Rare diseases (RD), though individually rare, collectively affect millions globally, spanning 5 to 8 thousand distinct conditions with unique challenges. These conditions often lack comprehensive information. The Brazilian Rare Diseases Network (RARAS) is a nationwide collaborative initiative comprising 40 healthcare institutions that, among its objectives, seeks to improve the visibility of rare diseases and disseminate evidence-based information through social media. A retrospective descriptive analysis of RARAS' social media metrics from March 2021 to July 2025 used data from Meta Business Suite. Between March 2021 and July 2025, the RARAS Network’s social media platforms accumulated 11,772 followers on Instagram® and 1,529 on Facebook®. Followers were predominantly Brazilian, female, and most frequently aged 35–44 years. A total of 576 Instagram posts were analyzed. Posts classified as Awareness & Education achieved the highest mean reach and engagement, whereas reels significantly outperformed static images and carousels (p < 0.001). Posts published during Rare Disease Month (February) also demonstrated substantially greater reach and engagement than those published during the remaining months. These findings suggest that strategic content planning, multidisciplinary collaboration, and continuous refinement of digital communication approaches may contribute to expanding the dissemination of evidence-based information on rare diseases through social media.
Purpose This study evaluates a patient-centered photography project aimed to enhance phenotypic characterization, assess caregiver quality of life, and foster public awareness for undiagnosed rare diseases. Methods Twenty patients with complex, undiagnosed conditions at Seoul National University Hospital were enrolled. Photography sessions captured natural facial expressions and typical body postures in everyday context. Caregivers completed the WHOQOL-BREF questionnaire. The resulting images were used in expert diagnostic forums and shared through public media. Results The cohort exhibited high medical complexity and early symptom onset with a median of 2 weeks. Caregivers reported significantly reduced QOL, with the physical domain and psychological domain scoring lower than caregivers of known neurodevelopmental disorders or chronic diseases. Qualitatively, families valued the sessions as meaningful emotional milestones beyond clinical documentation. Following the project, 17 news articles were generated, enhancing social inclusion and public understanding of the diagnostic odyssey. In addition, four patients received new diagnoses of genetic diseases, including RNU2-2 and RNU5B-1. Conclusion Patient-centered professional photography serves as a high-impact, low-risk intervention in rare disease care. By capturing real-life phenotypes, it facilitates expert collaboration and hypothesis generation while providing essential psychosocial support to families. This integrated approach extends the impact of undiagnosed disease programs beyond traditional genomics, addressing the emotional, identity-related, and societal dimensions of living with a rare condition.
Despite advances in genomic testing, a subset of patients with suspected monogenetic disorders remains undiagnosed for several years. Here, we report the resolution of a long-standing unsolved case through the 2024 Undiagnosed Hackathon in Nijmegen, highlighting the value of collaborative genome reanalysis. The patient was a 37-year-old man with global developmental delay, mild intellectual disability, facial dysmorphism, and severe hypertrophic cardiomyopathy. A molecular diagnosis remained elusive despite extensive prior testing including clinical exome sequencing performed in 2019. During the Undiagnosed Hackathon, analysis of short-read genome sequencing identified a novel heterozygous variant, c.71 G>A; p.(Gly24Asp) in RRAS2, a gene only recently associated with Noonan syndrome. Although the variant was absent from GnomAD, had a moderate REVEL score, and affected a highly conserved residue in a critical protein region, it initially remained classified as a variant of uncertain significance, due to the poorly characterized clinical spectrum associated with pathogenic RRAS2 variants, and the unavailability of parental samples to test for (expected) de novo occurrence. We therefore performed structural and functional studies of the variant, which provided evidence of a gain-of-function effect, enabling its reclassification as pathogenic and hereby establishing the diagnosis. Retrospective review of the 2019 exome data demonstrated that the variant had already been present in the original dataset but had not been prioritized because RRAS2 was not yet incorporated into the applied OMIM-based filtering pipeline. This case highlights the diagnostic value of collaborative genome reanalysis and the importance of functional studies in establishing pathogenicity in newly recognized rare disease genes.
