemic disease, and, in some patients, cutaneous manifestations may precede muscle involvement or represent the sole clinical feature. The spectrum of skin lesions in DM is broad and includes pathognomonic, characteristic, rare, or atypical manifestations, ranging from classic Gottron’s sign and heliotrope rash to uncommon subtypes such as vesiculobullous dermatomyositis, Wong-type dermatomyositis, or flagellate dermatitis. Particular cutaneous phenotypes often correlate with distinct clinical subtypes, autoantibody profiles, systemic involvement, and prognosis. The diversity of dermatological presentations and their resemblance to other dermatoses may delay accurate diagnosis, especially in amyopathic and hypomyopathic forms of the disease. The aim of this review is to comprehensively discuss the wide spectrum of cutaneous manifestations of dermatomyositis, emphasize less recognized and rare dermatological clinical presentations, and highlight their diagnostic and prognostic significance. However, histopathological examination may support the diagnostic process in challenging cases. Early identification of characteristic skin lesions remains crucial for prompt diagnosis, appropriate screening for systemic complications and malignancy, and optimal management. Close interdisciplinary cooperation among dermatologists, rheumatologists, and other specialists is essential to ensure accurate diagnosis and improve outcomes in patients with dermatomyositis. Full article

Background. Autoimmune sclerosing cholangitis (ASC) is a rare clinical entity characterized by overlapping features of autoimmune hepatitis and primary sclerosing cholangitis. It predominantly affects pediatric patients. Therapeutic management is often complex, requiring a multidisciplinary and individualized approach, especially in the context of associated autoimmune diseases. Case presentation. We present the case of a female patient diagnosed at the age of 10 with ASC, for which immunosuppressive therapy with prednisone, azathioprine (AZA), and ursodeoxycholic acid (UDCA) was initiated, with an initially favorable course. One year later, following a Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infection, the patient experienced reactivation of liver disease and subsequently developed ulcerative pancolitis (UC), for which 5-aminosalicylic acid (5-ASA) therapy was initiated. Due to repeated hepatic flares and/or colitis relapses, therapy was escalated successively to mycophenolate mofetil, tacrolimus, and eventually infliximab (IFX). Despite treatment, the liver disease progressed, culminating in liver cirrhosis. Our patient developed portal hypertension and esophageal varices, with two episodes of upper gastrointestinal bleeding requiring endoscopic band ligation. At the age of 14, the patient developed recurrent episodes of non-infectious ulcerative stomatitis. Biopsy of the lesions revealed non-specific chronic inflammation, unrelated to colitis activity (confirmed microscopic remission of UC). By exclusion, an adverse drug reaction was suspected, with AZA being the most likely cause. Following its discontinuation, the lesions resolved. Beyond the physiological and therapeutic aspects, the patient displays marked emotional fragility due to prolonged and repeated hospitalizations (18 out of 60 months), which have impacted treatment adherence. Conclusions. This case highlights the complexity of managing pediatric patients with multiple autoimmune diseases. The necessary combination of immunosuppressive therapies may lead to significant adverse effects and further complicate disease progression. Moreover, psychological components play a crucial role in treatment compliance and therapeutic success, emphasizing the need for an integrated approach that includes specialized psychological support. Full article

Pulmonary hypertension is a progressive syndrome characterised by pulmonary vascular dysfunction, inflammation, maladaptive remodelling, and progressive right-ventricular strain. Translational progress remains limited because experimental models reproduce only selected aspects of the complexity of human disease. This narrative review evaluates naturally occurring canine disease as a comparative and spontaneous model of human pulmonary hypertension within a One Health framework. To achieve this, we synthesise recent human and veterinary literature, international consensus statements, and key registry and imaging studies. We outline current human definitions and diagnostic pathways based on right-heart catheterisation, together with the veterinary probability-based approach centred on echocardiography; compare epidemiology across species; and summarise contemporary mechanisms spanning vascular dysfunction, immune and metabolic signalling, and right-ventricular adaptation. We then examine canine conditions that parallel major human pulmonary hypertension phenotypes, including left-heart disease due to myxomatous mitral valve degeneration, fibrotic interstitial lung disease in West Highland White Terriers, sleep-related airway obstruction in brachycephalic breeds, and rare venous and capillary disorders. When combined, these spontaneous models provide opportunities to investigate disease-modifying techniques other than vasodilation and allow for the longitudinal, real-world evaluation of imaging, functional assessments, and circulating biomarkers. To improve care for both veterinary and human patients, we conclude by outlining priorities for mechanism-based clinical trials, shared outcome measures, prospective registries and biobanks, and harmonised definitions. Full article

