Search

Hypophosphatasia (HPP) is a rare inherited disorder characterized by the decreased activity of tissue-nonspecific alkaline phosphatase (TNSALP), caused by mutations in the ALPL gene. The aim of this study was to conduct differential diagnostics in HPP patients using whole-exome sequencing (WES). The medical records of HPP patients and the genetic testing of the ALPL gene were reviewed. Seven patients were recruited and underwent WES using the Illumina or MGI sequencing platforms. All of the exome samples were matched onto a GRCh38.p13 reference genome assembly by using the Genome Analysis ToolKit (GATK) and the BWA MEM read aligner. We present the clinical and molecular findings of the seven patients referred for genetic analyses due to a clinical and biochemical suspicion of HPP. In two patients out of three (with identified heterozygous variants in the ALPL gene), we also identified c.682T>A in exon 3 of the WNT10A gene and c.3470del in exon 23 of the SMC1A gene variants for the first time. In four patients, variants in the ALPL gene were not detected, but WES allowed us to identify for the first time rare variants (c.5651A>C in exon 36 of the TRIO gene, c.880T>G in exon 6 of the TRPV4 gene, c.32078-1G>T in intron 159 of the TTN gene, c.47720_47721del in exon 235 of the TTN gene, and c.1946G>A in exon 15 of the SLC5A1 gene) and to conduct differential diagnostics with HPP. Using WES, for the first time, we demonstrate the possibility of early differential diagnostics in HPP patients with other rare genetic diseases. [ABSTRACT FROM AUTHOR]

Biochemical phenotyping has been the milestone for diagnosing and managing patients affected by inborn errors of intermediary metabolism (IEiM); however, identifying the genotype responsible for these monogenic disorders greatly contributes to achieving these goals. Herein, whole-exome sequencing (WES) was used to determine the genotypes of 95 unrelated Mexican pediatric patients suspected of having IEiM. They were classified into those bearing specific biochemical abnormalities (Group 1), and those presenting unspecific biochemical profiles (Group 2). The overall concordance between the initial biochemical diagnosis and final genotypic diagnoses was 72.6% (N = 69/95 patients), with the highest concordance achieved in Group 1 (91.3%, N = 63/69), whereas the concordance was limited in Group 2 (23.07%). This finding suggests that previous biochemical phenotyping correlated with the high WES diagnostic success. Concordance was high for urea cycle disorders (94.1%) and organic acid disorders (77.4%). The identified mutational spectrum comprised 83 IEiM-relevant variants (pathogenic, likely pathogenic, and variants of uncertain significance or VUS), including three novel ones, distributed among 29 different genes responsible for amino acid, organic acid, urea cycle, carbohydrate, and lipid disorders. Inconclusive WES results (7.3%, N = 7/95) relied on monoallelic pathogenic genotypes or those involving two VUS for autosomal-recessive IEiMs. A second monogenic disease was observed in 10.5% (N = 10/95) of the patients. According to the WES results, modifications in treatment had to be made in 33.6% (N = 32/95) of patients, mainly attributed to the presence of a second monogenic disease, or to an actionable trait. This study includes the largest cohort of Mexican patients to date with biochemically suspected IEiM who were genetically diagnosed through WES, underscoring its importance in medical management. [ABSTRACT FROM AUTHOR]

Simple Summary: Treatment outcomes in chronic myeloid leukemia (CML) have improved in recent years because of the use of tyrosine kinase inhibitors. However, treatment responses to myeloid blast-phase CML (MBP-CML) are still unsatisfactory. In this paper, we summarize the biological mechanisms of progression to MBP and the most frequently used treatment regimens for MBP-CML. We also review why some patients develop resistance to tyrosine kinase inhibitors. Myeloid blast-phase chronic myeloid leukemia (MBP-CML) is a rare disease with a dismal prognosis. It is twice as common as lymphoid blast-phase CML, and its prognosis is poorer. Despite the success with tyrosine kinase inhibitors in the treatment of chronic-phase CML, the same does not hold true for MBP-CML. In addition to the Philadelphia chromosome, other chromosomal and molecular changes characterize rapid progression. Although some progress in elucidating the biology of MBP-CML has been made, there is need to discover more in order to develop more satisfactory treatment options. Currently, most common treatment options include tyrosine kinase inhibitors (TKIs) as monotherapy or in combination with acute myeloid leukemia-based intensive chemotherapy regimens. Some patients may develop resistance to TKIs via BCR-ABL1-dependent or BCR-ABL1-independent mechanisms. In this paper, we provide an overview of the biology of MBP-CML, the current treatment approaches, and mechanisms of resistance to TKIs. In order to improve treatment responses in these patients, more emphasis should be placed on understanding the biology of myeloid blastic transformation in CML and mechanisms of resistance to TKIs. Although patient numbers are small, randomized clinical trials should be considered. [ABSTRACT FROM AUTHOR]

Smith–Magenis syndrome (SMS) is a rare, underdiagnosed condition due to limited public awareness of genetic testing and a lengthy diagnostic process. Voice analysis can be a noninvasive tool for monitoring and detecting SMS. In this paper, the cepstral peak prominence and mel-frequency cepstral coefficients are used as disease monitoring and detection metrics. In addition, an efficient neural network, incorporating synthetic data processes, was used to detect SMS in a cohort of individuals with the disease. Three study cases were conducted with a set of 19 SMS patients and 292 controls. The three study cases employed various oversampling and undersampling techniques, including SMOTE, random oversampling, NearMiss, random undersampling, and 16 additional methods, resulting in balanced accuracies ranging from 69% to 92%. This is the first study using a neural network model to focus on a rare genetic syndrome using phonation analysis data. By using synthetic data (oversampling and undersampling) and a CNN, it was possible to detect SMS with high levels of accuracy. Voice analysis and deep learning techniques have proven to be a useful and noninvasive method. This is a finding that may help in the complex identification of this syndrome as well as other rare diseases. [ABSTRACT FROM AUTHOR]

Simple Summary: This study investigated the impact of the general health status on the survival of patients with high-grade chondrosarcoma, a rare type of bone cancer. This systemic health status is often summarized using the American Society of Anesthesiologists (ASA) score. By analyzing data from 249 patients, the study found that a higher ASA score, older age, and more aggressive tumors were linked to poorer survival rates. This study highlights that a patient's general health, especially for those with severe systemic diseases, should be considered when determining treatment plans, alongside traditional factors like tumor grade and age. These findings can improve decision-making for complex surgeries in patients with high-grade chondrosarcoma. Background: Due to the relatively advanced age and high mortality rate of patients with high-grade chondrosarcoma (CS), it is important to holistically assess patient- and tumor characteristics in multidisciplinary team and shared decision-making with regard to treatment options. While current prognostic models include multiple tumor and treatment characteristics, the only patient characteristics that are commonly included are age and gender. Based on clinical experience, we believe that factors related to patient preoperative systemic health status such as the American Society of Anesthesiologists (ASA) score may be equally important prognostic factors for overall survival (OS). Methods: A retrospective nationwide cohort study was identified from four specialized bone sarcoma centers in The Netherlands. Patients with a primary CS grade II, III, and dedifferentiated CS were eligible. Prognostic factors including age at presentation, gender, ASA score, CVD, tobacco use, BMI, histological tumor grade, tumor size, pathological fracture, presentation after unplanned excision, type of surgery and surgical margin were evaluated. The outcome measure was OS at the time of surgery. The Kaplan–Meier methodology was employed to estimate OS; a log-rank test was used to assess the difference in survival. To study the impact of prognostic factors on OS, a multivariate Cox proportional hazard regression model was estimated. Results: In total, 249 patients were eligible for this study, and 89 were deceased at the end of follow-up. In multivariate analysis, histological grade (HR 2.247, 95% CI 1.334–3.783), ASA score III (HR 2.615, 95% CI 1.145–5.976, vs. ASA I), and age per year (HR: 1.025, 95% CI 1.004–1.045) were negatively associated with OS. No association was found between tobacco use, BMI, gender or cardiovascular disease and OS in this cohort. Pathological fracture and tumor size were only associated with OS in univariate analysis. Conclusions: This multicenter study is the first on sarcomas to include ASA in a prognostic model. Results show that ASA score as a proxy for patients' systemic health status should be included when providing a prognosis for patients with a high-grade primary CS, besides the conventional risk factors such as tumor grade and age. Specifically, severe systemic disease (ASA score III) is a strong negative predictor. Conversely, we found no difference in OS between ASA scores I and II. These findings aid multidisciplinary team and shared decision-making with regard to these complex sarcoma patients that often require life-changing surgeries. Level of Evidence: Prognostic level III. See the instructions for authors for the complete description of levels of evidence. [ABSTRACT FROM AUTHOR]

