Cerebral venous thrombosis is a rare stroke type that primarily affects younger women. Contemporary large international efforts have improved our understanding of the natural history and management of this rare disease, yet important evidence gaps persist across the disease continuum. Management of cerebral venous thrombosis can be conceptualized into multiple phases: acute management, post-acute management (including primary anticoagulation and secondary prevention), and recovery. Acute treatment centers on anticoagulation, including in the presence of intracranial hemorrhage. Endovascular therapy and decompressive craniectomy are reserved for selected severe cases. Direct oral anticoagulants appear comparable to vitamin K antagonists for most patients during primary treatment, though optimal lead-in duration and treatment length remain uncertain. Decisions regarding extended anticoagulation for secondary prevention require individualized assessment of recurrence and bleeding risk. Patients with cancer, antiphospholipid antibody syndrome, prior venous thromboembolism, and idiopathic events are at the highest thromboembolic risk. Long-term sequelae, including fatigue, headache, cognitive and mood disturbances, epilepsy, and intracranial hypertension, contribute substantially to morbidity despite high rates of functional independence. Heavy menstrual bleeding may impact young women on anticoagulation. Recognition and management of these outcomes are essential for comprehensive care.

Sudan virus disease in humans.

Metabolic associated fatty liver disease (MAFLD) has become the most common chronic liver disease in China, yet a comprehensive review of the natural history of disease progression and its risk factors is still lacking. This review evaluates integrated natural history characteristics and key risk factors from Chinese cohort studies of MAFLD. In the MAFLD cohorts, the incidence rate of liver fibrosis progression was 19.2%-38.4% over 3-6 years. The hepatocellular carcinoma incidence rate was 0-2.7% over 6-11 years. The all-cause mortality rate was 2.0%-12.0% over 4.6-10 years. Diabetes and abnormal blood glucose were strong predictors of disease progression, and overweight and obesity, hypertension, and age were other risk factors. The article suggests that MAFLD can progress rapidly in certain Chinese cohorts, with multiple risk factors driving the course of the disease. Future large-scale prospective studies are necessary to clarify the mechanisms and optimize intervention strategies.

Understanding disease natural history is important for the development of potential treatments for people with MSA. We describe the natural progression of early MSA in a Chinese population. Observational, 12-month study conducted in 8 sites across China. Eligible participants were aged 40-75years, with possible or probable MSA of the parkinsonian (MSA-P) or cerebellar (MSA-C) subtype, and anticipated survival of ≥ 3years. Disease progression was analyzed using a linear mixed model of Total UMSARS (Part I + II) progression, including baseline, Month 6 and Month 12 data. A total of 89 participants with a mean ± SD time since diagnosis of 0.4 ± 0.6years were enrolled. Of these 52% had MSA-C and 48% participants had MSA-P. The mean ± SE [95%CI] rate of Total UMSARS progression was 1.27 ± 0.13 [1.01, 1.53] points per month. Participants showed a progression of 0.64 ± 0.06 [0.51, 0.76] points/month on UMSARS Part I and 0.62 ± 0.07 [0.47, 0.77] points/month on UMSARS Part II. Differences in the rates of UMSARS progression between patients with MSA-P and MSA-C were not statistically significant (p > 0.05). This is the first multicenter natural history study of MSA progression conducted in China. While prior studies have indicated a predominance of MSA-C in Asian populations, we found a more even split of MSA-C and MSA-P subtypes. In this early population, patients showed an average progression rate of ~ 15 Total UMSARS points/year; rates of progression were similar between the two subtypes and were in alignment with previous studies that assessed disease progression using UMSARS in Western populations. Clinicaltrals.gov, NCT05453058 (registered June 16, 2022).

SUMMARYJorge Lobo's disease (JLD) is a chronic cutaneous and subcutaneous mycosis endemic to the Amazon Basin and tropical rainforests of Latin America. Despite more than a century of study, the disease remains underrecognized, poses significant diagnostic challenges, and is often therapeutically refractory. Here, we synthesize historical, clinical, and ecoepidemiological evidence; provide a practical diagnostic approach; and highlight unresolved questions. Clinically, JLD presents as slowly progressive keloid-like nodules and plaques on exposed areas. Diagnosis relies on direct microscopy and histopathology showing chains of thick-walled yeast-like cells connected by narrow-neck budding; culture is not feasible, and molecular assays are rarely available outside reference centers. We contrast JLD with key mimickers (cutaneous leishmaniasis, chromoblastomycosis, leprosy, atypical mycobacterioses, and non-infectious lesions such as keloid scars) and summarize current management options, emphasizing when surgery alone suffices and when prolonged azole therapy should be considered. From an ecoepidemiological perspective, historical settlement patterns, occupational exposures, and environmental disturbance in humid forest biomes appear to have amplified human contact with putative environmental reservoirs. New phylogenomic data position Paracoccidioides lobogeorgii as an early-diverging lineage within Paracoccidioides, refining prior MLST-based inferences. We outline practical surveillance steps to address under-ascertainment, standardized case definitions, sentinel reporting, and laboratory quality assurance and propose research priorities spanning environmental detection, host-pathogen interactions, and therapeutic evaluation. We contextualize the disease within broader frameworks of fungal emergence, structural neglect, and environmental disruption, arguing that revisiting JLD is not merely retrospective but a necessary scientific and ethical priority.