Cardiomyopathies comprise a heterogeneous group of myocardial disorders characterized by intrinsic structural and functional abnormalities that are not explained by secondary cardiovascular or systemic conditions. Although genetically determined cardiomyopathies have traditionally been interpreted within a Mendelian framework, this paradigm does not fully account for the marked variability in penetrance, expressivity, and clinical outcomes observed in affected individuals. Increasing evidence indicates that disease manifestation arises from a complex interplay between rare pathogenic variants, common genetic variation, epigenetic regulation, environmental factors, and stochastic molecular processes. This review focuses on hypertrophic and dilated cardiomyopathies, the most prevalent and extensively studied forms, and critically examines how epigenetic mechanisms, genetic modifiers, and molecular noise challenge classical pathophysiology concepts. We discuss how these factors contribute to phenotypic heterogeneity and influence disease severity, progression, and therapeutic response. Recognition of this multilayered genetic architecture has important clinical implications, supporting more refined risk stratification, improved genetic counseling, and the development of personalized and potentially variant-agnostic therapeutic strategies. Full article

Background and Clinical Significance: Mucopolysaccharidosis type VI is a rare lysosomal storage disorder due to arylsulfatase B enzyme deficiency, leading to progressive multisystem disease and complex airway. Acute respiratory infections can precipitate airway embarrassment. A structured treatment guideline is currently lacking. We present a 7-year-old MPS VI male with respiratory distress, highlighting the challenges in management. Case Presentation: Case review focusing on clinical presentation, imaging findings, and multidisciplinary decision-making during acute deterioration. A child diagnosed with MPS VI at the age of 3.5 years old, due to low arylsulfatase B enzyme activity and homozygous for c.275C>A p.(Thr92Lys) variant in the ARSB gene. At 7 years of age, he showed the signs of dyspnoea, increased respiratory effort with bilateral crepitations, and noisy breathing. Initial management included facemask oxygen, nebulised adrenaline, corticosteroids, and bronchodilators. Computer tomography scan of the neck and chest showed a complex upper airway, multiple tracheal narrowing, tortuosity, and an extra loop of truncus brachiocephalicus from the arch of the aorta. Potential interventions carried substantial risks due to abnormal airway and multisystem disease. Following extensive multidisciplinary discussion after careful consideration of the significant risks associated with invasive airway interventions, a shared decision was reached with the family to adopt a comfort-focused palliative care approach. Despite the best supportive care, the child unfortunately passed away after 3 months. The family was involved in every decision process and was fully supported. Conclusions: MPS VI is associated with complex airways and multisystem disease. Multidisciplinary decision-making with family is critical to safe and appropriate care. The rarity of the disease, lack of guidelines, complex airways, and multiple comorbidities make management challenging. Full article

Background: X-linked immunodeficiency with magnesium defect, Epstein–Barr virus (EBV) infection, and neoplasia (XMEN) disease is a rare inborn error of immunity caused by loss-of-function mutations in MAGT1, leading to impaired N-linked glycosylation. Although chronic EBV viremia is a hallmark of XMEN disease, the mechanisms underlying its marked clinical heterogeneity remain poorly understood. Methods: We performed an in-depth clinical, immunological, and genetic characterization of two siblings carrying a pathogenic MAGT1 variant (c.369_370insCC; p.Gly124fs), validated and deposited in ClinVar (SCV007293792). Assessments included whole-exome sequencing, multiparametric flow cytometry focusing on NKG2D expression, and longitudinal clinical follow-up. Results: Despite shared absence of NKG2D expression, the siblings exhibited strikingly divergent phenotypes. One sibling developed progressive neurodegeneration with central nervous system atrophy. The other presented with a complex immuno-hematologic phenotype, including EBV-positive Hodgkin lymphoma, recurrent autoimmune cytopenias, and lymphoma-associated thrombotic microangiopathy, representing a novel clinical association in XMEN disease. Comparative immunophenotyping revealed shared defects in B-cell maturation but distinct T-cell differentiation patterns. To contextualize neurological variability, we propose a descriptive, hypothesis-generating three-category conceptual classification comprising early-onset neurodevelopmental forms, adult-onset neurodegenerative manifestations, and secondary immune-mediated or vascular involvement of the nervous system. Conclusions: These findings demonstrate profound intrafamilial heterogeneity in XMEN disease and suggest a model in which modifier-sensitive factors influence organ-specific disease expression. The observation of lymphoma-associated thrombotic microangiopathy and the proposed descriptive neurological classification provide a conceptual framework that may help guide tailored, multidisciplinary surveillance beyond the primary genetic defect. Full article

