Genomics is transforming health care but its implementation raises challenges. This paper reports a 2025 workshop on justice in the implementation of genomics for rare disorders. The workshop goals were to develop a consensus understanding of the problems faced by rare disease patients and families where justice is at stake, to achieve a shared perspective on support for rare disease patients, and to consider the implications for justice in several areas of rare disease genomics, in both research and healthcare. We heard about the diverse experiences and needs of patients. Inequity between different rare diseases is marked. The need for coordination of care for rare disease patients is under-recognized but good models of rare disease care exist. The value of conscientious professionalism to nurture a rare disease mindset needs to be emphasized in the training of each new generation of healthcare students//trainees. The circumstances of different population groups differ systematically. The needs of indigenous and other historically marginalised groups must also be addressed. However, the subordination of individuals to the benefit of the population (i.e. eugenics) must be resisted. Those engaged in genomics projects or diagnostics may need protection from hype and misuse of their personal data, There are different perspectives on the fair allocation of resources to healthcare and research for rare conditions. Health economics and health technology assessment can be practised equitably, so as to meet the challenges of rare disease clinical trials and address the needs of patients and communities.

Architectural and translational perspectives on clinical decision support systems for rare disease diagnosis: a scoping review.

With around 7% of the population affected, rare diseases (RD) altogether represent arelevant group of conditions in Europe. One of the central problems of RD care is delayed diagnosis (on average 6-8years), which has serious implications for the prognosis, treatment and quality of life of those affected. Primary caretakers play acrucial role in attempts to improve this situation, since they are the ones who identify suspected cases and take charge of their coordination. The implementation of astructured diagnostic pathway could considerably reduce the burden on primary caretakers, effectively shorten the time to diagnosis and lower costs for the healthcare system. Therefore, the following article maps out aconcrete strategy. It contributes to strengthening primary caretakers in their role as central coordinators, as well as to improving cooperation between primary caretakers, patients affected by RD, specialists and centres for RD.

Patient experience informing outcomes and research in rare disease: Citrin deficiency as a case study.

Health technology assessment (HTA) informs evidence-based decision-making for resource allocation in healthcare; however, the topic selection phase that determines which technologies proceed to full assessment is underexplored and often lacks fairness and transparency, particularly disadvantaging orphan medicinal products (OMPs) for rare diseases. We drew on selectively identified literature and illustrative HTA experiences to advance an opinion-driven argument about equity in topic selection for OMPs, grouping insights into three domains: structural challenges, conceptual frameworks and policy strategies. Structural barriers in topic selection include a lack of institutionalised, participatory processes, overreliance on prioritisation criteria implicitly aligned with population-wide impact and minimal engagement with stakeholders representing the rare disease community, resulting in the systematic under-prioritisation of OMPs. Procedural and value frameworks, including multi-criteria decision analysis (MCDA), evidence-informed deliberative processes (EDPs), accountability for reasonableness (A4R), equity weighting and Health Equity Impact Assessment (HEIA), can help agencies incorporate social value and fairness before formal appraisal, but remain unevenly operationalised. Policy strategies such as equity-oriented horizon scanning, open nomination systems, and special pathways for OMPs are highlighted as feasible approaches to promote fairness. Achieving equity in HTA topic selection for OMPs requires both policy and cultural change, and embedding pluralistic value frameworks, engaging stakeholders and adopting specific policy tools are essential steps towards ensuring that rarity is met with heightened ethical attention rather than exclusion.

Resistance to thyroid hormone alpha (RTHα) is a rare genetic disorder with symptoms of hypothyroidism, but normal or close-to-normal thyroid function tests. Treatment with levothyroxine (L-T4) may be beneficial. This study investigated the efficacy, safety and biochemical changes of high-dose L-T4 and liothyronine (L-T3) treatment. Four RTHα (Ala263Val) patients were treated with L-T4 (1.75 µg/kg) in a pilot open-label study and monitored for three years. Quality of life (QoL) was assessed using ThyPro. Analysis of auxiological- and biochemical-parameters, bone mineral density (BMD) and exploratory metabolomics was performed. A partial replacement of L-T4 with L-T3 was attempted. Treatment with L-T4 increased FT4, FT3, and rT3 to supraphysiological concentrations (relative to reference intervals) and suppressed thyroid-stimulating hormone with no adverse effects. Heart rate, bone markers, and sex hormone-binding globulin transiently increased. Several classes of lipids were reduced. BMD appeared unaltered. Patients reported improved QoL. One patient presented a short non-sustained ventricular tachycardia on L-T3 + L-T4. L-T4 treatment of adult RTHα patients was safe and improved QoL in adherent patients.