A 6-year-old female with global developmental delay, chronic kidney disease (stage III), and renal tubular dysfunction was evaluated in the National Institutes of Health Undiagnosed Diseases Program. Although exome sequencing did not yield a diagnosis, family genome sequencing revealed biallelic variants in NDUFAF6, i.e., a paternally inherited intronic variant (NM_152416.3:c.298-768T>C) and a maternally inherited 1.6 kb deletion (NC_000008.11:g.95044573_95046180del, spanning exon 5). NDUFAF6 plays an important role in mitochondrial complex I assembly by regulating ND1 biogenesis and facilitating the incorporation of NDUFS8. Variants in NDUFAF6 are associated with two OMIM disorders i.e., Fanconi renotubular syndrome 5 (OMIM #618913) and Mitochondrial complex I deficiency, nuclear type 17 (OMIM #618239). The associated phenotypes include proximal tubule dysfunction and degeneration of the central nervous system. The intronic single nucleotide variant in this case (sometimes referred to as the Acadian variant) has been reported to cause aberrant splicing. This case highlights the need to consider comprehensive sequencing methods, such as genome sequencing, to identify atypical variants in planning a comprehensive diagnostic strategy.
Background: HNRNPH2-related neurodevelopmental disorder (H2-RNDD) is an ultra-rare genetic condition characterized by cognitive, motor, and behavioral impairments. Existing outcome measures often fail to capture the lived experiences of individuals with this disorder, particularly from the caregiver perspective. Objective: This study aimed to develop a person-centered conceptual model of daily functioning in individuals with HNRNPH2-related neurodevelopmental disorder based on caregiver perspectives. Methods: Using an adapted grounded theory approach, semi-structured interviews were conducted with 20 caregivers of individuals with HNRNPH2-related neurodevelopmental disorder across Europe and the United States. Thematic analysis was used to identify key domains of functioning, modifiers, and caregiver impacts. A conceptual model was iteratively developed and refined through caregiver feedback and literature triangulation. Results: Caregivers identified core symptoms (cognitive, communication, neurological, behavioral, visual, musculoskeletal, gastrointestinal), proximal and distal impacts on functioning (activities and participation), and personal and environmental modifiers. Caregivers also described their roles in supporting daily function and the emotional, physical, and financial impacts of caregiving. Communication, anxiety, seizures, socialization, planning for the future and guidance on practical care strategies were among the most meaningful aspects of functioning. The final conceptual model integrates these domains and highlights the central role of caregivers. Conclusions: This study presents the first caregiver-informed conceptual model of HNRNPH2-related neurodevelopmental disorder. The model provides a foundation for developing meaningful outcome measures and guiding clinical care and policy.
Objective Congenital anomalies affect about 2–3% of pregnancies of which 20% is likely to have genetic causes. Identifying the cause of fetal anomaly contributes significantly to successful genetic counseling for future pregnancies. This study aims to highlight the effectiveness of genetic testing of fetal tissues after mid-trimester pregnancy termination (MTPT) in deciphering the cause of fetal anomaly, predicting the risk of recurrence of anomalies in future pregnancy while also providing closure to the parents. Method This study is a case series of six pregnancies with fetal anomalies detected on ultrasonogram (n = 5), and/or history of miscarriages (n = 4), and planned for MTPT. Fetal tissue was collected after MTPT and appropriate genetic testing (CMA and/or WES/WGS and/or single gene/panel testing) was done based on the fetal anomaly. Result Testing resulted in identification of pathogenic or likely pathogenic cause for 4 out of 6 families. The remaining 2 families underwent comprehensive genetic testing, including single-gene or gene panel analysis, CMA, WES/WGS, and other relevant investigations, which did not yield any pathogenic findings. Conclusion In this case series, genetic evaluation of products of conception yielded a diagnosis in 4 out of 6 families, highlighting value of post termination genetic testing in couples with fetal anomalies.
