Rare Disease Research Articles

Neoadjuvant chemotherapy followed by definitive local treatment in locally advanced sinonasal squamous cell carcinoma

BackgroundSinonasal squamous cell carcinoma (SCC) is a rare disease entity, comprising less than 5% of malignancies of the head and neck. While surgery is the primary treatment approach, neoadjuvant and adjuvant therapies play crucial roles in enhancing the prognosis of patients undergoing treatment with the goal of cure. In this study, we aimed to explore the treatment outcomes of neoadjuvant chemotherapy (NAC) in patients with locally advanced sinonasal SCC.MethodsMedical records of patients diagnosed of locally advanced (cT3-4b, N0-3) sinonasal SCC treated with a definitive aim between January 2005 and March 2023 were retrospectively reviewed. Patients were categorized into the following groups based on the initial treatment: NAC followed by surgery, NAC followed by concurrent chemoradiotherapy (CCRT), definitive CCRT, or upfront surgery. Initial treatment plan was decided by a multidisciplinary team. Primary endpoint was overall survival (OS) and objective response rate, and secondary endpoints were progression free survival (PFS), cumulative incidence of local and distant failures, and treatment-related toxicity. The treatment response was assessed according to the RECIST criteria.ResultsTotal 126 patients were included, and the median follow-up period was 25.6 months. The objective response rate to NAC was 48.2%. The subsequent resection rate was 70%, 42.9%, and 16.7% for patients with stage T3, T4a, and T4b disease, respectively. Two-year progression-free survival did not differ significantly between the NAC followed by surgery and upfront surgery groups (53.6% vs. 60.6%, P = 0.615) or between the NAC followed by CCRT and definitive CCRT groups (26.7% vs. 37.4%, P = 0.506).ConclusionNAC may be a valuable treatment option for patients with locally advanced sinonasal SCC, as it provides an opportunity for curative surgery and exhibits non-inferior oncological outcomes compared with upfront definitive local treatments.

Drug Repurposing for Rare (Orphan) Diseases—Scope and Limitations

Effective and affordable treatment for rare diseases remains a huge challenge. Only a few drugs have made inroads into the therapeutic arena for rare diseases. The current focus is shifted to different uses for expensive new drugs, referred to as drug repurposing. It is also called drug repositioning or reprofiling, refers to the identification of new therapeutic applications of existing or investigational drugs. This concept and novel approaches have promising role in the treatment of many potentially incurable diseases, particularly certain forms of cancer, neurodegenerative conditions, immunological disorders and uncommon infectious diseases. There are huge expectations filled with optimism that the drug repurposing would offer fresh opportunities for the treatment and management of rare diseases. This is undoubtedly more relevant for low and middle income countries.

Mail art methods and the social and cultural geographies of families affected by rare disease

ABSTRACT Building on geographic scholarship around disability and drawing on a programme of arts-based research, we bring attention to the social and cultural geographies of families affected by rare disease. Seeking creative methodological opportunities, we invited families to send us postcards as a means of sharing experiences and reflections. We contextualize the emergence of the postcard as a modality of communication, situating our work within a wider epistolary and artistic tradition, before examining the opportunities postcarding might produce for geographic and broader qualitative research, noting the forms conduciveness to multimodality and recent calls for more engagement with the medium. We detail our own practices of participatory postcarding and the questions, challenges, and hopes such raised. Analysing the postcards received, we discuss how such helps understand the shifting social and cultural geographies of rare disease, reflecting on themes of (in)accessibility and exclusion, changing domestic geographies, and the importance of, and challenges associated with, family-based identities and communities in the context of rare disease. Such highlights opportunities for disability geography to engage in cross-cutting conversations and agenda-building with the nascent area of family geographies, along with further geographic inquiry into the spaces and worlds of rare disease.

Genetic Variants Supporting the Diagnosis of Primary Ciliary Dyskinesia in Japan.

Primary ciliary dyskinesia (PCD; OMIM 244400) is a rare genetic disorder affecting motile cilia and is characterized by impaired mucociliary clearance in the airway epithelium that leads to chronic oto-sinopulmonary manifestations. To date, over 50 PCD-causing genes have been identified, with these genes and their variants varying globally across populations. We performed targeted resequencing of 42 PCD-causative genes in 150 Japanese patients suspected of having PCD and identified pathogenic or likely pathogenic variants in 51 patients. Among these, 24 patients exhibited a homozygous deletion of DRC1 exons 1-4, the most common cause of PCD in Japan. The allele frequency of this deletion was estimated at 0.0034 (95% CI: 0.0025-0.0044), based on bioinformatic analysis of 7906 whole-genome sequences from the general Japanese population. Additionally, RNA sequencing of nasal samples supplemented in silico variant predictions, aiding in the identification of causative variants. Considering potential ethnic differences, it is essential to accumulate global data on these variants and their functional impacts.