Primary ciliary dyskinesia (PCD) is a rare genetic disorder that causes chronic lung disease. Patients with PCD often experience pulmonary exacerbations with worsening symptoms and lung function decline. This review provides an overview of the existing knowledge regarding the PEx in PCD and reveals understudied topics that should be addressed in the future. We describe the different PCD-specific PEx definitions that exist in the literature, and provide data on the frequency of PEx. Few studies targeted the pathophysiology of PEx, with a focus on the most common microorganisms in the airways and on inflammatory markers that are increased in the sputum (total cells, neutrophils, neutrophil elastase, interleukin-8). Several risk factors for PEx have been identified, among them female sex, age, and airway infection with Pseudomonas aeruginosa. Lung clearance index appears to be a good prognostic factor for future PEx. Current treatment and prevention strategies are described. Further research is needed to enhance our knowledge on PEx mechanisms, on appropriate treatment therapies, and on the long-term consequences of this condition.

Xia-Gibbs syndrome (XGS) is a rare neurodevelopmental disorder caused by heterozygous variants in the AHDC1 gene. While the core phenotype includes developmental delay, hypotonia, and expressive language impairment, the syndrome displays considerable clinical and genetic heterogeneity. Data from non-European populations remain scarce. We report the clinical and molecular findings of five unrelated Turkish patients with XGS diagnosed via whole-exome sequencing (WES). This is a multicenter study, and clinical data were collected from participating centers using standardized forms. All patients carried heterozygous, de novo AHDC1 variants (three frameshift, two nonsense), all of which were classified as pathogenic or likely pathogenic. Three of these, p.(Ala1432Profs13), p.(Val900Glyfs2), and p.(Val704Profs*26), are novel and predicted to cause protein truncation. Nonsense mutations are p.(Arg108*) and p.(Trp638*), which were previously reported as disease-causing. One patient had dual diagnoses with AHDC1 and CDK13 variants, explaining ocular and cardiac anomalies, leading to a particularly severe neurodevelopmental phenotype. This is the largest study reported to date in Turkey on XGS, a rare genetic disorder, further expanding the disease's genotypic and phenotypic spectrum. Recognition of dual diagnoses in a single patient underscores the value of WES in detecting complex genotypes and avoiding misattributed genotype-phenotype associations. As a recently described syndrome, careful evaluation of patients with XGS for atypical phenotypes may provide important contributions to the clinical presentation described in the literature.

Fibrillary glomerulonephritis (FGN) is a rare glomerular disease characterized by proteinuria, hematuria, renal insufficiency, and hypertension and was first described in 1977. Rare cases of lupus nephritis (LN) have been reported to show fibril formation similar to that observed in FGN. To date, only 6 cases of FGN associated with systemic lupus erythematosus have been reported. We report a case of LN combined with FGN in a 27-year-old Chinese woman presenting with World Health Organization class III LN (full-house immunofluorescence staining, strong C1q staining, high-density electron-dense immune complex deposits). At higher magnification, electron microscopy revealed randomly oriented, non-branching fibrils averaging 20nm in the mesangial, subepithelial, and endothelial regions. Immunohistochemical staining of DnaJ homologous subfamily B member 9 (DNAJB9) is a recently discovered marker of FGN, featuring high sensitivity (98%) and specificity (>99%), and is now widely regarded as a pathological feature of FGN. Mass spectrometry, an analytical technique that ionizes chemicals and ranks them according to their mass-to-charge ratio, is a promising approach for studying extremely rare and unknown causes of kidney disease. We used immunohistochemistry and mass spectrometry to confirm the high sensitivity and specificity of DNAJB9 in this case, thereby establishing the diagnosis of LN combined with FGN. The patient was treated with prednisone, hydroxychloroquine, and mycophenolate mofetil. Two years after treatment, kidney function remained normal. Rare cases of LN show fibrogenesis similar to that of FGN. It remains uncertain whether fibril formation in such cases represents a unique manifestation of LN or LN with superimposed FGN. This case highlights the importance of mass spectrometry and DNAJB9 immunostaining in confirming rare glomerular disease patterns.