Simple Summary: Medullary thyroid carcinoma (MTC) is a rare but aggressive form of thyroid cancer accounting for over 10% of deaths related to thyroid malignancies. MTC can be either hereditary or sporadic. Although it can be cured if it is detected early and completely removed, most patients with MTC are diagnosed when the cancer has already spread beyond the thyroid gland, making it difficult to treat. Managing MTC is complex, despite the availability of newer treatment options like targeted therapy, which works in less than 30% of cases and can lead to severe side effects in some patients. MTC behaves differently in each patient, making the selection of appropriate treatments challenging, even for multidisciplinary teams of experts. This article aims to describe the challenges faced during the diagnostic workup and management of MTC patients. It highlights how holomics, which is an integrated approach combining various biological data types, and artificial intelligence (AI) can assist in improving patient outcomes. By simultaneously analyzing and integrating findings from biochemical, radiological, and histological investigations, genetic studies, and other sources, along with the personal information of a patient, AI can enhance decision-making processes. This innovative approach has the potential to personalize and optimize treatment strategies, leading to better management and improved outcomes for patients with MTC. Background/Objective: Medullary thyroid carcinoma (MTC) is a rare yet aggressive form of thyroid cancer comprising a disproportionate share of thyroid cancer-related mortalities, despite its low prevalence. MTC differs from other differentiated thyroid malignancies due to its heterogeneous nature, presenting complexities in both hereditary and sporadic cases. Traditional management guidelines, which are designed primarily for papillary thyroid carcinoma (PTC), fall short in providing the individualized care required for patients with MTC. In recent years, the sheer volume of data generated from clinical evaluations, radiological imaging, pathological assessments, genetic mutations, and immunological profiles has made it humanly impossible for clinicians to simultaneously analyze and integrate these diverse data streams effectively. This data deluge necessitates the adoption of advanced technologies to assist in decision-making processes. Holomics, which is an integrated approach that combines various omics technologies, along with artificial intelligence (AI), emerges as a powerful solution to address these challenges. Methods: This article reviews how AI-driven precision oncology can enhance the diagnostic workup, staging, risk stratification, management, and follow-up care of patients with MTC by processing vast amounts of complex data quickly and accurately. Articles published in English language and indexed in Pubmed were searched. Results: AI algorithms can identify patterns and correlations that may not be apparent to human clinicians, thereby improving the precision of personalized treatment plans. Moreover, the implementation of AI in the management of MTC enables the collation and synthesis of clinical experiences from across the globe, facilitating a more comprehensive understanding of the disease and its treatment outcomes. Conclusions: The integration of holomics and AI in the management of patients with MTC represents a significant advancement in precision oncology. This innovative approach not only addresses the complexities of a rare and aggressive disease but also paves the way for global collaboration and equitable healthcare solutions, ultimately transforming the landscape of treatment and care of patients with MTC. By leveraging AI and holomics, we can strive toward making personalized healthcare accessible to every individual, regardless of their economic status, thereby improving overall survival rates and quality of life for MTC patients worldwide. This global approach aligns with the United Nations Sustainable Development Goal 3, which aims to ensure healthy lives and promote well-being at all ages. [ABSTRACT FROM AUTHOR]

Simple Summary: Appendiceal neuroendocrine neoplasms are very rare in pediatric populations; thus, there are no common guidelines or consensus for the management in children and adolescents, and adult protocols are usually adopted. In the present study, we report on 17 patients that underwent appendectomy for appendicitis with incidental diagnosis of a neuroendocrine tumor revealed upon histologic examination. Patients' characteristics, tumor histology, follow-up and outcome are described and compared to data from the literature, with similar results being reported in various studies. Analysis of previous scientific publications on children with appendiceal neuroendocrine neoplasms was performed and recommendations for treatment and follow-up were reviewed. This tumor displays benign behavior and an excellent outcome in children and adolescents; thus, many authors agree that aggressive surgery after the patient's first appendectomy is not necessary and follow-ups can be reduced. Background/Objectives: Appendiceal neuroendocrine neoplasms (ANENs) are usually found incidentally during histology examination after appendectomy for appendicitis. Due to their rarity in pediatric populations, there is no consensus on treatment or follow-up. The analysis of patients with ANENs of our and other studies will increase the understanding of this tumor. Methods: Pediatric patients with ANENs were uniformly managed at our center between 1998 and 2023. Patients' presenting symptoms, surgery, tumor histology, post-surgical work-up, follow-up and outcome were analyzed. Results: Our report describes 17 patients with a diagnosis of ANEN after appendectomy. The median age was 14 years (range of 4–17 years). Tumors were located at the tip of the appendix in 58.8% of cases and only one had a diameter >1 cm. All were well-differentiated tumors with free resection margins. The submucosa was invaded in five cases, muscularis propria in eight and subserosa in four. Post-appendectomy work-up included tumor marker measurement, abdominal ultrasound and computed tomography or magnetic resonance imaging, chest X-ray and octreotide scintigraphy. No residual tumors or metastases were detected. Additional surgery was not necessary. Follow-up was carried out for a median duration of 6 years (range of 1–10 years). Only one patient was lost to follow-up and all other patients are alive without tumor recurrence. Conclusions: The tumor characteristics of our patients confirmed data from the literature. With the lack of a sufficient number of large prospective trials, it is important to add more information to confirm the benign nature and excellent outcome of this tumor, even without additional surgery. Consensus guidelines are needed for ANENs in pediatric populations. [ABSTRACT FROM AUTHOR]

Rare diseases are heterogeneous diseases characterized by various symptoms and signs. Due to the low prevalence of such conditions (less than 1 in 2000 people), medical expertise is limited, knowledge is poor and patients' care provided by medical centers is inadequate. An accurate diagnosis is frequently challenging and ongoing research is also insufficient, thus complicating the understanding of the natural progression of the rarest disorders. This review aims at presenting the multimodal approach supported by the integration of multiple analyses and disciplines as a valuable solution to clarify complex genotype–phenotype correlations and promote an in-depth examination of rare disorders. Taking into account the literature from large-scale population studies and ongoing technological advancement, this review described some examples to show how a multi-skilled team can improve the complex diagnosis of rare diseases. In this regard, Facio-Scapulo-Humeral muscular Dystrophy (FSHD) represents a valuable example where a multimodal approach is essential for a more accurate and precise diagnosis, as well as for enhancing the management of patients and their families. Given their heterogeneity and complexity, rare diseases call for a distinctive multidisciplinary approach to enable diagnosis and clinical follow-up. [ABSTRACT FROM AUTHOR]

Introduction: Intrawound application of vancomycin is becoming increasingly controversial for the prevention of surgical site infection (SSI). As children undergoing spinal fusion for secondary scoliosis are at high risk for SSIs, evidence regarding the impact of intraoperative vancomycin installation on SSI rates in these patients is of utmost importance. Methodology: A single surgeon cohort of patients under 18 years of age undergoing surgery for secondary scoliosis in 2017 was analyzed with regard to the development of SSIs requiring surgical revision and adverse events. Use of vancomycin was restricted to cases with higher risk of infection. Patients undergoing distraction surgery for growing devices were excluded. Results: After exclusions, 64 patients remained (vancomycin n = 39, control n = 25). The SSI rates were 12.8% in patients receiving vancomycin (n = 5/39) and 4% in the control group (n = 1/25, p = 0.785). None of the patients suffered from adverse events. Univariable logistic regression revealed younger age (p = 0.03) and meningomyelocele as predictors for SSI (p = 0.006), while the high-risk group receiving vancomycin was not at higher odds for SSI, also after adjustment for possible confounders such as age or MMC (p = 0.031; p = 0.009). Discussion: SSI rates were comparable between groups, suggesting a normalization of SSI risk in the vancomycin-treated patients with a preoperatively increased risk of SSI. Future, larger studies in these rare diseases are needed to confirm these results. [ABSTRACT FROM AUTHOR]

Motor deficit is a core symptom of Rett syndrome, a rare neurological disease caused in most cases by mutations of the methyl-CpG-binding protein2 (MECP2) gene. Serotonin reuptake inhibitors improve motor coordination in Mecp2 heterozygous (Het) mice and serotonin depletion prevented this effect. Here, we assess alterations in indole levels in various brain regions and whether boosting brain serotonin synthesis with the serotonin precursors tryptophan, 5-hydroxytryptophan and α-lactalbumin rescued motor coordination deficit of Mecp2 Het mice. Motor coordination was assessed in the accelerated rotarod during and after systemic administration of serotonin precursors for 2–3 weeks. Since no data are available, the effect of α-lactalbumin on tryptophan, serotonin and 5-hydroxyindoleacetic acid levels was evaluated in various brain regions in order to identify the dose of ALAC to evaluate on motor coordination. As compared to WT, Mecp2 Het mice show reduced levels of serotonin in the whole brain, hippocampus, brainstem and cerebral cortex, but not the striatum. Reduced levels of 5-hydroxyindoleacetic acid were observed in the hippocampus and brainstem. Doses of serotonin precursors increasing brain tryptophan and/or serotonin production and metabolism had no effect on motor coordination. The results indicate that boosting serotonin synthesis is not sufficient to improve motor coordination of Mecp2 Het mice. [ABSTRACT FROM AUTHOR]

Simple Summary: Sarcomas are rare and diverse tumors that develop in various tissues like bone, muscle, and fat. This study examines the outcomes of two types of surgical removal of these tumors: planned resections (PEs), where the tumor is diagnosed a-priori and surgically removed with a plan, and unplanned resections (UEs), where the tumor is removed without prior diagnosis. We found that planned surgeries, while better at completely removing the tumor initially, are associated with more advanced tumors that have a higher chance of spreading and leading to cancer-related deaths. On the other hand, unplanned surgeries tend to have higher chances of the tumor coming back locally but do not significantly affect long-term survival. These findings highlight the importance of early detection and timely treatment at specialized centers to improve patient outcomes. Our research aims to help develop better tools for predicting and managing sarcomas to enhance patient care. Background: Sarcomas, a diverse group of malignant tumors arising from mesenchymal tissues, pose significant diagnostic and therapeutic challenges. This study compares the outcomes of planned resections (PEs) and unplanned resections (UEs) to inform better clinical practices. Methods: Data were analyzed from the Swiss Sarcoma Network (SSN), including patients with soft tissue and bone sarcomas treated at two major hospitals. This study utilized logistic regression and Cox regression models to examine the odds of UEs and their impact on local recurrence-free survival. Results: Among 429 patients registered by SSN members, 323 (75%) underwent PEs and 106 (25%) experienced UEs. PEs were associated with significantly larger tumors (94 mm vs. 47 mm, p < 0.001) and higher-grade tumors (Grade 3: 50.5% vs. 37.4%, p = 0.03). Despite achieving superior resection margins (R0: 78.8% vs. 12.6%, p < 0.001), PEs showed higher metastasis rates at follow-up (31.0% vs. 10.4%, p < 0.001) and greater cancer-specific mortality (16.7% vs. 6.6%, p = 0.01). UEs, while linked to higher local recurrence, did not significantly affect metastasis-free survival (MFS) or overall survival (OS). Conclusions: PEs achieve superior immediate surgical outcomes but are linked to higher metastasis and cancer-specific mortality due to the advanced stage of tumors. UEs, while associated with higher local recurrence rates, do not significantly impact MFS or OS. Early detection, comprehensive diagnostics, and timely referrals to specialized sarcoma hubs are essential to avoid UEs and reduce metastatic risk. Future research should focus on developing diagnostic tools using individual tumor and patient characteristics to improve sarcoma management. [ABSTRACT FROM AUTHOR]