Cystic fibrosis (CF) is an autosomal recessive disorder caused by pathogenic variants in the cystic fibrosis transmembrane conductance regulator (CFTR) gene and primarily affects the respiratory, digestive, and reproductive systems. Globally, CF is most prevalent among European ancestry, with an incidence rate of approximately 1/2500 to 1/3500. In China, the incidence is about 1/128,000. However, CF is not extremely rare in the Chinese population; rather, its prevalence is significantly underestimated. The CFTR mutation spectrum in China is highly unique, characterized by an extremely low frequency of p.Phe508del. Instead, region-specific mutations such as p.Gly970Asp, p.Ile1023Arg, and p.Arg553Ter predominate, alongside a high proportion of splicing variants and complex rearrangements. A significant proportion of Chinese CF patients primarily present with CF-like phenotypes within the CF-related disease spectrum (such as congenital bilateral absence of the vas deferens and pseudo-Bartter syndrome), exhibiting overlapping features with classic CF but lacking typical respiratory-dominant symptoms. This review examines how these atypical symptoms deviate from the diagnostic pathways established in Western countries. Establishing localised data and functional platforms is a prerequisite for achieving precision medicine. Achieving a transition from symptom-focused care to defect-correcting therapy will require coordinated multicenter collaboration and sustained infrastructure development. Full article

Hypertrophic cardiomyopathy (HCM), the most common inherited cardiomyopathy, represents a paradigmatic condition for precision cardiovascular medicine. Once regarded as a monogenic autosomal dominant disorder driven by rare sarcomeric variants, HCM is now recognized as a genetically complex disease characterized by incomplete penetrance, variable expressivity, and heterogeneous clinical trajectories. This review summarizes current evidence on the evolving genetic architecture of HCM, emphasizing the predominant role of definitively validated sarcomeric genes, particularly MYBPC3 and MYH7, and the clinical value of gene panel expansion. Phenotypic variability reflects interactions among variant classes, gene-specific mechanisms, and modifying factors. Differences between missense and truncating variants, haploinsufficiency and poison-peptide effects, allelic imbalance, and age-dependent penetrance contribute to diverse disease expression. Emerging data further support oligogenic inheritance and polygenic modulation, with genome-wide association studies and polygenic risk scores elucidating their contribution to disease susceptibility and variability, especially in genotype-negative patients and carriers of rare variants. We also address genes with emerging evidence and underrecognized pathogenic mechanisms, including deep intronic and splice-altering variants that may explain part of the missing heritability. The importance of distinguishing phenocopies is highlighted, advocating for phenotype-anchored diagnostic pathways integrating clinical assessment, multimodality imaging, and targeted genetic testing. Overall, contemporary data support a targeted, gene-validity-driven approach to genetic testing, where molecular findings primarily inform diagnosis and cascade screening, while risk stratification remains phenotype-led and longitudinal. Future progress will depend on integrative models combining rare variants, polygenic background, imaging, and biomarkers to translate genetic complexity into actionable precision care. Full article

Background/Objectives: Nasal reconstruction after non-melanoma skin cancer excision remains challenging due to the need to restore both nasal form and function while ensuring oncologic safety. Beyond surgical success, patient-reported outcomes are increasingly recognized as essential components of postoperative evaluation. The aim of this study was to retrospectively assess oncologic, surgical, and patient-reported outcomes in a real-world cohort of patients undergoing nasal reconstruction following skin cancer excision. Methods: A retrospective cohort study was conducted on 60 patients treated at the University Hospital “G. Martino” (Messina, Italy) between 2019 and 2022. Reconstructive techniques included direct closure, full-thickness skin grafts, local or regional flaps. Oncologic outcomes and postoperative complications were recorded during routine follow-up. Patient-reported outcomes were evaluated using a semi-structured PROM-derived questionnaire adapted from the FACE-Q Skin Cancer Module, NOSE, and SCaFF domains. Internal consistency of the questionnaire was assessed using Cronbach’s alpha. Results: Basal cell carcinoma was the most frequent diagnosis (55%), and the nasal ala, dorsum, and tip were the most commonly involved subunits. Local flaps were performed in 42% of cases. No histologically confirmed recurrences were observed in the flap-reconstructed subgroup during the available follow-up, whereas recurrences were observed in patients managed with non-flap reconstructive approaches. Postoperative complications were uncommon; however, one fatal infectious event occurred in a high-risk patient undergoing complex reconstruction for recurrent disease. The PROM-derived questionnaire demonstrated good internal consistency (Cronbach’s α = 0.82). Functional symptoms were rare, with 93% of patients reporting no snoring or nasal obstruction and 97% reporting no nasal voice alteration. Aesthetic satisfaction was rated as satisfactory or very satisfactory by 63% of patients, and social relationships were not affected in 85%. Patient-perceived recurrence risk (38%) exceeded histologically confirmed recurrence (15%). Conclusions: In this elderly real-world cohort, flap-based nasal reconstruction was associated with generally favorable patient-centered outcomes and low complication rates. The discrepancy between patient-perceived and confirmed recurrence highlights the role of oncologic anxiety. Prospective studies using fully validated PROMs are warranted to support standardized outcome comparison and guide clinical decision-making. Full article