Desmoplastic small round cell tumor (DSRCT) is an ultra-rare, fusion-driven sarcoma with a dismal prognosis despite multimodal therapy. Most patients present with advanced intra-abdominal and/or metastatic disease at diagnosis, and long-term survival remains uncommon. This review summarizes recent advances in the molecular and biological understanding of DSRCT. It highlights current diagnostic and therapeutic standards, and discusses emerging targeted and immunotherapeutic strategies with translational relevance. DSRCT is defined by the pathognomonic EWSR1::WT1 fusion, which acts as an aberrant transcription factor driving oncogenesis. Although there is no consensus standard of care, multimodal strategies combining dose-intense chemotherapy, complete cytoreductive surgery, and whole abdominopelvic radiotherapy remain the cornerstone of management when feasible. However, outcomes remain poor, particularly in patients with extra-peritoneal disease. Recent genomic studies have identified actionable vulnerabilities, including dysregulation of the angiogenic pathways, and IGF axis. In parallel, innovative immunotherapeutic approaches - particularly antibody-drug conjugates targeting HER2 and B7-H3 - have shown encouraging early signals of activity. Despite multimodal treatment, DSRCT remains a highly lethal malignancy. Advances in molecular characterization are reshaping the therapeutic landscape and supporting the development of targeted strategies, especially antibody-drug conjugates. Enrollment in prospective clinical trials and international collaborative efforts are essential to improve outcomes in this orphan disease.

The Orphan Disease: Outcomes After Lung Transplantation for Pulmonary Veno-Occlusive Disease: A Propensity-Matched National Database Study

Congenital myasthenic syndromes (CMS) are inherited disorders caused by mutations in genes encoding proteins essential for neuromuscular junction (NMJ) function. Pathogenic variants have been identified in more than 35 genes, underscoring the complexity of synaptic biology and the wide range of mechanisms that can compromise neuromuscular transmission. Among these, CMS due to mutations in AGRN, LRP4, and MUSK genes represent presynaptic and postsynaptic defects that offer valuable mechanistic insights. These mutations impair agrin/LRP4/MuSK signaling, disrupt NMJ formation and stability, and underlie phenotypes with variable clinical presentations, ranging from ptosis and fatigability to distal, bulbar, or respiratory weakness. These subtypes often show limited efficacy or even clinical worsening with acetylcholinesterase inhibitors, whereas adrenergic agonists such as salbutamol or ephedrine can provide significant benefit in selected cases. The study of these forms not only provides key insights into the molecular regulation of synapse development and maintenance, but also illustrates the challenges of establishing genotype-phenotype correlations in rare diseases, in which inter-individual variability complicates diagnosis and management. Recent advances in next-generation sequencing and functional studies have expanded the recognized mutation spectrum, uncovered novel pathogenic mechanisms, and improved the accuracy of molecular diagnosis. In this review, we provide a comprehensive overview of AGRN, LRP4, and MUSK-related CMS, integrating clinical, genetic, and mechanistic data from patients and experimental models. By highlighting diagnostic strategies, pathogenic pathways, and emerging therapeutic concepts, we show how these rare subtypes refine our understanding of NMJ biology and open the way toward personalized and mechanism-based treatments.

It all began, so they say, with Theodore Woodward, "Don't look for zebras on Greene Street." This aphorism has since been passed on to generations of residents and medical students at the University of Maryland School of Medicine and beyond. A zebra is a "medical condition whose appearance at a particular time and place, in a particular person, is both unexpected and astonishing. The 'condition' may be an item from the history, a physical finding, a laboratory test, or a diagnosis." This maxim nudges clinicians to consider competing or paradoxical hypotheses when assessing patients for common, unexpected, and rare diseases. Whereas errors are unavoidable, considering zebras (uncommon diagnoses) helps avoid "not-to-miss" diagnoses, patient harm, and the associated regret of failure. Perhaps there's also the tug to "bag the big one." On the one hand, pursuing zebras may result in overestimating probability assessments with the potential for harming patients and wasting resources, while applying the science of formal medical decision-analysis lessens the chances of overzealous workups. Unfortunately, conducting studies to evaluate the utility of clinical findings for rare diseases is difficult. The key is to identify symptoms and signs, preferably in combination, with high specificity and sensitivity. On the other hand, assuming horses (common diagnoses) for too long also has its risks. Both the failure to recognize when the current therapeutic plan is ineffective and to appreciate the diagnostic value of the history, physical, and routine laboratory tests can delay the search for alternative hypotheses and ultimately efficacious treatment. Sir William Osler admonished us over a century ago, "Use the knife and cautery to cure the moral necrosis which you will feel in the posterior parietal region, in Gall and Spurzheim's centre of self-esteem, where you will find a sore spot after you have made a mistake in diagnosis."