Purpose Practicing a healthy lifestyle can be challenging for rare cancer (RC) survivors, as they may experience a more complex disease trajectory and higher psychosocial burden, compared to common cancer (CC) survivors. This study aimed to assess lifestyle differences between RC and CC survivors, and to evaluate which sociodemographic and clinical factors are associated with RC survivors’ lifestyle. Methods Cross-sectional data on five lifestyle factors were extracted from the PROFILES registry: alcohol consumption, tobacco smoking, body mass index (BMI), physical activity, and dietary changes. For each behaviour, a ‘healthy’ and ‘unhealthy’ score was defined, and a total lifestyle score was generated. Univariate and multivariate linear regression analyses were performed. Results Lifestyle factors differed significantly between RC (n = 2294) and CC (n = 12,212) survivors, with RC survivors classified as healthier regarding alcohol consumption, BMI, physical activity, and dietary changes, yet, unhealthier regarding tobacco smoking (all: p < 0.05). RC survivors showed a higher total lifestyle score than CC survivors (p < 0.001), and healthier lifestyles in RC survivors were found in, e.g., females and those having a medium or high socioeconomic status; unhealthier lifestyles were found in those aged 40–64 years (all: p < 0.05). Conclusion Except for tobacco smoking, RC survivors were found to have a healthier lifestyle and a higher total lifestyle score compared with CC survivors. Although findings are relatively positive for RC survivors, factors associated with unhealthy behaviour should be acknowledged and acted upon by healthcare professionals, and lifestyle programs in which RCs’ needs are being met, specifically for tobacco smoking, should be developed.
Purpose Families caring for children with rare diseases face sustained financial, emotional, and systemic challenges, yet cross-disease, cross-regional data remain limited. This study investigates the financial impact of caregiving from the perspective of rare disease advocacy organisations, rather than by caregivers themselves, focusing on costs, structural barriers, and potential reforms. Methods Semi-structured interviews were conducted with 45 rare disease organisations (24 U.S., 21 Europe). Purposive and snowball sampling ensured breadth. Interviews were transcribed, translated where needed, and thematically coded by six analysts using a validated framework (Cohen’s κ ≥ 0.80). Frequency analysis quantified recurring themes; narrative synthesis integrated cross-case patterns. Findings Eighty-two percent of organisations reported chronic caregiver financial distress, with average household income losses of €500–€2000 per month. Out-of-pocket costs for therapies, assistive devices, home adaptations, and travel were widely cited and often unreimbursed. Structural barriers, including restrictive eligibility, administrative complexity, and geographic inequities, were reported in more than 250 references. Approximately 80 % of caregivers were women, disproportionately facing employment disruption and emotional strain. Secondary impacts included debt, housing instability, marital breakdown, and reduced educational participation for affected children. Conclusion The financial toll of rare disease caregiving is compounded by fragmented support systems and inequitable access to benefits. Advocacy organisations identify urgent needs for caregiver recognition and compensation, streamlined benefit processes, expanded coverage for non-clinical costs, and harmonized cross-regional standards. These findings provide a policy-relevant evidence base to address structural drivers of caregiver financial hardship.
Rare diseases are often associated with a delayed diagnosis, poor outcomes, and fragmented care. It is estimated 170,000 people in Wales are living with a rare disease. The Syndrome Without A Name (SWAN) Clinic was established as the first service of its kind in the United Kingdom, to support patients with probable, undiagnosed rare diseases. Its objectives include reducing patients’ diagnostic odyssey, improving diagnostic rates, and enhancing care coordination. This pilot evaluation aimed to assess the impact the SWAN Clinic had on patient experiences and outcomes. Methods included patient-reported outcome measures (PROMs), patient-reported experience measures (PREMs), interviews with patients and their carers, and routinely collected clinical data. Results showed overwhelmingly positive user experience, particularly due to the clinic’s multidisciplinary and holistic approach. Non-significant improvements in self-management and perceived personal control were noted. Qualitative feedback indicated enhanced patient empowerment. To date, a diagnosis was achieved in 12.2% of adults, and 7.3% of paediatric patients referred to the clinic. However, among those who were reviewed and discharged, the combined diagnostic rate exceeds 61.0%. This suggests the clinic has the potential to meet its objectives. Beyond diagnosis, the SWAN Clinic improved treatment plans and provided reassurance to its users and has fostered international relationships and development. This evaluation demonstrated that the SWAN Clinic can provide more coordinated and patient-centred care than patients’ previous experiences of care.
