Search Results (94)

Background: Congenital insensitivity to pain with anhidrosis (CIPA) is a rare genetic disorder, often leading to injuries and serious infections. In 2018, we established a multidisciplinary clinic (MDC) to provide structured, proactive care. We assessed the MDC’s impact on hospitalizations, surgeries, and infection rates. Methods: A retrospective study of genetically confirmed CIPA patients, treated from 2014 to 2024. Data from electronic medical records were compared between the pre-MDC (2014–2017) and post-MDC (2018–2024) periods. The core MDC team includes an infectious disease specialist, orthopedic surgeon, and nurses. The patients are stratified according to their carriage of resistant organisms and are managed using strict infection control measures. Follow-ups are scheduled routinely or as needed. Treatment is guided by clinical findings and culture results. Results: A total of 59 patients were included in the study. The baseline age did not differ significantly between the two periods. Hospitalization rates declined by 30.7% (from 57.7 to 40.0 per 1000 days), and clinic visits decreased by 42.9% (25.5 to 14.6). Overall surgical rates remained stable (2.8 to 2.7), with a 61.9% decrease in eye surgeries and a 130.5% increase in elective tooth extractions. Infection rates increased by 52% (from 6.6 to 10.1 per 1000 days). Conclusions: The implementation of the MDC bundle led to reduced hospitalizations, clinic visits, and eye surgeries, alongside the increased use of elective tooth extractions and culture testing. Closer monitoring and early infection management contributed to fewer severe complications. These findings support the value of structured, proactive multidisciplinary care in improving outcomes for children with CIPA. Full article

Smith–Lemli–Opitz syndrome (SLOS) is a rare, autosomal recessive genetic disorder caused by mutations in the DHCR7 gene, which encodes the enzyme responsible for the final step in cholesterol biosynthesis. Impaired enzyme function leads to cholesterol deficiency, affecting the development and function of the entire organism. The accumulation of cholesterol precursors enhances the formation of oxysterols, which are involved in the pathomechanism of neurological, ophthalmological, and vascular changes in patients. This review analyzes 53 studies published between 2020 and 2025 on the molecular mechanisms underlying the clinical features of SLOS, including cholesterol deficiency, oxysterol accumulation, and the latest diagnostic methods, including LC-MS/MS chromatography and biomarkers such as GFAP for monitoring disease progression. MRI is discussed as a supportive tool for neuroimaging, along with advances in prenatal diagnostics, such as the detection of cholesterol precursors in neonatal hair. Therapeutic options are also reviewed, with particular emphasis on cholesterol supplementation, cholic acid, and experimental treatments such as vitamin E supplementation, statin therapy, gene therapy, and liver transplantation. Current research indicates that expanding knowledge in this area not only improves patient prognosis but also provides hope for the development of effective therapies in the future. Full article

Celiac disease (CD) is a chronic and immune-mediated disorder triggered by the ingestion of gluten in some genetically predisposed individuals. CD can be associated with extra-gastrointestinal manifestations and diseases affecting several organs. In this review, the aim is to analyze and discuss the pancreatic alterations and/or comorbidities that could arise in the context of pediatric CD. Exocrine pancreatic insufficiency (EPI) can be observed in a variable fraction (up to 30%) of children diagnosed with CD at the diagnosis; indeed, it usually resolves after the implementation of a gluten-free diet (GFD). The main pathophysiological mechanisms of EPI could be represented by the impaired pattern of gastrointestinal hormones in CD patients. Conversely, pancreatitis seems to be a very rare comorbidity in CD children, since very few cases have been described in children. Therefore, there is no evidence that pancreatitis (including autoimmune forms) represents a relevant comorbidity in pediatric CD. Type 1 diabetes mellitus (T1DM) is a well-known and frequent comorbidity in CD children. The main determinant of this epidemiological association is the common HLA-related predisposing background, even if other (non-HLA-related) genetic and environmental factors (viruses, gut microbiome, and others) are likely to be also implicated in the development of both these autoimmune diseases. T1DM children with concomitant CD may experience specific challenges in the adherence to GFD, which has no negative impact on the glycemic and, in general, metabolic control of diabetes, if it is properly implemented and followed up. Full article