Implementing Real-Time Image Processing for Radish Disease Detection Using Hybrid Attention Mechanisms

This paper developed a radish disease detection system based on a hybrid attention mechanism, significantly enhancing the precision and real-time performance in identifying disease characteristics. By integrating spatial and channel attentions, this system demonstrated superior performance across numerous metrics, particularly achieving 93% precision and 91% accuracy in detecting radish virus disease, outperforming existing technologies. Additionally, the introduction of the hybrid attention mechanism proved its superiority in ablation experiments, showing higher performance compared to standard self-attention and the convolutional block attention module. The study also introduced a hybrid loss function that combines cross-entropy loss and Dice loss, effectively addressing the issue of class imbalance and further enhancing the detection capability for rare diseases. These experimental results not only validate the effectiveness of the proposed method, but also provide robust technical support for the rapid and accurate detection of radish diseases, demonstrating its vast potential in agricultural applications. Future research will continue to optimize the model structure and computational efficiency to accommodate a broader range of agricultural disease detection needs.

Preclinical research (on rare diseases): we need to talk about health equity.

There is a thriving, worldwide, biomedical research community working to understand the molecular bases of diseases of all types, continuously driving improved diagnostics and therapies. Developments in genetics and experimental medicine are yielding novel genetic therapies that were hardly dreamt of 40 years ago. But along with these scientific achievements, there exist challenges in ensuring that 21st century medical interventions are accessible to all who need them. This perspective will discuss how preclinical research, with a focus on rare diseases, can better contribute to healthcare ecosystems that are oriented towards greater health equity. This contribution may require changes to the prevailing scientific research culture that will need support from relevant institutions and the wider community.

Atypical neonatal cutaneous myiasis: A diagnostic challenge mimicking pustular rash in a resource-limited setting.

Neonatal cutaneous myiasis is a rare disease in newborns. Although it is unlikely, the level of suspicion for this condition should be high, especially in tropical regions. Treatment may deviate from the standard approach when necessary, and chemical debridement can be considered, particularly for smaller lesions. Ultimately, clinical judgment plays a key role in decision-making. Myiasis is the infestation of the skin of a mammal by larvae or maggots. The skin is the most affected organ. However, it can also affect other organs of the body. Gasterophilus and Hypoderma are two flies that produce creeping myiasis, a type of cutaneous myiasis our patient had. The infestation is common in Sub-Saharan Africa and most especially among rural dwellers. We report on a case of a 7-day-old term neonate who reported to St. Mary's Hospital Lacor, a Private-not-for-Profit hospital situated in the Northern region of Uganda, who was admitted as a case of neonatal sepsis with a focus on the skin initially, however, while on the ward was eventually diagnosed with Cutaneous Myiasis. The management plan included chemical debridement with Hydrogen peroxide, IV antibiotics, and other supportive therapies, and the neonate was ultimately discharged home after 9 days in the NICU. This case report aims to inform healthcare workers of the importance of heightening the index of suspicion of myiasis for neonates who present with sudden-onset rash that can resemble pustules and be mistaken for a pustular rash. Additionally, chemical debridement, in this case, underscores the importance of an innovative approach to managing cutaneous myiasis in resource-limited settings. Mass education and awareness programs focusing on proper hygiene practices, safe handling of newborns, and early recognition of symptoms can help mitigate the risk of myiasis.

An Overview of Myeloid Blast-Phase Chronic Myeloid Leukemia

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.

Comprehensive reanalysis for CNVs in ES data from unsolved rare disease cases results in new diagnoses

We report the results of a comprehensive copy number variant (CNV) reanalysis of 9171 exome sequencing datasets from 5757 families affected by a rare disease (RD). The data reanalysed was extremely heterogeneous, having been generated using 28 different enrichment kits by 42 different research groups across Europe partnering in the Solve-RD project. Each research group had previously undertaken their own analysis of the data but failed to identify disease-causing variants. We applied three CNV calling algorithms to maximise sensitivity, and rare CNVs overlapping genes of interest, provided by four partner European Reference Networks, were taken forward for interpretation by clinical experts. This reanalysis has resulted in a molecular diagnosis being provided to 51 families in this sample, with ClinCNV performing the best of the three algorithms. We also identified partially explanatory pathogenic CNVs in a further 34 individuals. This work illustrates the value of reanalysing ES cold cases for CNVs.