Simple Summary: Central Nervous System (CNS) pediatric tumors represent the most common solid tumors in children with a wide variability in terms of survival and therapeutic response. Unlike their adult counterparts, the mutational landscape of pediatric CNS tumors is mostly characterized by oncogenic fusions rather than multiple mutated genes. We report four pediatric cases associated with rare oncogenic fusions, providing an overview of oncogenic fusion pathogenesis, histological phenotype, diagnostic and theranostic impact. Our work underlines that most of these rare oncogenic fusions are not specific to a single morpho-molecular entity among the pediatric CNS tumors. Even within tumors harboring the same oncogenic fusions, a wide range of morphological, molecular and epigenetic entities can be observed. These findings highlight the need for caution when applying the fifth CNS WHO classification, as the vast majority of these fusions are not yet incorporated in the diagnosis, including grade evaluation and DNA methylation classification. Background and Objectives: Central Nervous System (CNS) pediatric tumors represent the most common solid tumors in children with a wide variability in terms of survival and therapeutic response. By contrast to their adult counterpart, the mutational landscape of pediatric CNS tumors is characterized by oncogenic fusions rather than multiple mutated genes. CNS pediatric tumors associated with oncogenic fusions represent a complex landscape of tumors with wide radiological, morphological and clinical heterogeneity. In the fifth CNS WHO classification, there are few pediatric CNS tumors for which diagnosis is based on a single oncogenic fusion. This work aims to provide an overview of the impact of rare oncogenic fusions (NTRK, ROS, ALK, MET, FGFR, RAF, MN1, BCOR and CIC genes) on pathogenesis, histological phenotype, diagnostics and theranostics in pediatric CNS tumors. We report four cases of pediatric CNS tumors associated with NTRK (n = 2), ROS (n = 1) and FGFR3 (n = 1) oncogenic fusion genes as a proof of concept. Cases presentation and literature review: The literature review and the cohort that we described here underline that most of these rare oncogenic fusions are not specific to a single morpho-molecular entity. Even within tumors harboring the same oncogenic fusions, a wide range of morphological, molecular and epigenetic entities can be observed. Conclusions: These findings highlight the need for caution when applying the fifth CNS WHO classification, as the vast majority of these fusions are not yet incorporated in the diagnosis, including grade evaluation and DNA methylation classification. [ABSTRACT FROM AUTHOR]

Simple Summary: Low-grade serous ovarian cancer is a rare and complex subtype that usually develops slowly and predominantly affects younger women. Conventional treatment, which generally involves a combination of primary surgery and chemotherapy, often fails, leading to frequent recurrences. Due to the rarity of this cancer subtype, there are limited clinical data available to guide optimal treatment decisions. However, recent research is focusing on new, promising therapies, including targeted treatments that address specific molecular pathways and hormonal therapies. These emerging options offer hope for improved outcomes by enabling more personalized and effective management. This review aims to address the current treatment challenges and summarize the innovative therapies and their potential to enhance treatment strategies, aiming to provide better management for patients with this uncommon ovarian cancer subtype. Low-grade serous ovarian carcinoma (LGSOC) is a rare subtype of epithelial ovarian cancer, characterized by a unique molecular background and specific clinical behavior. A growing body of molecular data underscores LGSOC as a distinct disease entity; however, clinical evidence on the optimal treatment regimens for LGSOC remains limited due to the low incidence of the disease. Consequently, treatment recommendations for LGSOC are still often derived from findings on the more common high-grade serous ovarian carcinoma (HGSOC) and typically focus on radical cytoreductive surgery and platinum-based chemotherapy. Since LGSOCs typically exhibit only limited responsiveness to platinum-based chemotherapy, the clinical management of advanced and recurrent LGSOCs remains a significant therapeutic challenge and often results in limited treatment options and suboptimal outcomes. Recent advances in molecular profiling and the identification of new, promising targets, such as the mitogen-activated protein kinase (MAPK) pathway, offer hope for improving both the prognosis and health-related quality of life in affected patients. Given the high unmet clinical need to establish new therapeutic standards beyond cytotoxic chemotherapy, this review aims to summarize the most promising molecular targets and emerging targeted agents. [ABSTRACT FROM AUTHOR]

Zinc plays a crucial role in cell structure and functionality. Neurodegenerative Duchenne muscular dystrophy (DMD) alters muscle membrane structure, leading to a loss of muscle mass and strength. The objective of this study was to evaluate the changes in phase angle (PA) and bioelectrical impedance vector analysis (BIVA) results in patients with DMD after oral zinc supplementation. This clinical trial included 33 boys aged 5.6 to 24.5 years diagnosed with DMD. They were divided into three groups according to age (G1, G2, and G3) and supplemented with oral zinc. The mean serum zinc concentration was 74 μg/dL, and 29% of patients had concentrations below the reference value. The baseline values (mean (standard deviation)) of the bioelectrical impedance parameters PA, resistance (R), and reactance (Xc) were 2.59° (0.84°), 924.36 (212.31) Ω, and 39.64 (8.41) Ω, respectively. An increase in R and a decrease in PA and lean mass proportional to age were observed, along with a negative correlation (r = −0.614; p < 0.001) between age and PA. The average cell mass in G1 was greater than that in G3 (p = 0.012). There were no significant differences in serum zinc levels or bioelectrical impedance parameters before and after zinc supplementation. We conclude that this population is at risk of zinc deficiency and the proposed dosage of zinc supplementation was not sufficient to alter serum zinc levels, PA and BIVA results. [ABSTRACT FROM AUTHOR]

Backgroud: Rett syndrome is a neurodevelopmental disorder that affects 1 in 10,000 females. Various treatments have been explored; however, no effective treatments have been reported to date, except for trofinetide, a synthetic analog of glycine-proline-glutamic acid, which was approved by the FDA in 2023. Serological biomarkers that correlate with the disease status of RTT are needed to promote early diagnosis and to develop novel agents. Methods: In this study, we performed a high-depth proteomic analysis of extracellular vesicles containing preparations extracted from patient plasma samples to identify novel biomarkers. Results: We identified 33 upregulated and 17 downregulated candidate proteins among a total of 4273 proteins in RTT compared to the healthy controls. Among these, UBE3B was predominantly increased in patients with Rett syndrome and exhibited a strong correlation with the clinical severity score, indicating the severity of the disease. Conclusions: We demonstrated that the proteomics of high-depth extracellular vesicles containing preparations in rare diseases could be valuable in identifying new disease biomarkers and understanding their pathophysiology. [ABSTRACT FROM AUTHOR]

Crohn's disease (CD) is a chronic inflammatory bowel condition with increasing global incidence. Diagnosing CD is challenging and requires close collaboration between clinicians and pathologists due to the lack of specific diagnostic criteria. Histologically, CD is characterized by transmural inflammation, crypt distortion, metaplasia, and granulomas, although granulomas are not always present. Schaumann bodies (SB), initially described in sarcoidosis, are rare in CD but have been reported in about 10% of cases. This case report presents a 4-year-old female with chronic hemorrhagic diarrhea, severe anemia, and elevated inflammatory markers. Endoscopic and histological evaluations suggested CD, with the presence of SB in the gastric mucosa. Further investigations ruled out sarcoidosis, confirming a diagnosis of multi-segmental, very early onset CD with atypical histological features. SB are inclusions composed of calcium carbonate crystals and conchoid bodies, typically found within giant cells. The presence of SB in the mucosa is rare, limiting their diagnostic significance in endoscopic biopsies. Differential diagnosis should exclude other granulomatous diseases such as intestinal tuberculosis and sarcoidosis. This case highlights the importance of considering SB in the diagnosis of CD, particularly in pediatric patients. [ABSTRACT FROM AUTHOR]

Our study investigates the impact of FGF23 overexpression on SaOS-2 cells to elucidate its role in cellular stress and morphology, contributing to the understanding of skeletal pathologies like X-linked hypophosphatemia (XLH). Using transmission electron microscopy and protein analysis (Western blot), we analyzed the rough endoplasmic reticulum (rER) and mitochondria in SaOS-2 cells with FGF23 overexpression compared to controls. We found significant morphological changes, including enlarged and elongated rER and mitochondria, with increased contact zones, suggesting enhanced interaction and adaptation to elevated protein synthesis and secretion demands. Additionally, we observed higher apoptosis rates of the cells after 24–72 h in vitro and upregulated proteins associated with ER stress and apoptosis, such as CHOP, XBP1 (spliced and unspliced), GRP94, eIF2α, and BAX. These findings indicate a robust activation of the unfolded protein response (UPR) and apoptotic pathways due to FGF23 overexpression. Our results highlight the critical role of ER and mitochondrial interactions in cellular stress responses and provide new insights into the mechanistic link between FGF23 signaling and cellular homeostasis. In conclusion, our study underscores the importance of analyzing UPR-related pathways in the development of therapeutic strategies for skeletal and systemic diseases and contributes to a broader understanding of diseases like XLH. [ABSTRACT FROM AUTHOR]