Background Rare diseases affect a significant proportion of the global population and largely lack approved treatment options. With subsequent reliance on off-label use, medicine safety monitoring is important. A scoping review was conducted to identify what is known from the current global literature regarding adverse events associated with pharmacological treatments used for chronic rare diseases. Methods The scoping review was conducted according to the Arksey and O’Malley framework, and the Preferred Reporting Items for Systematic reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR) method. A Boolean search, including “rare disease” and “adverse” or “side effect”, was entered into Scopus, PubMed, Web of Science and Science Direct, to retrieve eligible publications from 2019 to 2024. Results In total, 4570 articles were retrieved and 139 included in the final analysis. Most were from high-income countries, involving biological agents, which were relatively well tolerated by patients. Immunosuppressant prescription was common (particularly corticosteroids), with associated typical adverse event profiles, highlighting the risk of infections. High treatment costs were observed, driven largely by biologicals, especially enzyme replacement therapies. Several articles featured repurposed medicines which varied in cost. Conclusions While newer treatments with improved safety profiles exist, their high cost prohibits access by many persons living with a rare disease (PLWRD), who are affected by long-term, sometimes fatal side effects of older therapies like immunosuppressants. Data is needed from low- and middle-income countries to address disparities in patient experiences. With ongoing safety monitoring, repurposing of medicines provides an important opportunity for progress toward equity for PLWRD.
Background Lipodystrophy syndromes are a group of very rare disorders characterized by a deficiency of adipose tissue, that can present with a broad range of symptoms. Delays in diagnosis are common, which can lead to potentially serious metabolic complications, high morbidity and poor quality of life. Methods Sixty-minute semi-structured interviews were conducted and objective analysis of transcribed responses performed in this qualitative assessment. Results Twelve individuals from across the UK with a lipodystrophy diagnosis (female 11/12) were included; familial partial lipodystrophy (10/12), congenital generalized lipodystrophy (1/12) and mandibular dysplasia with deafness and progeroid features (MDP) syndrome (1/12). The patient journey to lipodystrophy diagnosis can be long despite exhibiting signs and symptoms from a young age; age at diagnosis ranged from 16 to 60 years. Diagnosis was generally quicker in patients identified through family screening, whereas diagnosis took several years for those without a known familial case. Six participants were examined undressed, which in four cases helped lead to a diagnosis of lipodystrophy, although it was not always identified immediately. Some 'red flags' were identified in this analysis relating to insulin resistance and diabetes status, high blood pressure, and multiple negative tests for Cushing's Disease, which may serve to raise suspicion of lipodystrophy diagnosis and trigger further investigations. Conclusions Reaching a diagnosis of lipodystrophy may take years and is often too dependent on physicians' experience of the disease and determined individuals. Increased awareness and recognition of lipodystrophy syndromes may facilitate earlier diagnosis, better management and improved patient outcomes.