Quadriplegia In Accidently Diagnosed Distal Renal Tubular Acidosis with Pneumonia (Case Report)

Distal renal tubular acidosis (RTA1) is a rare disease. It confirms the lab’s data and rules out other differential diagnoses. Late evaluation can interfere with healthy development. We explain a 38-year-old patient with a late and accidental RTA1 diagnosis. Correct treatment with alkali consumption and potassium citrate improves her general condition and eliminates further weakness attacks. Early diagnosis is crucial for patient development and morbidity avoidance with accurate treatments.

Desmopressin dosing in children using real-world data and pharmacokinetic/pharmacodynamic model simulations.

Variability in pediatric dosing of desmopressin (ddAVP) in AVP-deficiency (AVP-D) is well-documented but dosing recommendations are limited. This study evaluates and optimizes ddAVP dosing regimens in children with AVP-D using pharmacokinetic and pharmacodynamic (PK/PD) simulations. Retrospective electronic health record review was done to identify children (<18 years) with AVP-D on ddAVP evaluated in the outpatient setting using ICD 9 and 10 codes. A previously developed PK/PD model from Michelet et al was used to simulate ddAVP concentrations and urine rates based on a child's age and ddAVP dose. The effects of demographic characteristics (age, weight, etc.) on dose and urine rate were investigated through simulations to optimize doses of ddAVP for children who were wet overnight. A total of 276 dosing records were identified among 53 children with AVP-D. Simulations indicated that in children under 5 years of age who were wet overnight, increasing the outpatient dose to 50 mcg was predicted to decrease urine rate to a pattern similar to those who remained dry. An initial outpatient dose of at least 50 mcg for children between 1 and 5 years of age would improve efficacy of ddAVP. 50 mcg is likely a safe initial outpatient dose of oral desmopressin tablet for young children 1-5 yrs of age with central Diabetes Insipidus/AVP-Deficiency. We confirmed that desmopressin doses vary greatly in children with central Diabetes Insipidus/AVP-deficiency. Real-world clinical data can be leveraged to improve medication dosing in rare diseases.

Riedel’s thyroiditis: A case report and review of the ultrasound findings of this rare disease entity

Introduction: Riedel’s thyroiditis is a rare inflammatory disease of the thyroid with non-specific and varied presentations. A typical presentation and ultrasound findings are reported in this case. Case Report: A 68-year-old male is referred to Ear, Nose and Throat for a neck lump that varied in size over 2 years. An ultrasound scan identified a suspicious nodule on the left thyroid that was biopsied confirming the diagnosis of Riedel’s thyroiditis. Discussion: The aetiology, presentation and management of Riedel’s thyroiditis are explored. The use of ultrasound and the utility of other imaging and biochemical tests are discussed. Conclusion: Riedel’s thyroiditis is a difficult condition to diagnose due to rarity, varied presentation, with non-specific clinical, biochemical and radiographic findings which often mimic thyroid cancers. Definitive diagnosis of Riedel’s thyroiditis requires histological analysis, and while fine-needle aspirations are typically insufficient, diagnostic samples can be taken with ultrasound-guided core biopsies.

Regulation of HTT mRNA Biogenesis: The Norm and Pathology

Huntington’s disease (HD) is a neurodegenerative disorder caused by the expansion of the CAG repeat in exon 1 of the HTT gene, leading to the formation of a toxic variant of the huntingtin protein. It is a rare but severe hereditary disease for which no effective treatment method has been found yet. The primary therapeutic targets include the mutant protein and the mutant mRNA of HTT. Current clinical trial approaches in gene therapy involve the application of splice modulation, siRNA, or antisense oligonucleotides for RNA-targeted knockdown of HTT. However, these approaches do not take into account the diversity of HTT transcript isoforms in the normal conditions and in HD. In this review, we discuss the features of transcriptional regulation and processing that lead to the formation of various HTT mRNA variants, each of which may uniquely contribute to the progression of the disease. Furthermore, understanding the role of known transcription factors of HTT in pathology may aid in the development of potentially new therapeutic tools based on endogenous regulators.