Simple Summary: Temporal bone paragangliomas are rare neuroendocrine tumors that typically arise from the parasympathetic nervous system. Since they are not a common pathology in the daily practice of an otorhinolaryngologist, we would like to provide an overview of current treatment strategies for patients with tympanomastoid paragangliomas. In addition, we present our approach for patients with class A and B tympanomastoid paragangliomas and reiterate that surgical therapy is an effective and safe treatment modality. In cases where surgery is refused and the tumor has grown to class C or more, radiotherapy is an alternative method to control tumor growth. (1) Background: Head and neck paragangliomas are neuroendocrine tumors that typically originate from the parasympathetic nervous system and are predominantly non-secretory. Their clinical manifestations result from their mass effect on the surrounding tissues. The approach to treating these tumors depends on factors such as their location, size, impact on adjacent structures, and the patient's overall health and preferences. (2) Methods: A retrospective analysis of the management of temporal bone paraganglioma classes A and B (according to the modified Fisch classification) was performed at the University Medical Centre, Ljubljana, between 2011 and 2023. (3) Results: We analyzed 23 cases, 19 of which underwent surgery; complete tumor removal was achieved in 18 of them. Four patients were irradiated due to tumor progression to class C. Three of these four patients initially refused surgery and were treated with radiotherapy (RT) 7, 13, and 18 years after diagnosis. In the fourth patient, complete surgical resection was not achieved and she was treated with RT four years after surgery, due to the growth of the tumor to class C. The average follow-up time from diagnosis was 8.9 years (median 6 years; range 1–26 years). (4) Conclusions: The surgical treatment of patients with class A and B paragangliomas is effective and safe. In cases where surgery is refused but the tumor continues to grow to class C, RT is an alternative and efficient method of controlling tumor growth. [ABSTRACT FROM AUTHOR]

Simple Summary: Atypical spindle cell/pleomorphic lipomatous tumor (ASCPLT) is a novel entity of benign adipocytic neoplasm that can show variable CD34 immunoreactivity, loss of Rb expression, and RB1 gene deletion. Due to the rarity of the disease, ASCPLT remains poorly understood. This review aims to provide a comprehensive reference, offer valuable insights into the clinicopathological characteristics and pathogenesis, and discuss the differential diagnosis of ASCPLT. Atypical spindle cell/pleomorphic lipomatous tumor (ASCPLT) is a rare and recently described adipocytic neoplasm that primarily occurs in the subcutis of the limbs and limb girdles, particularly of middle-aged adults. It has locally recurrent potential if incompletely excised but no risk for distant metastasis. ASCPLT is histologically similar to spindle cell/pleomorphic lipoma and atypical lipomatous tumor and shows a mixture of atypical spindle cells, adipocytes, lipoblasts, floret-like multinucleated giant cells, and/or pleomorphic cells. It has been recently recognized that ASCPLT can undergo sarcomatous transformation. However, the biological significance of morphological sarcomatous transformation in ASCPLT remains uncertain. Immunohistochemically, the tumor cells show variable expression of CD34, S-100 protein, and desmin. Loss of nuclear Rb expression is observed in the majority of cases. ASCPLT lacks MDM2 gene amplification but can show RB1 gene deletion in a significant subset of cases. Complete surgical excision is the treatment of choice. This review provides an overview of the current knowledge on the clinicoradiological features, pathogenesis, histopathology, and treatment of ASCPLT. In addition, we will discuss the differential diagnosis of this new entity. [ABSTRACT FROM AUTHOR]

Simple Summary: Dermatofibrosarcoma protuberans (DFSP) is a rare proliferative condition representing skin sarcomas which is known to locally recur yet very rarely metastasizes. Its genetic background is a reciprocal translocation t(17;22)(q22;q13) that produces COL1A1-PDGFB gene fusion. Complete resection is the primary treatment. The aim of this reappraisal is to review various correlates of the condition. Our review underlines that cases of low-to-moderate grade DFSP with excellent prognosis must be distinguished from high grade fibrosarcomatous DFSP with a much worse prognosis. Dermatofibrosarcoma protuberans (DFSP) is a rare proliferative condition representing skin sarcomas which is known to locally recur yet very rarely metastasizes. Its genetic background is a reciprocal translocation t(17;22)(q22;q13) that produces COL1A1-PDGFB gene fusion. Complete resection is the primary treatment. The aim of this review is to outline the pathogenesis, diagnosis, and management of DFSP. A clear-cut distinction between low-to-moderate-grade DFSP with excellent prognosis and high-grade fibrosarcomatous DFSP with a much worse prognosis is underlined. Malignant transformation within DFSP (or high histologic grade), older age, being female, large primary tumor size (≥10 cm), narrow surgical margins of excision (<3 cm), surgical margin positivity for tumor cells, short time to recurrence, numerous recurrences, tumor that was recently rapidly enlarging, and presence of pain in the tumor have all been proposed as clinicopathological risk factors for recurrence and metastasis. A tendency for local growth and local relapses of well- and moderately differentiated DFSPs is an argument for their surgical excision, possibly combined with reconstructive surgery, even in patients of advanced age. Another main point of this review is that cases of DFSP with fibrosarcomatous transformation are a challenge and require careful medical attention. Both anatomopathological evaluation of the presence of lymphovascular space invasion and sentinel lymph node biopsy at DFSP surgery merit further study. [ABSTRACT FROM AUTHOR]

Although decades of intensive drug discovery efforts to treat neurodegenerative disorders (NDs) have failed, around half a million patients in more than 2000 studies continue being tested, costing over USD 100 billion, despite the conclusion that even those drugs which have been approved have no better effect than a placebo. The US Food and Drug Administration (FDA) has established multiple programs to innovate the treatment of rare diseases, particularly NDs, providing millions of USD in funding primarily by encouraging novel clinical trials to account for issues related to study sizes and adopting multi-arm studies to account for patient dropouts. Instead, the FDA should focus on the primary reason for failure: the poor bioavailability of drugs reaching the brain (generally 0.1% at most) due to the blood–brain barrier (BBB). There are several solutions to enhance entry into the brain, and the FDA must require proof of significant entry into the brain as the prerequisite to approving Investigational New Drug (IND) applications. The FDA should also rely on factors other than biomarkers to confirm efficacy, as these are rarely relevant to clinical use. This study summarizes how the drugs used to treat NDs can be made effective and how the FDA should change its guidelines for IND approval of these drugs. [ABSTRACT FROM AUTHOR]

Background: Rare diseases constitute a heterogeneous group of approximately 7000–8000 conditions, distinguished by their low prevalence. Collectively, they present a significant global health challenge, affecting millions of people worldwide. It is estimated that rare diseases affect approximately 10% of the global population, which places a significant burden on individuals, families, and society. It is, therefore, important to consider strategies to improve the overall well-being and quality of life of individuals with rare diseases. One potential avenue for exploration is the incorporation of physical activity (PA). The scope of this study was to ascertain whether PA has a positive impact on measures of well-being and to determine its potential to enhance the quality of life of these individuals. Methods: The data were collected via an online survey. The one-way ANOVA test for multiple groups and multivariate Poisson models were employed to identify the significant predictors of the outcomes of interest. Results: The protective effects of PA become evident with a minimum of six hours of activity per week. Our data confirm that the weekly hours devoted to PA can serve as a significant protective factor for QoL. The study also provided some insights into the motivations behind patients' engagement in PA. These included improving QoL and physical well-being, as well as the desire to interact socially, with the goal of meeting friends or making new acquaintances. Finally, for adults and older adults, engaging in PA can also be a way to control weight. Conclusions: It is becoming increasingly clear that individuals with rare diseases stand to benefit greatly from PA, so it is only sensible to educate them on the advantages of an active lifestyle. [ABSTRACT FROM AUTHOR]

Neurocysticercosis (NCC), a parasitic infection of the central nervous system caused by the larval stage of Taenia solium, presents a diagnostic conundrum due to its rare and often nonspecific clinical manifestations. This paper aims to unravel the diagnostic mystery surrounding NCC, shedding light on its epidemiology, pathophysiology, clinical presentation, and the challenges encountered in its diagnosis. Despite being considered a rare disease, NCC is the leading cause of acquired epilepsy worldwide, underscoring its clinical significance. The complexity of NCC diagnosis lies in its diverse clinical presentations, which can range from headaches, dizziness, and seizures to more severe neurological cognitive deficits. This diversity often leads to misdiagnosis. Furthermore, the limitations of current diagnostic methods, including serological tests and neuroimaging, contribute to the diagnostic dilemma. This paper emphasises the need for improved diagnostic criteria and novel diagnostic tools to enable early and accurate detection of NCC. By enhancing our understanding of NCC, we can pave the way for better management strategies, ultimately improving patient outcomes in this under-recognised disease. [ABSTRACT FROM AUTHOR]

Autosomal dominant retinitis pigmentosa (AD-RP) is caused by several genes, among which RHO is one of the most investigated. This article will be focused on RHO and its role in explaining AD-RP cases in the Italian population, taking advantage of the experience of the Genomic Medicine Laboratory UILDM at the Santa Lucia Foundation IRCCS. The retrospective evaluation of the distribution of RHO variants in the Italian patients with a clinical suspicion of RP pointed out eight variants. Of them, four variants (c.632A>T, c.1040C>T, c.1030C>T, c.383_392del) were pathogenic and made it possible to confirm the diagnosis of AD-RP in nine affected patients, highlighting a lower frequency (17%) of RHO variants compared to previous studies (30–40%). In addition, this study identified four variants classified as Variants of Uncertain Significance (VUS). In conclusion, the experience of the Genomic Medicine Laboratory provides an overview of the distribution of RHO variants in the Italian population, highlighting a slightly lower frequency of these variants in our cases series compared to previous reports. However, further studies on RHO variants are essential to characterize peculiar RP phenotypes and extend the spectrum of disease associated with this gene. [ABSTRACT FROM AUTHOR]