Introduction: Tuberous sclerosis complex (TSC) is a rare multisystemic genetic disorder characterized by the formation of benign tumors in various organs, including the central nervous system, skin, kidneys, and heart. The diagnosis is based on well-defined clinical criteria, such as those from Schwartz (2007) updated in 2012 by the International Tuberous Sclerosis Complex Consensus Group. The study aims to investigate the clinical, imaging, and molecular characteristics of patients diagnosed with tuberous sclerosis and to explore the correlation between specific genetic mutations (TSC1 and TSC2 genes) and the severity of clinical manifestations. Material and Methods: This is a retrospective longitudinal study of 13 patients diagnosed with tuberous sclerosis, identified in the records of the Bihor Regional Center for Medical Genetics (BRCMG) within the Bihor County Emergency Clinical Hospital from 1984 to 2024. Clinical, imaging, and molecular features were assessed. Patients were evaluated by a multidisciplinary team, including a geneticist, pediatrician, neurologist, psychiatrist, and psychologist. Clinical and imaging data were retrospectively collected from the congenital malformations and genetic disease records of BRCMG Bihor and statistically analyzed. Results: All patients showed clinical and imaging signs consistent with the diagnosis of tuberous sclerosis. Neurological manifestations were present in 83% of patients, including epilepsy and cognitive delays. Renal lesions were detected in 46% of cases, and dermatological lesions, such as facial angiofibromas, were observed in 69% of patients. Mutational variants identified in the TSC2 gene correlated with a more severe clinical presentation, including severe intellectual disability and treatment-resistant seizures, compared to variants in the TSC1 gene. Conclusions: Our study, although involving a small number of patients, highlights the clinical heterogeneity of tuberous sclerosis and the importance of a multidisciplinary approach in patient management. Early diagnosis and ongoing monitoring are essential to improving the quality of life for patients. Further studies are needed to assess the impact of therapeutic interventions and genetic correlations within the studied population. Full article

Background: Behçet’s Disease (BD) is a complex vasculitis affecting multiple organ systems, with Neuro-Behçet’s Disease (NBD) representing a rare yet severe manifestation. Data on NBD are limited, particularly in Middle Eastern populations. Methods: This retrospective observational study, spanning from 2000 to 2021, involved 262 BD patients at a tertiary medical center in Lebanon. NBD was diagnosed based on International Consensus Recommendation diagnostic criteria. Clinical data, including demographics, manifestations, inflammatory blood markers, genetics, and treatments, were collected. The modified Rankin Scale (mRS) was used to assess disease severity. Results: Among the cohort, 27 (10.3%) had NBD, with headaches, weakness, and dizziness as the most common presenting symptoms. The prevalence of NBD was similar across genders, which differs from some regional studies. HLA-B51 positivity was found in 50 out of 60 (83.3%) tested BD patients. Parenchymal NBD cases exhibited greater disease severity than non-parenchymal cases, with female patients experiencing a more severe course compared to males. Elevated inflammatory markers (CRP and ESR) were more common in patients with severe NBD. Corticosteroids and colchicine were the most commonly used therapies overall, while patients with better disease severity were more frequently prescribed methotrexate, mycophenolate, cyclophosphamide, adalimumab, and rituximab. An analysis of disease progression showed that at presentation, 57.1% (n = 12) of NBD patients had mild to moderate disability, which increased to 76.2% (n = 16) at the last follow-up, including 10 patients who showed an improvement in their mRS score. Conclusions: This study provides valuable insights into the prevalence and clinical characteristics of NBD in a Middle Eastern population. These findings enhance our understanding of NBD in the Middle East, highlighting the need for further research to improve diagnosis and management. Full article

Atypical hemolytic uremic syndrome (aHUS) is a rare, life-threatening thrombotic microangiopathy (TMA) characterized by complement dysregulation, leading to microvascular thrombosis and multi-organ injury. TMAs are defined by thrombocytopenia, microangiopathic hemolytic anemia and organ dysfunction caused by small-vessel thrombosis. Unlike thrombotic thrombocytopenic purpura, which results from severe ADAMTS13 deficiency, aHUS is driven by uncontrolled activation of the alternative complement pathway. While the kidneys are most frequently affected, other vital organs can also be involved. Genetic susceptibility contributes significantly to disease risk, but a trigger such as infection, pregnancy or autoimmune disease is usually required. Diagnosis is challenging due to overlapping features with other TMAs and relies on exclusion and complement testing. C5 inhibitors, such as eculizumab and ravulizumab, have revolutionized treatment but necessitate prophylactic vaccination and ongoing clinical surveillance. While these therapies provide effective disease control, discontinuing treatment remains complex, especially in patients with complement gene mutations. New therapies targeting various points in the complement cascade are under investigation and may offer safer, more cost-effective options. Progress in genetic profiling and biomarker discovery is essential for earlier diagnosis, individualized therapy and relapse prevention. This review highlights recent advances in the understanding of aHUS pathophysiology, clinical features and evolving therapeutic strategies aimed at improving patient outcomes. Full article