Clinical characteristics of renal anastomotic hemangioma.

In this editorial, we comment on the article by Chen and Cai. We focus on renal anastomotic hemangioma, which is a rare benign hemangiomatous disease. This disease has unique clinical characteristics. Its biological behavior is benign, but its imaging results are similar to those of renal cancer. Renal anastomotic hemangioma is easy to misdiagnose and can lead to unnecessary radical nephrectomy. Therefore, urologists need a better understanding of this disease. We believe that patients with renal anastomotic hemangioma should receive individualized diagnosis and treatment to avoid overtreatment.

A novel MAOA gene variant: Brunner syndrome, a rare syndrome, is associated with a wide range of psychiatric symptoms.

Brunner syndrome is a rare genetic disorder that associated with mutations in the MAOA gene. It has been linked to a number of psychiatric disorders. We present detailed information on psychiatric evaluation of a case carrying a novel MAOA gene variant of p.(Thr408Met). The patient was referred to our clinic with a history of attention problems, motor coordination difficulties and a tendency to bite objects. Following a comprehensive psychiatric evaluation, the patient was diagnosed with developmental coordination disorder, articulation disorder and attention deficit hyperactivity disorder (ADHD). MAOA mutations are rarely reported in the literature. To date, a total of 23 MAOA gene variants, mostly missense variants, have been reported through the HGMD database (Professional 2023.4). Neurodevelopmental symptoms may vary in severity and diversity among patients with Brunner syndrome. Different degrees of intellectual disability have been found in previously reviewed cohorts of Brunner syndrome. In our affected patient, cognitive development and academic achievement were at a similar level to his peers. Additionally, our patient exhibited symptoms suggestive of developmental coordination disorder. Our findings show that genetic mutations in MAOA can lead to a wide range of clinical symptoms and underline the need for comprehensive genetic and clinical evaluations.

Fibrodysplasia ossificans progressiva: a comprehensive review

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder that causes heterotopic ossification of soft tissues, leading to abnormal bone growth in muscles, tendons, and ligaments. First identified in the 17th century, FOP was classified in 1968 and is linked to a mutation in the Activin A receptor type I gene (ACVR1) which affects bone morphogenetic protein (BMP). The autosomal dominant condition FOP has the potential to lead to aberrant bone development. At birth, FOP individuals appear normal, except for characteristic malformations of the great toes. FOP patients develop painful, inflammatory soft tissue swellings during the first decade of life, often precipitated by soft tissue injury. Minor trauma can trigger new flare-ups and leads to progressive heterotopic ossification. Most FOP sufferers are wheelchair-bound by their third decade and needs lifelong assistance with daily living tasks. Bone morphogenetic proteins (BMPs) are bound by the transmembrane kinase receptor ALK2, which is encoded by the (ACVR1/ALK2 gene). FOPs induce heterotopic bone formation in skeletal muscle and can be caused by mutations in the activin A receptor type I (ACVR1) and activin-like kinase 2 (ALK2) gene. Clinical therapy focuses on preventing and controlling inflammation, with ongoing research focusing on specific therapies targeting receptor activity, aberrant pathways, or cellular components influencing bone neo-formation.

Wilson’s disease: A Comprehensive Review of Genetics, Pathophysiology, Clinical Symptoms, Diagnostic Techniques and Current Treatment

Introduction: Wilson's disease (WD) is a genetic disease, inherited in an autosomal recessive manner, caused by a mutation in the ATP7B gene, which results in impaired excretion of copper in the bile. This causes the accumulation of copper in various tissues and organs, leading to their damage. The range and severity of symptoms are wide, so diagnosis is difficult and requires a high index of suspicion. The most common clinical symptoms are hepatic and neuropsychiatric symptoms. Diagnosis is based primarily on clinical suspicion, typical symptoms and reduced serum ceruloplasmin concentration. Treatment includes pharmacological therapies, and in some cases liver transplantation is necessary. Wilson's disease, if left untreated, inevitably leads to serious disability and death. Purpose of the work: This study aims to review and characterize the clinical and pathophysiological aspects of Wilson’s disease. Materials and methods: A comprehensive analysis of research papers available on PubMed, Google Scholar, Web of Science, Embase and Scopus was undertaken using the searchterms encompassing the following keywords: Wilson’s disease, Copper metabolism, Copper toxicity, ATP7B, Ceruloplasmin, Gene Mutation Results: Wilson's disease is a rare genetic disorder that can lead to severe disability and even death. For this reason, rapid diagnosis and appropriately selected and individualized treatment play a key role. Wilson's disease remains a major diagnostic challenge, but new techniques for its diagnosis, such as genotype analysis, mainly through sequencing, as well as newborn screening, may significantly improve patient prognosis in the future.