A squamous odontogenic tumor (SOT) is an epithelial locally benign neoplasia derived from the periodontium of the jaws. It is considered a lesion of low incidence. Predominantly, it affects the mandible, although both jaw bones may be involved. Here, we discuss the malignant clinical evolution of an SOT lesion in an 80-year-old female patient. The patient exhibited an expansive triangular lesion at the inferior right quadrant. Surgery was performed and an SOT was diagnosed (2019). Two years after, the lesion grew, and the analysis of the biopsy revealed SOT malignization with pleomorphic atypical squamous cells, characteristics of a squamous cell carcinoma (2021). Massive DNA sequencing of formalin-fixed–paraffin-embedded specimens of the initial and relapsed tumors indicated pathogenic mutations in RET and POLE genes in both tumors, loss of ALK, and gain of CDKN1B and MAP2K in the relapse. In addition, the clinical, radiographic, and microscopic features of this neoplasm are discussed and compared with those already published. The case presented contributes to the better understanding of this SOT tumor entity and to indicates its malignant evolution, together with its biological behavior and its histologic, clinical, and radiographic features. Also, it aims to stress the importance of deeper genetic analyses in rare diseases to uncover mutations that help to select a personalized treatment. [ABSTRACT FROM AUTHOR]

Brody disease (BD) is an "ultra-rare" human genetic disorder of skeletal muscle function due to defects in the atp2a1 gene causing deficiency of the SERCA protein, isoform1. The main clinical signs are exercise-induced stiffness and delayed muscular relaxation after physical exercises, even mild ones. No mouse model nor specific therapies exist for Brody myopathy, which is therefore considered an orphan disease. Bovine congenital pseudomyotonia (PMT) is a muscular disorder characterized by an impairment of muscle relaxation and is the only mammalian model of human BD. The pathogenetic mechanism underlying bovine PMT has been recently clarified. These findings prompted us to purpose a potential pharmacological approach addressing a specific population of BD patients who exhibit reduced expression but still exhibit activity of the SERCA1 pump. Preclinical research involving in vivo studies is essential and necessary before clinical trials can be pursued and SERCA protein shows a high degree of conservation among species. So far, the only animal models available to study BD in vivo are a group of zebrafish mutant lines known as accordion zebrafish (acc). In this paper, we focused on a comprehensive characterization of the "acctq206" zebrafish variant. Our aim was to use this mutant line as an experimental animal model for testing the novel therapeutic approach for BD. [ABSTRACT FROM AUTHOR]

Background: A major challenge faced by patients with rare diseases (RDs) often stems from delays in diagnosis, typically due to nonspecific clinical symptoms or doctors' limited experience in connecting symptoms to the underlying RD. Using patient-oriented questionnaires (POQs) as a data source for machine learning (ML) techniques can serve as a potential solution. These questionnaires enable patients to portray their day-to-day experiences living with their condition, irrespective of clinical symptoms. This systematic review—registered at PROSPERO with the Registration-ID: CRD42023490838—aims to present the current state of research in this domain by conducting a systematic literature search and identifying the potentials and limitations of this methodology. Methods: The review adheres to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and was primarily funded by the German Federal Ministry of Education and Research under grant no. 16DHBKI056 (ki4all). The methodology involved a systematic search across the databases PubMed, Semantic Scholar and Google Scholar, covering articles published until June 2023. The inclusion criteria encompass examining the use of POQs in diagnosing rare and common diseases. Additionally, studies that focused on applying ML techniques to the resulting datasets were considered for inclusion. The primary objective was to include English as well as German research that involved the generation of predictions regarding the underlying disease based on the information gathered from POQs. Furthermore, studies exploring identifying predictive indicators associated with the underlying disease were also included in the literature review. The following data were extracted from the selected studies: year of publication, number of questions in the POQs, answer scale in the questionnaires, the ML algorithms used, the input data for the ML algorithms, the performance of these algorithms and how the performance was measured. In addition, information on the development of the questionnaires was recorded. Results: This search retrieved 421 results in total. After one superficial and two comprehensive screening runs performed by two authors independently, we ended up with 26 studies for further consideration. Sixteen of these studies deal with diseases and ML algorithms to analyse data; the other ten studies provide contributing research in this field. We discuss several potentials and limitations of the evaluated approach. Conclusions: Overall, the results show that the full potential has not yet been exploited and that further research in this direction is worthwhile, because the study results show that ML algorithms can achieve promising results on POQ data; however, their use in everyday medical practice has not yet been investigated. [ABSTRACT FROM AUTHOR]

Simple Summary: Breast cancer is the most common cancer and the leading cause of cancer-related deaths among women globally, with over 2.26 million new cases in women in 2020. Male breast cancer, while rare (less than 1% of cases), is treated similarly to female breast cancer despite some clinical differences. Advances in treatment, such as using genomic and immunohistochemical markers, have significantly improved survival rates for women. Men with breast cancer are often older at diagnosis, and their prognosis may differ due to age and other factors. The survival analysis conducted on 2162 patients (19 males and 2143 females) suggests that male breast cancer may have a poorer prognosis compared to female breast cancer. Breast cancer is one of the most common cancers and the leading cause of cancer death in women. Less than 1% of breast cancer cases are male breast cancers. Although there has been significant progress made in the management of breast cancer, due to its rarity among men, the question of whether men and women with breast cancer have the same treatment response and survival rate still needs to be answered. The primary goal of this study is to compare survival outcomes between male and female breast cancer patients. Material and Method: This cohort study represents a retrospective and anonymized data analysis of 2162 breast cancer cases (19 males and 2143 females), registered over a period of 12 years, from 1 January 2010 to 31 December 2021, in the Clinic of Obstetrics and Gynecology, Diakoneo Diak Klinikum Schwäbisch Hall, Germany. Results: According to the Kaplan–Meier survival analysis, the estimated overall 3-year survival rate was 91.1% for women and 88.9% for men. The log-rank test of equality of survival distributions indicated a statistically significant difference in survival times between the two groups (p = 0.009). In the subsequent age-matched Kaplan–Meier analysis, the p-value was below the significance threshold (p = 0.068). Conclusions: Male breast cancer is a rare disease that may show some particularities in terms of survival compared to female breast cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: Liposarcoma is a rare cancer of adipose tissue with limited treatment options. Here, we studied the fuel used by liposarcoma to develop a new strategy for treatment. Liposarcoma was found to rely on the amino acid Asparagine for tumor growth, especially in its most aggressive form. By combining treatments that limit both synthesis and uptake of Asparagine within liposarcoma cells, we demonstrated a unique sensitivity that reduced tumor growth in animal models. Altogether, findings from this study suggest that targeting Asparagine could be a promising new therapy in liposarcoma. Background: mTORC1 activity is dependent on the presence of micronutrients, including Asparagine (Asn), to promote anabolic cell signaling in many cancers. We hypothesized that targeting Asn metabolism would inhibit tumor growth by reducing mTORC1 activity in well-differentiated (WD)/dedifferentiated (DD) liposarcoma (LPS). Methods: Human tumor metabolomic analysis was utilized to compare abundance of Asn in WD vs. DD LPS. Gene set enrichment analysis (GSEA) compared relative expression among metabolic pathways upregulated in DD vs. WD LPS. Proliferation assays were performed for LPS cell lines and organoid models by using the combination treatment of electron transport chain (ETC) inhibitors with Asn-free media. 13C-Glucose-labeling metabolomics evaluated the effects of combination treatment on nucleotide synthesis. Murine xenograft models were used to assess the effects of ETC inhibition combined with PEGylated L-Asparaginase (PEG-Asnase) on tumor growth and mTORC1 signaling. Results: Asn was enriched in DD LPS compared to WD LPS. GSEA indicated that mTORC1 signaling was upregulated in DD LPS. Within available LPS cell lines and organoid models, the combination of ETC inhibition with Asn-free media resulted in reduced cell proliferation. Combination treatment inhibited nucleotide synthesis and promoted cell cycle arrest. In vivo, the combination of ETC inhibition with PEG-Asnase restricted tumor growth. Conclusions: Asn enrichment and mTORC1 upregulation are important factors contributing to WD/DD LPS tumor progression. Effective targeting strategies require limiting access to extracellular Asn and inhibition of de novo synthesis mechanisms. The combination of PEG-Asnase with ETC inhibition is an effective therapy to restrict tumor growth in WD/DD LPS. [ABSTRACT FROM AUTHOR]

Simple Summary: Previous studies have reported the gene mutational landscapes and PD-L1 expression levels of thymic epithelial tumors. However, due to the rarity of the disease, heterogeneity, whether from the different sequencing methods or the patients, does exist across these studies, hampering the large-scale application of targeted therapy and immunotherapy. Thus, we conducted a meta-analysis on the genetic alterations and molecular landscapes of TETs and obtained the pooled estimated mutation rates of the most frequently mutated genes in TETs, as well as the PD-L1 expression levels in TETs. Confounding factors that may contribute to the heterogeneity are also discussed in our manuscript. Our efforts have provided a more accurate overview of the gene mutation landscape and PD-L1 expression levels in TETs, which may contribute to the cure of TETs, advanced TETs, or metastatic TETs in particular. Thymic epithelial tumors (TETs), consisting of thymomas, thymic carcinomas (TCs), and thymic neuroendocrine tumors, are rare diseases. Surgery remains the prime option in resectable and early-stage TETs, while chemotherapy, targeted therapy, and immunotherapy are also potential treatment modalities. However, the inadequate comprehension of the molecular landscape of TETs impedes the exploitation of such therapies. Hence, we conducted a meta-analysis which includes 21 studies reporting on genomic alterations in TETs and 14 studies reporting on PD-L1 expression levels, respectively. The pooled estimated rates of the most frequently mutated genes and PD-L1 expression levels were analyzed using the R software. We uncovered that the pooled estimated overall mutation rate is 0.65 ([0.49; 0.81]), and the top three genes with highest mutation frequency in thymomas and TCs are GTF2I (0.4263 [0.3590; 0.4936]), TP53 (0.1101 [0.0000; 0.2586]), and RAS (0.0341 [0.0104; 0.0710]), and TP53 (0.1797 [0.0732; 0.3203]), CDKN2A (0.0608 [0.0139; 0.1378]), and TET2 (0.0318 [0.0087; 0.0639]), respectively. A uniform GTF2I mutational rate in thymomas and TP53 mutational rate in thymic squamous cell carcinomas (TSCCs) are also observed. The pooled estimated expression level of PD-L1 is 0.71 ([0.59–0.81]). This systematic review provides an overview of the gene alteration landscape and PD-L1 expression levels in TETs, discovers several potential confounding factors that may contribute to the high heterogeneity, and facilitates deeper investigations into the elucidation of the molecular landscape of TETs. [ABSTRACT FROM AUTHOR]