Soft-tissue sarcomas (STSs) comprise a rare, heterogeneous group of mesenchymal malignancies in which histologic grade remains the strongest determinant of outcome, metastatic risk, and therapeutic strategy. Intermediate/high-grade STSs exhibit a pronounced propensity for early distant relapse, yet growing evidence indicates that metastatic behaviour is not uniform. Within this spectrum, an oligometastatic phenotype, characterised by a limited number of metastases, often confined to the lung, has emerged as a clinically and biologically distinct state associated with more indolent metastatic kinetics and improved survival when treated with aggressive local interventions. However, the criteria that define true oligometastatic STSs remain unsettled, and prospective evidence is lacking. Emerging molecular and immunological correlates provide a potential framework for biological triage. Low genomic complexity (low-risk CINSARC), a B-cell/TLS-rich tumour microenvironment, high immune-cytotoxic signatures, and persistently low or undetectable circulating tumour DNA (ctDNA) are each linked to reduced metastatic competence and may underpin oligometastatic trajectories. Conversely, high chromosomal instability, immunosuppressive microenvironments, and elevated ctDNA levels align with covertly polymetastatic biology despite limited radiographic disease. In this context, artificial intelligence and machinelearning approaches applied to computational genomics, immune profiling, imaging, and liquid-biopsy data offer a powerful strategy to integrate these multi-dimensional features and refine predictions of metastatic behaviour in STS. Oligometastatic STS therefore represents a biologically definable subset amenable to multimodal management integrating local ablative therapies, systemic agents, and immune-based strategies. Prospective, biomarker-stratified trials are needed to validate selection frameworks and optimise treatment sequencing in this evolving therapeutic space. Full article

Next-generation sequencing (NGS) and antisense oligonucleotide (ASO) technologies are converging to transform the diagnosis and treatment of rare monogenic disorders. NGS enables comprehensive, single-test molecular diagnoses through targeted panels, whole-exome sequencing, and whole-genome sequencing, which together reveal pathogenic variants across coding, intronic, and structural domains. Integration with transcriptomic analyses, including RNA sequencing, further refines genotype–phenotype correlations and identifies splicing aberrations amenable to correction by ASOs. Therapeutic advances now span RNase H1-dependent gapmers for transcript knockdown, splice-modulating phosphorodiamidate morpholino oligomers (PMOs), and peptide/antibody-conjugated PMOs that enhance muscle and cardiac delivery. These platforms underpin the rise in N-of-1 ASO therapies—customized drugs developed for individual patients with unique pathogenic variants. Landmark cases such as Milasen and Atipeksen illustrate the clinical feasibility and ethical complexities of personalized RNA therapeutics, while updated FDA guidance supports expedited, patient-specific investigational pathways. Despite progress, challenges persist in delivery efficiency, long-term efficacy, and equitable access. Emerging approaches—including long-read sequencing, AI-driven oligo design, and improved delivery—promise to extend ASO precision and reach. This review synthesizes current advances linking genomic diagnosis to individualized RNA-targeted interventions, outlining how integrated NGS-ASO pipelines are reshaping the therapeutic landscape for rare genetic diseases. Full article