Navigating the methodological, ethical, and operational challenges of Trials within Cohorts (TwiCs): insights from a French pediatric research-based cohort.

Artificial intelligence in rare pediatric solid tumor research and clinical care: A scoping review.

A 52-year-old man with multiple scalp nodules for more than 30 years and a right occipital mass that had been progressively enlarging for the past 2 years and rupturing and draining for more than 6 months was pathologically confirmed to be secondary malignant proliferating trichilemmal cyst (MPTC). 18F-FDG PET/CT showed active glucose metabolism in the scalp lesion and similar hypermetabolism in the dorsal and right iliac spine skin nodules. This case demonstrates the significant advantages of 18F-FDG PET/CT whole-body imaging in evaluating malignant proliferating trichilemmal cyst, a rare disease.

Epidermal deletion of Kindlin-1 drives matrix changes in the mouse skin and altered responses to ultraviolet radiation.

To evaluate real-world use of advanced cardiovascular imaging in less common and rare rheumatic immune-mediated inflammatory diseases (IMIDs) and identify variation in practice to inform future studies and clinical guidelines. A retrospective, multi-centre quality improvement project was conducted across four major hospitals in the UK. Adults with systemic lupus erythematosus, systemic sclerosis, inflammatory myopathy, vasculitis or primary Sjögren's disease who underwent cardiac magnetic resonance (CMR), CT coronary angiography (CTCA) or positron emission tomography (PET) between January 2023 and December 2024 were included. Demographics, underlying IMID, cardiovascular risk factors, imaging indications, findings and management were extracted using a standardised proforma and analysed. A total of 294 imaging studies were performed in 261 patients (72.4% female, 65.9% aged 40-74 years) comprising 137 (46.6%) CMR, 40 (13.6%) CTCA, and 117 (39.8%) PET scans. Indications varied by modality and centre. Cardiovascular abnormalities were reported in 175/294 (59.5%), most commonly in vasculitis (53.7%). Notably, 54/63 (85.7%) of abnormal PET and 61/89 (68.5%) of abnormal CMR scans were in asymptomatic patients. Imaging findings prompted cardiology referral/ongoing follow-up in 59.5% and changes to IMID treatment in 31.3%, but only 23.1% were discussed in a formal multidisciplinary team (MDT). Advanced cardiovascular imaging frequently identifies cardiovascular involvement in rheumatic IMIDs, including in asymptomatic patients. Treatment adjustments occurred in a third of patients, although largely undertaken outside established MDT processes. These findings emphasise the need for better understanding of imaging-based findings and for cardio-rheumatology MDTs to support integrated decision-making to improve patient outcomes.

Neuromyelitis optica spectrum disorders (NMOSDs) comprise rare autoimmune diseases of the CNS in which disabilities accrue with relapses. The ability to predict and prevent relapses could dramatically improve clinical outcomes, potentially reducing morbidity and quality-of-life declines. This proteomic study aimed to identify individual and composite candidate serum biomarkers predictive of NMOSD relapse. Patients with NMOSD previously enrolled in the Collaborative International Research in Clinical and Longitudinal Experience Study (CIRCLES) cohort were selected based on documented relapses simultaneous with retrievable banked cryopreserved serum. Longitudinal serum proteomic profiles were characterized using high-resolution mass spectrometry. We used linear models with logistic regression, Cox proportional hazards models with fixed-time intervals, and time-dependent Cox proportional hazards models to analyze individual proteins and proteomic profiles for their association with future relapses factoring demographics, clinical phenotype/course, and treatments. We characterized a total of 305 longitudinally collected serum samples (N = 126), using high-resolution mass spectrometry, and identified 265 proteins overall. There was a 10-protein signature with the highest average association coefficient consistently across at least 4 of the 6 modeling analyses, including factor XI, surfactant protein B, C1RL, filamin A, cholesteryl ester transfer protein, cathelicidin antimicrobial peptide, C4A, transferrin receptor, for consistency immunoglobulin kappa constant, and serum amyloid A2 protein. This signature could significantly stratify patients with higher vs lower risk of subsequent relapse. These proteins differed in their increasing or decreasing abundance trajectories in advance of relapse. Most belong to pathways plausibly related to the immunopathology of NMOSD. Collectively, these findings provide a basis for novel biomarker development to predict NMOSD relapses sufficiently in advance to enable preventive treatment.

Aspergillosis complicating idiopathic lung fibrosis: a multicentric series.