Leukoencephalopathy with brain calcifications and cysts (LCC), also known as Labrune Syndrome, is a rare cerebral microangiopathy caused by biallelic variants in the SNORD118 gene, which encodes the small nucleolar RNA (snoRNA) U8, a critical component of ribosome biogenesis. We present LCC cases with unusually protracted diagnostic trajectories. Case 1 had symptom onset in adolescence but remained undiagnosed until adulthood, while Case 2 had a transient occurrence of seizures in childhood and developed disabling motor symptoms in adulthood. Both were initially misdiagnosed—one with neurocysticercosis, the other with Fahr’s disease and multiple sclerosis—leading to inappropriate treatments. On evaluation, both probands exhibited asymmetrical spasticity with upper motor neuron weakness and pseudobulbar features. Genetic analyses confirmed compound heterozygous SNORD118 variants, including a rare upstream non-coding change (n.–6G>A). Neuroimaging revealed extensive leukoencephalopathy and calcifications, with cysts present in only one case. Notably, the severity of neuroimaging abnormalities contrasted with the milder or delayed clinical manifestations, underscoring phenotypic variability and the insidious nature of the disease process. These cases expand the clinical and imaging spectrum of SNORD118-related LCC, highlight diagnostic pitfalls and demonstrate challenges in variant detection due to incomplete coverage or reporting of non-coding regions in exome and genome sequencing. Greater awareness of LCC and improved interrogation of non-coding RNAs through clinical sequencing are essential for timely and accurate diagnosis.
Background Early diagnosis of Fabry disease (FD) is crucial to initiate treatment and mitigate disease progression but is hindered by the rarity and non-specific symptoms of disease. This study surveyed 20 index patients to explore their journey to diagnosis and sought to identify knowledge gaps and medical education needs for UK primary care physicians (PCPs) and specialists through interviews and meetings with Fabry specialist nurses and expert clinicians. Results Patients’ (13 females, 7 males) presented with symptoms at the median age of 13.0 years, with a median diagnosis delay of 10.1 years in index patients diagnosed between 2013 and 2023. Some had symptoms in childhood but were referred to a specialist after their 20 s; 45 % (9) were misdiagnosed (e.g. irritable bowel syndrome, rheumatoid arthritis, fibromyalgia). Neuropathic pain was the most common initial symptom. Patients consulted multiple specialists before a diagnosis; 55 % (11) of cases were identified by cardiologists, primarily following cardiac events, and 20 % (4) by ophthalmologists. Gaps in the diagnostic pathway included lack of awareness about FD symptoms by primary care practitioners and specialists, low referral rates, incorrect referrals, and misdiagnosis. Experts emphasised educating on key principles: FD’s treatability, the importance of early referral, consideration of FD in all patients regardless of age, sex, number of symptoms, or family history, and education with a holistic approach to patients’ symptoms. Conclusion A multidisciplinary medical education programme is required to boost disease awareness and improve diagnosis and, subsequently, treatment and outcomes in FD.
Testing for Childhood Cancer Predisposition (ChiCaP) syndromes is increasingly common in pediatric oncology as early identification can help adapt treatment and initiate surveillance. As such, ChiCaP testing can have medical, ethical, and psychological consequences for both the patients and their families, and present significant diagnostic challenges for pediatric oncologists. In response to these new opportunities and challenges, the Nordic ChiCaP Network was established in 2021, bringing together experts from pediatric and adult oncology, clinical genetics, molecular genetics, bioinformatics, epidemiology, psychology, anthropology, community medicine, law and ethics. Its primary goal is to advance our knowledge of ChiCaP in pediatric oncology research and care through an interdisciplinary approach. The network aims to achieve several key objectives: (1) to improve ChiCaP diagnostics, including gene-associated phenotypes and variant interpretation; (2) to advance understanding of the natural history, cancer risks, adverse treatment reactions, and comorbidities associated with ChiCaP syndromes; (3) to optimize and harmonize treatment protocols and surveillance strategies for affected patients and their families; (4) to address the ethical, legal and psychosocial aspects involved in testing, communication and counseling, diagnosing ChiCaP syndromes, and the impacts of surveillance on patients and their families; (5) to identify novel ChiCaP syndromes and explore their underlying mechanisms; and (6) to facilitate translation of research findings into clinical practice. By gathering interdisciplinary expertise and fostering collaboration across the Nordic countries, the Nordic ChiCaP Network will enhance knowledge and awareness of ChiCaP, improve early diagnosis, patient care, family support, and contribute to a better understanding of these complex genetic conditions.