Background and Clinical Significance: Pulmonary hypertension (PH) is a recognized complication of chronic liver disease, most commonly manifesting as portopulmonary hypertension (POHP) prior to liver transplantation. While the natural history and management of pre-transplant PH are well described, the development of de novo pulmonary arterial hypertension (PAH) following liver transplantation remains exceedingly rare and poorly understood. In such cases, establishing true causality is challenging, and alternative explanations—including previously unrecognized or masked disease—must be carefully considered. This entity poses significant diagnostic and therapeutic challenges and may adversely affect post-transplant outcomes if not promptly recognized and treated. Case Presentation: We report the case of a 46-year-old man with end-stage liver disease secondary to alcohol use who underwent deceased donor liver transplantation without preoperative evidence of PH. His pre-transplant evaluation revealed preserved biventricular function and no measurable PH. Eight days postoperatively, he was readmitted with acute dyspnea, hypoxemia, and signs of right ventricular failure. Transthoracic echocardiography demonstrated severe right ventricular dilation and dysfunction with markedly elevated pulmonary artery systolic pressure. Right heart catheterization confirmed severe PAH. Secondary causes of PH were excluded. The patient was initiated on sildenafil and continuous intravenous epoprostenol, resulting in clinical, echocardiographic, and hemodynamic improvement. Subsequent follow-up demonstrated sustained response to therapy despite concurrent progression of coronary artery disease requiring complex percutaneous intervention. Conclusions: This case highlights a rare presentation of severe PAH occurring shortly after liver transplantation, in the absence of documented pre-transplant PH. While a causal relationship cannot be definitively established, the temporal association raises important clinical considerations. It underscores the need for heightened clinical vigilance for pulmonary vascular disease in post-transplant patients presenting with cardiopulmonary symptoms. Further research is warranted to elucidate the underlying mechanisms, risk factors, and optimal management strategies for PAH diagnosed after liver transplantation. Full article

Background: Senior–Loken syndrome (SLS) is a rare autosomal recessive ciliopathy classically defined by the concurrence of nephronophthisis, frequently progressing to end-stage renal disease (ESRD), and retinal dystrophy, most commonly presenting as retinitis pigmentosa (RP). Given its phenotypic overlap with other renal–retinal syndromes, establishing a definitive diagnosis necessitates integrated clinical evaluation and molecular confirmation. Case Presentation: A 28-year-old Chinese female presented with a two-month history of binocular floaters. Her medical history was significant for ESRD of five years’ duration, managed with maintenance hemodialysis. Ophthalmic assessment revealed retinal pigment mottling along the inferior temporal arcades and generalized arterial attenuation. Spectral-domain optical coherence tomography demonstrated outer retinal thinning with loss of the ellipsoid zone at corresponding locations. Perimetry confirmed visual field constriction, and full-field electroretinography showed severely reduced rod- and cone-mediated responses. Genetic testing was performed and a pathogenic variant in the NPHP1 gene was identified. Segregation studies confirmed both parents as heterozygous carriers, consistent with autosomal recessive inheritance. Collectively, these findings established a diagnosis of SLS. Conclusions: This case reinforces that SLS should be considered in the differential diagnosis of any young patient exhibiting RP alongside chronic kidney disease, particularly in the setting of early-onset ESRD. It also illustrates the essential role of a coordinated, multidisciplinary approach—encompassing nephrology, ophthalmology, and genetics—in diagnosing complex ciliopathies. Genetic confirmation not only validates the clinical diagnosis but also provides a foundation for family counseling, prognostic stratification, and future eligibility for gene-specific therapeutic trials. Full article

This narrative review summarizes current evidence on the molecular and cellular effects of low-dose methotrexate (LD-MTX) on bone tissue. In addition, it critically examines the limited and heterogeneous data on LD-MTX-associated osteopathy, a rare and incompletely understood condition that may be underrecognized in clinical practice. Finally, the review highlights key knowledge gaps and outlines future research directions aimed at improving diagnosis, management, and prevention. In total, 451 relevant articles were retrieved, and 71 studies were included in our review. Methotrexate (MTX) has been shown to prevent bone loss associated with inflammatory rheumatic diseases, primarily through its anti-inflammatory properties. However, current evidence highlights a variety of negative effects on bone associated with LD-MTX therapy, including osteoblast dysfunction, increased osteoclastogenesis, and endothelial damage. Collectively, these effects may result in deterioration of microarchitecture, impaired bone healing and insufficiency fractures. Despite the long and successful use of MTX in rheumatology, our knowledge of its effects on bone and awareness of LD-MTX osteopathy remain limited, potentially leading to delayed or missed diagnoses. Recent clinical studies highlight the potential underestimation of this condition and emphasize the need for further research to establish clear diagnostic criteria and treatment guidelines, as well as to achieve a more comprehensive understanding of the complex pathophysiology underlying LD-MTX osteopathy. Full article