Simple Summary: Breast cancer is the most common cancer in females. Although rare in the younger population, individuals with a susceptible genetic background are at higher risk of breast cancer. A study was conducted on 63 Finnish breast cancer patients without any BRCA1/2 variants who had an onset of breast cancer at age 40 or younger. These patients were sequenced, and variants in DNA repair genes were identified. These variants were then prioritized based on their allele frequency in the population and pathogenicity prediction scores to identify potential new risk variants. Seventy-two deleterious variants were found, including eight novel variants. For the novel variants, protein structure modeling was conducted, and all deleterious variants were validated in another Finnish BRCA1/2-negative breast cancer population. Background: Breast cancer is the most common malignancy, with a mean age of onset of approximately 60 years. Only a minority of breast cancer patients present with an early onset at or before 40 years of age. An exceptionally young age at diagnosis hints at a possible genetic etiology. Currently, known pathogenic genetic variants only partially explain the disease burden of younger patients. Thus, new knowledge is warranted regarding additional risk variants. In this study, we analyzed DNA repair genes to identify additional variants to shed light on the etiology of early-onset breast cancer. Methods: Germline whole-exome sequencing was conducted in a cohort of 63 patients diagnosed with breast cancer at or before 40 years of age (median 33, mean 33.02, range 23–40 years) with no known pathogenic variants in BRCA genes. After filtering, all detected rare variants were sorted by pathogenicity prediction scores (CADD score and REVEL) to identify the most damaging genetic changes. The remaining variants were then validated by comparison to a validation cohort of 121 breast cancer patients with no preselected age at cancer diagnosis (mean 51.4 years, range 28–80 years). Analysis of novel exonic variants was based on protein structure modeling. Results: Five novel, deleterious variants in the genes WRN, RNF8, TOP3A, ERCC2, and TREX2 were found in addition to a splice acceptor variant in RNF4 and two frameshift variants in EXO1 and POLE genes, respectively. There were also multiple previously reported putative risk variants in other DNA repair genes. Conclusions: Taken together, whole-exome sequencing yielded 72 deleterious variants, including 8 novel variants that may play a pivotal role in the development of early-onset breast cancer. Although more studies are warranted, we demonstrate that young breast cancer patients tend to carry multiple deleterious variants in one or more DNA repair genes. [ABSTRACT FROM AUTHOR]

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAVs) are a group of rare diseases with a chronic and relapsing course. Recent treatment guidelines offer many therapeutic options depending mainly on the type of diagnosis and disease manifestations. Areas that remain under discussion include whether all patients diagnosed with AAV belong to a homogeneous group with a similar prognosis at baseline or if the type and duration of remission-inducing treatment should depend on factors other than just diagnosis and disease severity. The aim of this review is to present the recent literature on the tools available to use while evaluating the risk of relapse in patients upon presentation as well as potential biomarkers of proceeding flare in patients upon remission. [ABSTRACT FROM AUTHOR]

Most rare diseases are caused by mutations and can have devastating consequences. Precise gene editing by CRISPR/Cas is an exciting possibility for helping these patients, if no irreversible developmental defects have occurred. To optimize gene editing therapy, reporter mice for gene editing have been generated which, by expression of reporter genes, indicate the efficiency of precise and imprecise gene editing. These mice are important tools for testing and comparing novel gene editing methodologies. This review provides a comprehensive overview of reporter mice for gene editing which all have been used for monitoring CRISPR/Cas-mediated gene editing involving DNA double-strand breaks (DSBs). Furthermore, we discuss how reporter mice can be used for quickly checking genetic alterations by base editing (BE) or prime editing (PE). [ABSTRACT FROM AUTHOR]

Background: The purpose of this paper is to address how to handle uncertainty when performing an economic valuation of a medical innovation R&D project in orphan diseases from the perspective of the investor. Methods: We describe the specific uncertainty related to cash flows and the cost of capital for innovation in orphan diseases. The uncertainty in cash flows relates to sales, manufacturing and R&D costs, and probabilities of failure for each phase in the clinical trial program. We consider different net present values (NPVs) and higher standard deviations for orphan drugs compared to non-orphan drugs. Results: Numerical case base examples showed the differences in trade-off by an investor for R&D projects with differences in NPV and level of uncertainty. The investor will transfer the additional uncertainty in cash flows in a higher cost of capital. An alternative approach is the application of an "acceptability curve" based on a probabilistic sensitivity analysis, which displays the cumulative probabilities at a range of different values for the NPV. Finally, we consider uncertainty in the cost of capital itself by applying the Capital Asset Pricing Model (CAPM). Conclusions: In this paper, we described various types of uncertainty and explored various approaches to how to handle uncertainty in the economic valuation of medical innovation in orphan diseases. The bridging of health economics with economic valuation theory in the healthcare market is to our knowledge a novel approach for the valuation of medical innovation by investors. [ABSTRACT FROM AUTHOR]

In summary, squamous cell carcinoma (SCC) of the gallbladder, although rare, poses significant diagnostic and therapeutic challenges. We report the case of a 51-year-old woman with no previous medical history, with SCC discovered during complicated cholecystitis with cholangitis, treated by palliative chemotherapy, underscoring the difficulty in early detection and the poor prognosis associated with advanced-stage diagnosis. Treatment options are limited, with palliative chemotherapy often being the primary recourse for unresectable tumors. Gallbladder cancers, including SCC, share risk factors with adenocarcinomas, but their distinct histopathological features and clinical presentations warrant careful consideration. Despite recent advancements in treatment modalities, including adjuvant therapy, optimal management strategies remain elusive, highlighting the need for further research to improve outcomes for patients with this aggressive malignancy. [ABSTRACT FROM AUTHOR]

Background: Caregiving experiences in rare diseases (RDs) vary based on factors such as specific clinical entity, disease severity, the child's age, and available support and resources, leading to challenges that significantly impact caregivers' lives. This study investigates whether caregivers of children with different RDs encounter varied aspects of care. Methods: This study was conducted as a self-administered, anonymous, computer-assisted online survey, focusing on the challenges of caregiving for children with RDs. Questions covered aspects such as information availability on RDs, diagnostic processes, modern treatment accessibility, family physicians and specialists, the impact of caregiving on personal life, family dynamics, and financial challenges. To achieve our study objectives, we categorized caregivers of children with RDs into two groups to compare various aspects of caregiving: caregivers of children with phenylketonuria (PKU) (n = 175) and those caring for children with life-limiting rare diseases (LLRD) (n = 226). Results: Caregivers of children with LLRD reported greater emotional challenges, personal sacrifices, and financial burdens compared to caregivers of children with PKU. Significant differences included heightened emotional distress, more frequent conflicts, and lower assessments of healthcare support among LLRD caregivers. Although family support ratings were similar between the groups, perceptions of financial concerns and interactions with the healthcare system varied significantly. Conclusions: This study, representing the inaugural systematic comparison of specific caregiver cohorts overseeing children with RDs across a substantial sample size, provides valuable insights. The findings lay a crucial foundation for precisely tailoring assistance and support initiatives to meet the unique needs of caregivers facing various RDs in diverse contexts. [ABSTRACT FROM AUTHOR]

Background: The diagnostic work-up of musculoskeletal tumors is a multifactorial process. During the early phase, differential diagnoses are made using basic radiological imaging. In this phase, part of the decision making is based on the patient's age, as well as the incidence and predilection sites of different entities. Unfortunately, this information is based on older and fragmented data. In this study, we retrospectively evaluated all soft-tissue and bone tumors around the knee in children treated at our tertiary center in the last 20 years, with the aim of verifying the data used today. Methods: In this retrospective study, the databank of our tertiary center was used to give an overview of treated tumors around the knee in children. Results: We were able to include 224 children with bone and soft-tissue tumors around the knee. The cohort consisted of 184 bone tumors, of which 144 were benign and 40 malignant. The 40 soft-tissue tumors comprised 30 benign and 10 malignant masses. The most common lesions were osteochondromas (88) in the bone and tenosynovial giant-cell tumors (12) in the soft tissue. Conclusions: With this original work, we were able to verify and supplement earlier studies, as well as deepen our insight into these very rare diseases. [ABSTRACT FROM AUTHOR]

The identification of the genetic causes of inherited disorders from next-generation sequencing (NGS) data remains a complicated process, in particular due to challenges in interpretation of the vast amount of generated data and hundreds of candidate variants identified. Inconsistencies in variant classification, where genetic centers classify the same variant differently, can hinder accurate diagnoses for rare diseases. Publicly available databases that collect data on human genetic variations and their association with diseases provide ample opportunities to discover conflicts in variant interpretation worldwide. In this study, we explored patterns of variant classification discrepancies using data from ClinVar, a public archive of variant interpretations. We found that 5.7% of variants have conflicting interpretations (COIs) reported, and the vast majority of interpretation conflicts arise for variants of uncertain significance (VUS). As many as 78% of clinically relevant genes harbor variants with COIs, and genes with high COI rates tended to have more exons and longer transcripts, with a greater proportion of genes linked to several distinct conditions. The enrichment analysis of COI-enriched genes revealed that the products of these genes are involved in cardiac disorders, muscle development, and function. To improve diagnoses, we believe that specific variant interpretation rules could be developed for such genes. Additionally, our findings underscore the need for the publication of variant pathogenicity evidence and the importance of considering every variant as VUS unless proven otherwise. [ABSTRACT FROM AUTHOR]