Fabry disease (FD) is a rare X-linked lysosomal storage disorder caused by mutations in the GLA gene, leading to α-galactosidase A deficiency and subsequent accumulation of glycosphingolipids, including globotriaosylceramide (Gb3) and globotriaosylsphingosine (lyso-Gb3), in multiple organs. This accumulation can result in multisystemic disease and life-threatening complications. FD presents with a broad phenotypic spectrum, ranging from the classic form, with early and severe symptoms, to a later-onset form with variable manifestations. The severity of the disease in females is more variable due to X-chromosome inactivation (XCI). Renal involvement is a key feature, and kidney biopsy remains a valuable tool for diagnosing FD and assessing the extent of nephropathy. Although molecular genetic testing is the gold standard for diagnosis, kidney biopsy aids in confirming renal involvement, detecting coexisting conditions, and determining the pathogenicity of variants of uncertain significance (VUSs). Moreover, kidney biopsy can serve as a prognostic tool by identifying early markers of nephropathy, such as foot process effacement and glomerular sclerosis, which predict disease progression. Emerging technologies, including machine learning, offer the potential to enhance the analysis of renal histology, improving diagnostic accuracy and patient stratification. Despite the challenges posed by overlapping diseases and potential misdiagnoses, kidney biopsy remains an essential component of FD diagnosis and management, facilitating early detection, the monitoring of disease progression, and the evaluation of therapeutic responses. Full article

Background/Objectives: Fabry disease (FD) is a rare X-linked lysosomal storage disorder characterised by progressive glycolipid accumulation affecting multiple organs, including the peripheral nervous system. The dorsal root ganglia (DRG) play a key role in Fabry-related neuropathy, but non-invasive biomarkers of DRG involvement and their association with overall disease severity remain limited. This study evaluated lumbosacral DRG T2 relaxation time (DRG-T2) in FD patients as a potential imaging biomarker of FD severity. Methods: In a prospective, single-centre study, 80 genetically confirmed FD patients underwent 3T MRI with quantitative T2 mapping of the lumbosacral DRG. DRG-T2 was analysed in relation to sex, genetic subtype and Fabry-specific biomarkers. Results: Results showed that DRG-T2 was higher in patients with classical FD mutations than in those with nonclassical mutations (p = 0.03). Furthermore, DRG-T2 showed a negative correlation with body weight (ρ = −0.31, p = 0.005) and BMI (ρ = −0.32, p = 0.004), while no associations were found with lyso-Gb3 levels or alpha-galactosidase A activity. The inter-rater and test–retest reliability of DRG-T2 were good to excellent (ICC = 0.76 and 0.89, respectively). Conclusions: These results demonstrate DRG-T2 as a marker of neuronal involvement, making it a strong and reliable imaging biomarker of disease severity in FD. However, future studies need to correlate its changes with clinical and histological studies. Full article

Background/Objectives: Tuberous sclerosis complex (TSC) is a rare, autosomal dominant genetic disorder caused by mutations in the TSC1 and TSC2 genes, which disrupt the regulation of the mammalian target of rapamycin (mTOR) pathway, a critical regulator of cellular growth. The disorder presents as a multisystem condition, with benign tumors (hamartomas) developing in organs such as the brain, skin, heart, kidneys, and lungs, leading to significant clinical variability and impact on quality of life. This review aims to summarize recent advances in the understanding of TSC pathogenesis and clinical variability and evaluate the therapeutic breakthroughs in targeted treatments. Methods: A narrative review was conducted using various available databases. We applied objective evaluation metrics, such as the impact factor of the journals and the citation count, to assess the quality of the studies. Results: Targeted therapies, particularly mTOR inhibitors (mTORis), have shown efficacy in reducing hamartoma size, improving neuropsychiatric symptoms, and enhancing patient outcomes. Despite these advances, variability in disease expression poses challenges in diagnosis and individualized management strategies. Conclusions: Challenges such as early diagnosis, optimizing long-term outcomes, and addressing residual unmet needs remain critical. Future research should prioritize precision medicine approaches and patient-centered care models within centers of expertise to improve treatment efficacy and quality of life for individuals with TSC. Full article