The Ewing sarcoma family includes various bone and soft tissue tumors showing different degrees of neuroectodermal characteristics. Ewing's sarcoma primarily impacts the bones, with occurrences outside of these structures being quite rare. Extraosseous Ewing's sarcoma (EES), found outside of bones, is exceptionally rare, posing distinct diagnostic and therapeutic challenges. We describe a 49-year-old patient diagnosed with Ewing's sarcoma of the vulva. The patient initially noticed a painful vulvar mass measuring 3 cm in diameter near the urinary meatus. Imaging revealed a 5 cm tumor on the bladder's posterior base, extending into the pelvic fat. Initially misdiagnosed as a poorly differentiated infiltrating carcinoma, subsequent immunohistochemical staining identified the mass as vulvar Ewing sarcoma/PNET, with cells showing focal PS100 positivity and CD99 membrane positivity. A pelvic MRI confirmed 6.7 × 3.4 cm mass invading vulvar tissue. Further imaging and a bone marrow biopsy excluded metastasis. The treatment regimen included seven rounds of intensive chemotherapy using the VAC/IE protocol, supplemented by local definitive radiotherapy after the third chemotherapy cycle, showing positive results. The treatment plan was to continue with adjuvant chemotherapy. After four months, no disease recurrence was observed. This report details an uncommon case of EES that developed in the vulva, exploring its clinical signs, diagnosis, and treatment methods.
Objective: The Ehlers-Danlos Syndromes (EDS) are a group of multi-systemic, chronic conditions with complex symptomology. This systematic review aimed to synthesise what is known about the impact of EDS on Health-Related Quality of Life (HRQoL), and associated moderating factors, following a change in diagnostic criteria. Methods: Fifteen databases, grey literature and reference lists were systematically searched. A systematic review was performed following the Preferred Reporting Items for Systematic Reviews and guidelines for narrative synthesis. Findings were grouped according to outcomes, moderating factors, and measurement instrument. A further synthesis aligned outcomes with domains of HRQoL. Risk of bias was addressed using the Effective Public Health Practice Project assessment tool. Results: Eight quantitative studies met eligibility criteria. Findings indicate substantial impact due to symptoms and functional status. However, how HRQoL is measured potentially introduces bias such that other factors are overlooked. Conclusion: This review suggests key aspects of how HRQoL is experienced remain underexplored and underreported. Issues of methodological rigour raise further concerns around the usefulness of study findings. Further research is required to clarify how aspects of HRQoL are prioritised and experienced and how they can best be measured, to improve management of this debilitating condition.PROSPERO registration number CRD42022318979
Globally, millions of individuals are affected by rare diseases (RDs), yet there remains a significant gap in medical and life sciences education regarding RDs. This gap frequently leads to delays and challenges for patients in clinical settings and negatively impacts RD research. To address this, the EU-funded RareBoost project team organized the ‘Rare Hackathon’, as part of 2025 Rare Disease Day activities. The hackathon was designed as an educational event for undergraduate and graduate students, in which the student teams were asked to ‘solve’ two complex rare disease scenarios. Unlike similar hackathons, this event did not involve a patient cohort reanalysis. The teams developed diagnostic solutions, investigated genotype-phenotype correlations, and suggested experimental disease models to study gene-disease relationships. In a public session, the teams presented their solutions to a jury and received awards to further boost their scientific education. A post-event survey revealed that most students had limited prior exposure to RDs. The students reported that the hackathon helped them gain a better understanding of RD research, diagnosis, and challenges. Many students also expressed interest in working in the RD field in the future. Furthermore, students had valuable suggestions such as extending the event duration, incorporating training sessions, and including treatment design aspects. The Rare Hackathon successfully demonstrated how an extracurricular activity can raise awareness of RDs among medical and life sciences students. Incorporating similar events during students’ academic training can help close the gap in RD education, and as a result, improve outcomes for individuals living with rare conditions.