Genetic disorders affect over 6% of the global population and pose substantial obstacles to healthcare systems. Early identification of these rare facial genetic disorders is essential for managing related medical complexities and health issues. Many people consider the existing screening techniques inadequate, often leading to a diagnosis several years after birth. This study evaluated the efficacy of deep learning-based classifier models for accurately recognizing dysmorphic characteristics using facial photos. This study proposes a multi-class facial syndrome classification framework that encompasses a unique combination of diseases not previously examined together. The study focused on distinguishing between individuals with four specific genetic disorders (Down syndrome, Noonan syndrome, Turner syndrome, and Williams syndrome) and healthy controls. We investigated how well fine-tuning a few well-known convolutional neural network (CNN)-based pre-trained models—including VGG16, ResNet-50, ResNet152, and VGG-Face—worked for the multi-class facial syndrome classification task. We obtained the most encouraging results by adjusting the VGG-Face model. The proposed fine-tuned VGG-Face model not only demonstrated the best performance in this study, but it also performed better than other state-of-the-art pre-trained CNN models for the multi-class facial syndrome classification task. The fine-tuned model achieved both accuracy and an F1-Score of 90%, indicating significant progress in accurately detecting the specified genetic disorders. [ABSTRACT FROM AUTHOR]

Simple Summary: Neuregulin-1 (NRG1) is an important regulator of ErbB-mediated pathways involved in cancer development. Recently, there have been several studies analyzing NRG-1 gene fusions engaged in altering the dimerization of HER family proteins and the consecutive results of their activation in different types of cancer. Non-small cell lung cancer (NSCLC) patients can benefit from pan-HER inhibitors, and knowledge of NRG-1 fusions can help tailor the treatment to a specific group of patients. New drugs targeting cells with NRG-1 fusions are under clinical trials and show effectiveness in NSCLC treatment. Non-small cell lung cancer (NSCLC) presents a variety of druggable genetic alterations that revolutionized the treatment approaches. However, identifying new alterations may broaden the group of patients benefitting from such novel treatment options. Recently, the interest focused on the neuregulin-1 gene (NRG1), whose fusions may have become a potential predictive factor. To date, the occurrence of NRG1 fusions has been considered a negative prognostic marker in NSCLC treatment; however, many premises remain behind the targetability of signaling pathways affected by the NRG1 gene. The role of NRG1 fusions in ErbB-mediated cell proliferation especially seems to be considered as a main target of treatment. Hence, NSCLC patients harboring NRG1 fusions may benefit from targeted therapies such as pan-HER family inhibitors, which have shown efficacy in previous studies in various cancers, and anti-HER monoclonal antibodies. Considering the increased interest in the NRG1 gene as a potential clinical target, in the following review, we highlight its biology, as well as the potential clinical implications that were evaluated in clinics or remained under consideration in clinical trials. [ABSTRACT FROM AUTHOR]

Simple Summary: We systematically reviewed the literature on port site metastases in low- and intermediate-risk endometrial carcinoma. We searched six electronic databases and compared data on PSM from the included studies, finding seven studies and 13 cases of PSM in patients with low- or intermediate-risk endometrial carcinoma. Local resection and radiotherapy appear to be the most appropriate treatment approaches. Unfortunately, no consensus has been reached about treatment, and the prognosis appears poor. Background: Port site metastasis (PSM) has been reported as a rare metastasis in women with endometrial carcinoma (EC). However, even more rarely, it has also been described in patients with low- or intermediate-risk EC. Unfortunately, knowledge appears limited on the topic. Objectives: Our objective was to systematically review the literature on PSM in low- or intermediate-risk EC. Search Strategy: A systematic review of the literature was performed by searching six electronic databases from their inception to January 2023. Selection Criteria: We included in our research all peer-reviewed studies which reported PSM in low- or intermediate-risk EC women. Data Collection and Analysis: Data on PSM were collected from the included studies and compared. Results: Seven studies with 13 patients (including our case) were included in the systematic review. PSM was reported in patients with low- or intermediate-risk EC independently from tumor histologic characteristics, endoscopic approach, lymph node staging type, number and site of the port, route of specimen removal, prevention strategies for PSM, and concomitant metastases. Among several proposed treatments, local resection and radiotherapy with or without chemotherapy might be the most appropriate ones. Nevertheless, the prognosis appears poor. Conclusions: In patients with low- or intermediate-risk EC, PSM can occur as a rare metastasis, regardless of tumor characteristics or surgical strategy. Unfortunately, no consensus has been reached regarding treatment, and the prognosis appears poor. Additional cases are needed in order to confirm and further explore this rare EC metastasis. [ABSTRACT FROM AUTHOR]

Simple Summary: Pediatric, adolescent, and young adult (AYA) cancer patients, especially those with rare cancers, face unique challenges that traditional support systems may not adequately address. This study explores the potential of the metaverse, a virtual shared space, to provide psychological support and foster a sense of community among these patients. By utilizing customizable avatars and facilitating interactions across geographical and temporal barriers, the metaverse enables patients to connect with peers, share experiences, and receive emotional support. The anonymity provided by avatars helps reduce appearance-related anxiety and the stigma associated with cancer treatment. This research highlights the metaverse's potential to transform the delivery of psychosocial support for patients with rare cancers, offering a novel approach to patient care that transcends physical limitations and fosters a global patient community. The findings suggest that integrating virtual spaces into healthcare models can effectively meet the complex needs of pediatric and AYA cancer patients. This study investigated the potential of the metaverse in providing psychological support for pediatric and AYA cancer patients, with a focus on those with rare cancers. The research involved ten cancer patients and survivors from four distinct regions in Japan, who participated in metaverse sessions using customizable avatars, facilitating interactions across geographical and temporal barriers. Surveys and qualitative feedback were collected to assess the psychosocial impact of the intervention. The results demonstrated that the metaverse enabled patients to connect with peers, share experiences, and receive emotional support. The anonymity provided by avatars helped reduce appearance-related anxiety and stigma associated with cancer treatment. A case study of a 19-year-old male with spinal Ewing's sarcoma highlighted the profound emotional relief fostered by metaverse interactions. The findings suggest that integrating virtual spaces into healthcare models can effectively address the unique needs of pediatric and AYA cancer patients, offering a transformative approach to delivering psychosocial support and fostering a global patient community. This innovative intervention has the potential to revolutionize patient care in the digital age. [ABSTRACT FROM AUTHOR]

Branchio-oto-renal (BOR) and branchio-otic (BO) syndromes are characterized by anomalies affecting the ears, often accompanied by hearing loss, as well as abnormalities in the branchial arches and renal system. These syndromes exhibit a broad spectrum of phenotypes and a complex genomic landscape, with significant contributions from the EYA1 gene and the SIX gene family, including SIX1 and SIX5. Due to their diverse phenotypic presentations, which can overlap with other genetic syndromes, molecular genetic confirmation is essential. As sequencing technologies advance, whole-genome sequencing (WGS) is increasingly used in rare disease diagnostics. We explored the genomic landscape of 23 unrelated Korean families with typical or atypical BOR/BO syndrome using a stepwise approach: targeted panel sequencing and exome sequencing (Step 1), multiplex ligation-dependent probe amplification (MLPA) with copy number variation screening (Step 2), and WGS (Step 3). Integrating WGS into our diagnostic pipeline detected structure variations, including cryptic inversion and complex genomic rearrangement, eventually enhancing the diagnostic yield to 91%. Our findings expand the genomic architecture of BOR/BO syndrome and highlight the need for WGS to address the genetic diagnosis of clinically heterogeneous rare diseases. [ABSTRACT FROM AUTHOR]

Anderson–Fabry disease (AFD) is a genetic lysosomal storage disorder caused by mutations in the α-galactosidase A gene, leading to impaired lysosomal function and resulting in both macrovascular and microvascular alterations. AFD patients often exhibit increased intima-media thickness (IMT) and reduced flow-mediated dilation (FMD), indicating non-atherosclerotic arterial thickening and the potential for cardiovascular events. Nailfold capillaroscopy, a non-invasive diagnostic tool, has shown potential in diagnosing and monitoring microcirculatory disorders in AFD, despite limited research. This study evaluates nailfold capillaroscopy findings in AFD patients, exploring correlations with GLA gene variant subgroups (associated with classical or late-onset phenotypes and variants of uncertain significance (VUSs)), and assessing morpho-functional differences between sexes. It aims to determine whether capillaroscopy can assist in the early identification of individuals with multiorgan vascular involvement. A retrospective observational study was conducted with 25 AFD patients from AOUP "G. Rodolico-San Marco" in Catania (2020–2023). Patients underwent genetic testing, enzyme activity evaluation, and nailfold capillaroscopy using Horus basic HS 200 videodermatoscopy. Parameters like angiotectonic disorder, vascular areas, capillary density, and intimal thickening were assessed. The study identified significant differences in capillaroscopy findings among patients with different GLA gene variant subgroups. Classic AFD variant patients showed reduced capillary length and signs of erythrocyte aggregation and dilated subpapillary plexus. No correlation was found between enzymatic activity and capillaroscopy parameters. However, Lyso-Gb3 levels were positively correlated with average capillary length (ῤ = 0.453; p = 0.059). Sex-specific differences in capillaroscopy findings were observed in neoangiogenesis and average capillary length, with distinct implications for men and women. This study highlights the potential of nailfold capillaroscopy in the diagnostic process and clinical management of AFD, particularly in relation to specific GLA gene mutations, as a valuable tool for the early diagnosis and monitoring of AFD. [ABSTRACT FROM AUTHOR]