Otitis media is the most frequently diagnosed disease and a leading cause of hearing loss in young children. However, genetic contributors to susceptibility and pathogen–host–environment interactions in otitis media remain to be identified. Such knowledge would help identify at-risk individuals and effectively monitor, diagnose, and treat patients with otitis media. Through exome and Sanger sequencing, we identified a rare, deleterious splice variant SLPI c.394+1G>T co-segregating with otitis media in a large pedigree, with a genome-wide significant maximum LOD score of 4.59. Alternative splicing of SLPI was observed in saliva RNA of variant carriers. In bulk mRNA-seq data from an independent cohort of children with otitis media, SLPI was co-expressed with genes involved in infection, immune response, inflammation, and epithelial cell organization. After inoculation of non-typeable Haemophilus influenzae, Slpi was upregulated in polymorphonuclear leukocytes and epithelial cells of mouse middle ears. Furthermore, in the human middle ear, Haemophilus was significantly enriched in non-carriers, whereas Family-XI-Incertae-Sedis and Dialister were significantly enriched in variant carriers. Given the role of SLPI in immune modulation and host defense in mucosal epithelia, our findings support the SLPI variant as modulating susceptibility to otitis media. Full article

Anderson–Fabry disease (AFD) is a rare X-linked lysosomal storage disorder characterized by the accumulation of globotriaosylceramide, leading to multi-organ involvement and significant morbidity. Cardiovascular manifestations, particularly arrhythmias, are common and pose a considerable risk to affected individuals. This overview examines current approaches to arrhythmic risk stratification in AFD, focusing on the identification, assessment, and management of cardiac arrhythmias associated with the disease. We explore advancements in diagnostic techniques, including echocardiography, cardiac MRI, and ambulatory ECG monitoring, to enhance the detection of arrhythmogenic substrate. Furthermore, we discuss the role of genetic and biochemical markers in predicting arrhythmic risk and the implications for personalized treatment strategies. Current therapeutic interventions, including enzyme replacement therapy and antiarrhythmic medications, are reviewed in the context of their efficacy and limitations. Finally, we highlight ongoing research and future directions with the aim of improving arrhythmic risk assessment and management in AFD. This overview underscores the need for a multidisciplinary approach to optimize care and outcomes for patients with AFD. Full article

Background and Clinical Significance: Head and neck teratomas are embryonal tumors that develop when totipotent germ cells escape the developmental control of primary organizers and form a more-or-less organoid mass in which tissues from all three germ layers (ectoderm, endoderm, and mesoderm) can be identified. Mature teratomas may either transit into germ cell or non-germ cell malignancies or remain histologically mature with the possibility of growing, thus inducing certain complications when reaching a large size. This article aims to investigate a very rare case of a 6-year-old child who exhibited a recurrent intraoral mass with multiple conflicting biopsies. Case Presentation: A 6-year-old male patient was referred to the postgraduate clinic of the Department of Oral Medicine/Pathology, Dental School, Faculty of Health Sciences, Aristotle University of Thessaloniki, Greece, because his pediatric dentist noticed an exophytic, intraoral mass, distal to tooth #75 during a routine checkup. The first histopathological examination showed a gingival tumor, classified as a small round blue cell tumor, with greater similarity to adamantinoma-like Ewing sarcoma (ALES) and less to synovial sarcoma. The second pathologist examined the same tissue specimen and suggested the extremely rare presence of an immature malignant teratoma. Following chemotherapy, the rest of the teratoma with the adjacent tooth #75 was removed, and the histopathological examination showed a mature teratoma. Conclusions: This case illustrates the crucial role of the dentist, and in this case of the pediatric dentist, to promptly diagnose the underlying disease. Genetic screening may assist in detecting high-risk populations. In such complex histopathological cases, the importance of cooperating with experienced oral and maxillofacial pathologists is highlighted. We describe a rare case of intraoral malignant teratoma, and an extended literature review revealed that our case is the first ever reported. Full article