The Impact of COVID-19 on RNA Therapeutics: A Surge in Lipid Nanoparticles and Alternative Delivery Systems

The COVID-19 pandemic has significantly accelerated progress in RNA-based therapeutics, particularly through the successful development and global rollout of mRNA vaccines. This review delves into the transformative impact of the pandemic on RNA therapeutics, with a strong focus on lipid nanoparticles (LNPs) as a pivotal delivery platform. LNPs have proven to be critical in enhancing the stability, bioavailability, and targeted delivery of mRNA, facilitating the unprecedented success of vaccines like those developed by Pfizer-BioNTech and Moderna. Beyond vaccines, LNP technology is being explored for broader therapeutic applications, including treatments for cancer, rare genetic disorders, and infectious diseases. This review also discusses emerging RNA delivery systems, such as polymeric nanoparticles and viral vectors, which offer alternative strategies to overcome existing challenges related to stability, immune responses, and tissue-specific targeting. Additionally, we examine the pandemic’s influence on regulatory processes, including the fast-tracked approvals for RNA therapies, and the surge in research funding that has spurred further innovation in the field. Public acceptance of RNA-based treatments has also grown, laying the groundwork for future developments in personalized medicine. By providing an in-depth analysis of these advancements, this review highlights the long-term impact of COVID-19 on the evolution of RNA therapeutics and the future of precision drug delivery technologies.

Синдром Шпринтцзена-Гольдберга: клиническое наблюдение

Authors represent bibliographical review and a clinical case report of Shprintzen-Goldberg syndrome (SGS) in an infant. SGS is a rare genetic disease that has been poorly studied and is of a practical and scientific interest due to the difficulty of its diagnosis, a fairly complex description of the phenotype and clinical polymorphism of manifestations. The purpose for publishing of this particular case report was to familiarize pediatric practitioners with this rare hereditary syndrome since there are no consensual clinical guidelines for the management of patients with SGS as yet. Identification of hereditary diseases accompanied by disruption of the structure and function of the musculoskeletal, cardiovascular and nervous systems would allow determining a more accurate plan for managing of a pediatric patient as well as establishing a possible prognosis for the patient’s further development, which is the number one problem considered by both parents/caregivers and physicians.

The NIPBL-gene mutation of a Cornelia de Lange Syndrome patient causes deficits in the hepatocyte differentiation of induced Pluripotent Stem Cells via altered chromatin-accessibility

The Cornelia de Lange syndrome (CdLS) is a rare genetic disease, which is characterized by a cohesinopathy. Mutations of the NIPBL gene are observed in 65% of CdLS patients. A novel iPSC (induced Pluripotent Stem Cell) line was reprogrammed from the leukocytes of a CdLS patient carrying a missense mutation of the NIPBL gene. A mutation-corrected isogenic iPSC-line and two iPSC-lines generated from the healthy parents were used as controls. The iPSC lines were differentiated along the hepatocyte-lineage. Comparative immunofluorescence, RNA-seq and ATAC-seq analyses were performed on undifferentiated and differentiated iPSCs. In addition, chromatin organization was studied by ChIP-Seq analysis on the patient derived iPSCs as well as the respective controls. Relative to the mutation-corrected and the healthy-parents iPSCs, the patient-derived counterparts are defective in terms of differentiation along the hepatocyte-lineage. One-third of the genes selectively up-regulated in CdLS-derived iPSCs and hepatic cells are non-protein-coding genes. By converse, most of the selectively down-regulated genes code for transcription factors and proteins regulating neural differentiation. Some of the transcriptionally silenced loci, such as the DPP6 gene on chromosome 7q36.2 and the ZNF gene cluster on chromosome 19p12, are located in closed-chromatin regions. Relative to the corresponding controls, the global transcriptomic differences observed in CdLS undifferentiated iPSCs are associated with altered chromatin accessibility, which was confirmed by ChIP-Seq analysis. Thus, the deficits in the differentiation along the hepatocyte lineage observed in our CdLS patient is likely to be due to a transcriptional dysregulation resulting from a cohesin-dependent alteration of chromatin accessibility.