Moebius syndrome (MBS) is a rare congenital disorder characterized by non-progressive facial palsy and ocular abduction paralysis. Most cases are sporadic, but also rare familial cases with autosomal dominant transmission and incomplete penetrance/variable expressivity have been described. The genetic etiology of MBS is still unclear: de novo pathogenic variants in REV3L and PLXND1 are reported in only a minority of cases, suggesting the involvement of additional causative genes. With the aim to uncover the molecular causative defect and identify a potential genetic basis of this condition, we performed trio-WES on a cohort of 37 MBS and MBS-like patients. No de novo variants emerged in REV3L and PLXND1. We then proceeded with a cohort analysis to identify possible common causative genes among all patients and a trio-based analysis using an in silico panel of candidate genes. However, identified variants emerging from both approaches were considered unlikely to be causative of MBS, mainly due to the lack of clinical overlap. In conclusion, despite this large cohort, WES failed to identify mutations possibly associated with MBS, further supporting the heterogeneity of this syndrome, and suggesting the need for integrated omics approaches to identify the molecular causes underlying MBS development. [ABSTRACT FROM AUTHOR]

Polymyositis is a rarely reported complication of COVID-19 illness, especially in children. Molecular mimicry may be a cause of hyperactivated autoimmunity, leading to various clinical manifestations, including myopathies. Symptoms vary from mild muscle weakness to severe rhabdomyolysis. We review the literature on post-COVID myositis and report a case of severe polymyositis in a 7-year-old boy, following undefined viral infection 3 weeks before the onset of muscle pain. Patient's condition deteriorated from physical activity-associated pain in the lower limbs to severe muscle weakness leading to dysphagia and mechanical ventilation. As antibodies against SARS-CoV-2 were detected and other possible conditions causing myositis were excluded, the diagnosis of post-COVID polymyositis was considered as the most likely. The patient was treated with high doses of methylprednisolone and cyclophosphamide, resulting in improvement. Although COVID-19 is becoming a seasonal disease, the infection itself and post-viral disorders, such as polymyositis, are still of great interest and require better investigation to ensure appropriate management for each individual. Our experience suggests that aggressive immunosuppressive therapy might be a solution for severe post-COVID-related diseases. This literature review is provided in addition to the case report presented at the 29th European Paediatric Rheumatology Congress; the abstract is available online in the Proceedings of the 29th European Paediatric Rheumatology Congress. [ABSTRACT FROM AUTHOR]

Background: Abdominal tumors rarely occur in childhood but are associated with great psychological stress for patients and their families. Parents playing a central role in their children's treatment may experience adverse effects on their Health-Related Quality of Life (HRQoL) and mental health due to the children's illness and required treatment. Given the limited knowledge of the psychosocial burden of parents with children suffering from solid abdominal tumors, this study aims to assess their HRQoL and mental health along with the impact of various psychosocial factors. Methods: A cross-sectional cohort study was carried out involving 54 parents of children with solid abdominal tumors who had surgery at the University Medical Center Hamburg-Eppendorf in Germany. The results were compared with 46 parents of children undergoing routine surgeries without a prior tumor diagnosis, and with normative values. Data were obtained using standardized questionnaires. Results: Parents of the index group showed significantly worse HRQoL and limited mental health. Furthermore, they showed significantly higher parental burden in several subscales and less social support in comparison with the control group. Conclusions: Considering the lower parental HRQoL and the central role parents play in their children's lives, it is crucial to include prevention and intervention measures for parents as part of a multimodal treatment regime for children with solid pediatric abdominal tumors. [ABSTRACT FROM AUTHOR]

Simple Summary: This study analyzes 61 rare tumors and lesions mimicking peripheral nerve tumors using data from the German Peripheral Nerve Tumor Registry. These cases exhibit significant heterogeneity with various morphological features and biological potentials, including malignant peripheral nerve tumors, perineuriomas, and hybrid nerve sheath tumors. This study underscores the challenges in preoperatively differentiating these rare entities from benign tumors using clinical and radiological methods alone. It highlights the importance of a multidisciplinary approach involving radiologists, neurologists, neuropathologists, and neurosurgeons for accurate diagnosis and effective treatment. The supplementary material offers valuable insights to help clinicians recognize these rare tumors early, improving patient outcomes. The most common peripheral nerve tumors are of a benign nature and include schwannoma or neurofibroma. In rare cases, other tumors or non-tumorous lesions can mimic peripheral nerve tumors clinically or radiologically. Based on data from the multicentric German Peripheral Nerve Tumor Registry (PNTR), which encompasses current information on 315 surgically treated patients from three high-volume centers, we present 61 cases of rare tumors and lesions that mimic tumors associated with peripheral nerves. This cohort displays considerable heterogeneity, featuring a broad spectrum of morphological features and biological potentials. Histopathological diagnoses include various intrinsic peripheral nerve tumors such as malignant peripheral nerve tumors (MPNSTs) (n = 13), perineurioma (n = 17), and hybrid nerve sheath tumors (HPNSTs, comprising schwannoma/perineurioma and schwannoma/neurofibroma) (n = 14), as well as atypical neurofibromatous neoplasm with unknown biological potential (ANNUBP) (n = 1). Additionally, the cohort encompasses extrinsic tumorous lesions like lymphoma (n = 3), lymphangioma (n = 2), hemangioma (n = 2), solitary fibrous tumor (n = 2), metastatic disease (n = 1), and single cases of other rare tumor entities (n = 6). An overview of the underlying pathology, imaging features, and clinical presentation is provided, with a brief description of each entity. A definitive preoperative differentiation between benign peripheral nerve tumors and rare intrinsic and extrinsic tumors is often not possible. Clinical examination and subtle imaging clues can at least indicate the possibility of a rare entity. The basic requirement is close cooperation between radiologists, neurologists, neuropathologists, and neurosurgeons at a specialized center to develop a multidisciplinary concept and offer the patient the best therapeutic approaches. [ABSTRACT FROM AUTHOR]

Simple Summary: Epithelioid vascular tumors are rare bone vascular lesions with a spectrum of overlapping cancer entities with varying degrees of malignant potential that remain controversial because of their rarity, unusual morphologic features, and unpredictable biologic behavior. The classification of vascular tumors of bone proposed by the World Health Organization in 2020 incorporated morphologic findings with available genetic evidence, including mainly angiosarcoma, epithelioid hemangioma, pseudomyogenic hemangioendothelioma, and epithelioid hemangioendothelioma. Here, we report our experience with eleven patients suffering from epithelioid hemangioma (EH) of the spine. As very few cases of EH of the spine have been reported in the literature, the evidence-based decision-making process for these patients can be very difficult. Thus, we propose a treatment flowchart based on our single center's experience. Epithelioid hemangioma is recognized by the World Health Organization as a distinct benign neoplasm; however, it is characterized by locally aggressive and rarely metastasizing behavior. Epithelioid vascular tumors are rare bony vascular lesions with varying degrees of malignant potential that remain controversial because of their rarity, unusual morphological features, and unpredictable biological behavior. The application of new molecular tools, such as massive parallel sequencing technologies, have provided new diagnostic markers and an opportunity to further refine the classification of bone vascular neoplasms. Very few cases of EH of the spine have been reported in the literature; therefore, it is difficult to make evidence-based therapeutic decisions for these patients. We report herein our experience with eleven patients suffering from EH of the spine. The study population included three males and eight females treated in our center from 2016 to the present; the average age was 44.8 years (range 14–75 years). The surgical, clinical, and radiographic data were retrospectively analyzed. The mean follow-up was 34.8 months. All patients presented lytic vertebral body lesions, six of them with pathological fracture. The majority of patients (80%) presented myelo-radicular compression. All patients were surgically treated, and preoperative embolization was performed in all cases. In light of the literature review and the clinical experience of our center, we can consider EH a locally aggressive tumor that requires surgical treatment in case of symptoms. Here, we propose a treatment algorithm that could be useful in the management of patients with this rare disease. [ABSTRACT FROM AUTHOR]

Simple Summary: The European Network for Rare Cancers (EURACAN) Task Force on Ultra-Rare Brain Tumors (domain 10, subdomain 10) has reviewed the literature extensively regarding primary meningeal melanocytic tumors, which are ultra-rare entities that affect primarily children and young adults and represent an unmet need in neuro-oncology. The review covers the main histological and molecular factors, radiological findings, clinical features, and therapeutic challenges. Further efforts are needed to collect more knowledge on these rare brain tumors to improve the diagnostic tools and provide novel treatment strategies. Background: Primary meningeal melanocytic tumors are ultra-rare entities with distinct histological and molecular features compared with other melanocytic or pigmented lesions, such as brain and leptomeningeal metastases from metastatic melanoma. Methods: The European Network for Rare Cancers (EURACAN) Task Force on Ultra-Rare Brain Tumors (domain 10, subdomain 10) performed a literature review from January 1985 to December 2023 regarding the epidemiologic and clinical characteristics, histological and molecular features, radiological findings, and efficacy of local treatments (surgery and radiotherapy) and systemic treatments for these entities. Results: Molecular analysis can detect specific mutations, including GNAQ, GNA11, SF3B1, EIF1AX, BAP1, that are typically found in circumscribed primary meningeal melanocytic tumors and not in other melanocytic lesions, whereas NRAS and BRAF mutations are typical for diffuse primary meningeal melanocytic tumors. The neuroimaging of the whole neuroaxis suggests a melanocytic nature of a lesion, depicts its circumscribed or diffuse nature, but cannot predict the tumor's aggressiveness. Gross-total resection is the first choice in the case of circumscribed meningeal melanocytoma and melanoma; conversely, meningeal biopsy may be reserved for patients with diffuse and multinodular leptomeningeal spread to achieve a definitive diagnosis. High-dose radiotherapy is rarely indicated in diffuse melanocytic tumors except as palliative treatment to alleviate symptoms. Last, a definitive advantage of a specific systemic treatment could not be concluded, as most of the data available derive from case reports or small cohorts. Conclusions: As primary meningeal melanocytic tumors are extremely rare, the correlations between the clinical characteristics, molecular profile, radiological findings at diagnosis and progression are weak, and poor evidence on the best therapeutic approach is available. There is a need to develop shared platforms and registries to capture more knowledge regarding these ultra-rare entities. [ABSTRACT FROM AUTHOR]