Glycosylphosphatidylinositol (GPI) biosynthesis defect 11 (GPIBD11), part of the heterogeneous group of congenital disorders of glycosylation, is caused by biallelic pathogenic variants in PIGW. This rare disorder has previously been described in only 12 patients. We report four novel patients: two sib fetuses with congenital anomalies affecting several organs, including the heart; a living girl with tetralogy of Fallot, global developmental delay, behavioral abnormalities, and atypic electroencephalography (EEG) without epilepsy; a girl with early-onset, treatment-resistant seizures, developmental regression, and recurrent infections, that ultimately passed away prematurely due to pneumonia. We also illustrate evolving facial appearance and biochemical abnormalities. We identify two novel genotypes and the first frameshift variant, supporting a loss-of-function pathogenic mechanism. By merging our cohort with patients documented in the literature, we deeply analyzed the clinical and genetic features of 16 patients with PIGW-related disorder, revealing a severe multisystemic condition deserving complex management and with uncertain long-term prognosis. We consider the role of PIGW within the critical 17q12 region, which is already associated with genomic disorders caused by deletion or duplication and characterized by variable expressivity. Finally, we discuss PIGW dosage effects and a second hit hypothesis in human development and disease. Full article

Rare and ultra-rare diseases constitute a significant medical challenge due to their low prevalence and the limited understanding of their origin and underlying mechanisms. These disorders often exhibit phenotypic diversity and molecular complexity that represent a challenge to biomedical research. There are more than 6000 different rare diseases that affect nearly 300 million people worldwide. However, the prevalence of each rare disease is low, and in consequence, the biomedical resources dedicated to each rare disease are limited and insufficient to effectively achieve progress in the research. The use of animal models to investigate the mechanisms underlying pathogenesis has become an invaluable tool. Among the animal models commonly used in research, Drosophila melanogaster has emerged as an efficient and reliable experimental model for investigating a wide range of genetic disorders, and to develop therapeutic strategies for rare and ultra-rare diseases. It offers several advantages as a research model including short life cycle, ease of laboratory maintenance, rapid life cycle, and fully sequenced genome that make it highly suitable for studying genetic disorders. Additionally, there is a high degree of genetic conservation from Drosophila melanogaster to humans, which allows the extrapolation of findings at the molecular and cellular levels. Here, I examine the role of Drosophila melanogaster as a model for studying rare and ultra-rare diseases and highlight its significant contributions and potential to biomedical research. High-throughput next-generation sequencing (NGS) technologies, such as whole-exome sequencing and whole-genome sequencing (WGS), are providing massive amounts of information on the genomic modifications present in rare diseases and common complex traits. The sequencing of exomes or genomes of individuals affected by rare diseases has enabled human geneticists to identify rare variants and identify potential loci associated with novel gene–disease relationships. Despite these advances, the average rare disease patient still experiences significant delay until receiving a diagnosis. Furthermore, the vast majority (95%) of patients with rare conditions lack effective treatment or a cure. This scenario is enhanced by frequent misdiagnoses leading to inadequate support. In consequence, there is an urgent need to develop model organisms to explore the molecular mechanisms underlying these diseases and to establish the genetic origin of these maladies. The aim of this review is to discuss the advantages and limitations of Drosophila melanogaster, hereafter referred as Drosophila, as an experimental model for biomedical research, and the applications to study human disease. The main question to address is whether Drosophila is a valid research model to study human disease, and in particular, rare and ultra-rare diseases. Full article

In 2023, the genetics scientific community celebrated two special anniversaries: the discovery of the double helix structure of DNA was published in 1953 and in 2003 the Human Genome Project was declared completed and made publicly available. To this day, genetics and genomics research is continuing to evolve at high pace and is identifying a steadily increasing number of genes as causal for distinct genetic diseases. The success story of genetics and genomics would not be complete without taking due account of the role of patient advocacy organizations in this process. This paper is based on the personal narrative (oral history) of a father whose daughter was born with a rare genetic disease (RGD) in the 1960s. The first-hand experience of living as a family with an RGD in those days made him a leading pioneer not only in the foundation of patient organizations at national, pan-European, and international levels but also in the development of multi-stakeholder co-operation and networking. Today, patient advocacy organizations play an active role in shaping health and research policies at national, EU, and international levels to ensure that their needs in regard to advancing RGD diagnostics, care, and treatment are addressed. Full article