Chagas disease, caused by Trypanosoma cruzi, remains one of the leading infectious causes of non-ischemic cardiomyopathy worldwide. Although an estimated 6-7million individuals are chronically infected, 20-30% will develop Chagas cardiomyopathy (CCM), a progressive myocardial disease characterised by conduction abnormalities, ventricular arrhythmias, focal aneurysm formation, diffuse fibrosis, and heart failure. Cardiac involvement often evolves silently over decades, and conventional clinical markers frequently underestimate early myocardial injury. Advances in cardiac imaging have fundamentally reshaped the understanding of CCM, demonstrating that myocardial involvement frequently precedes symptoms and may occur despite normal electrocardiography. Contemporary modalities, including transthoracic echocardiography with deformation imaging and cardiac magnetic resonance, enable detailed characterisation of ventricular mechanics, myocardial fibrosis, inflammation, and perfusion abnormalities across disease stages. These techniques have revealed a distinctive, segmental pattern of myocardial injury and provided mechanistic insight into arrhythmogenesis and disease progression. This review synthesises current evidence on the natural history of Chagas disease, with a particular focus on the expanding role of multimodality cardiac imaging in the early detection, phenotypic characterisation, and risk stratification of CCM.

Rheumatic heart disease (RHD) frequently affects both mitral and aortic valves. While mitral valve replacement (MVR) is often prioritized, the natural history of coexisting aortic valve disease particularly when mild or moderate is less well understood. The objective of this study is to assess the progression of aortic stenosis (AS) and aortic insufficiency (AI) in patients undergoing isolated MVR for rheumatic mitral disease. We conducted a single-center retrospective cohort study involving 403 adult patients with rheumatic mitral valve disease who underwent isolated MVR at Rajaie Cardiovascular Medical and Research Center between 2010 and 2022. Patients with a history of aortic valve replacement or early postoperative mortality (defined as death within 30 days of surgery) were excluded. Serial transthoracic echocardiography was performed at baseline, 3 months postoperatively, and annually thereafter, with a mean follow-up duration of 78 months. We evaluated baseline and longitudinal changes in the severity of aortic stenosis (AS) and aortic insufficiency (AI), as well as alterations in left ventricular function and pulmonary artery pressures over time. The severity of aortic valve disease was classified according to the American Heart Association (AHA) 2020 and European Society of Cardiology (ESC) 2025 guidelines. At baseline, 9.2% had AS (6.2% mild, 3.0% moderate) and 67% had AI (57.6% mild, 9.4% moderate). During our follow up among patients with mild AS, we observed sever AS is 20% progressing to severe AS, compared with 41.7% progressing to moderate AS. For AI, we observed 3.0% progression to severe AI for patients with mild baseline disease and is 7.8% for patients with moderate baseline disease. Baseline aortic valve lesion severity independently predicted progression (HR 4.2, 95% CI 1.9-9.1, p < 0.001). No other clinical or echocardiographic parameters were significant. Survival analysis showed higher cumulative progression rates among those with baseline lesions (p < 0.001). Baseline aortic valve involvement predicts subsequent deterioration after MVR. Routine prophylactic AVR is not supported for mild AI, but moderate AS warrants closer follow-up and individualized surgical consideration. Larger, prospective studies are needed to refine risk prediction for concomitant aortic intervention.

e23020 Background: Overall response rate (ORR) is used as an early endpoint indicative of efficacy in oncology clinical trials, especially in accelerated approvals. Trials reporting ORR often include duration of response (DoR) as a secondary endpoint contextualizing durability. However, as a time-to-event endpoint, interpreting DoR, including in single-arm trials (SATs), is challenging given the inability to separate treatment effect from disease natural history and dependent censoring. In randomized controlled trials (RCTs), as DoR is limited only to responders, randomization is lost and potential subgroup effects arise. We analyzed DoR use in trials supporting original approvals in non-small cell lung cancer (NSCLC). Methods: The study included original approvals indicated for the treatment of NSCLC from August 26, 2011 through July 2, 2025. Data from the labels and multi-disciplinary review were found using the Drugs@FDA database. Descriptive analyses assessed the use of DoR as an endpoint, its reporting on the label, definitions, and associations with approval pathway and trial design. Results: Thirty drugs were included, representing 20 accelerated and 11 traditional approvals based on 39 trials (9 RCTs and 30 SATs). 74.2% of approvals used ORR as the primary endpoint (20 accelerated, 3 traditional) and DoR was a secondary endpoint in 87.1% (27/31) of approvals, including all accelerated approvals. The majority of trials (80.7%) supporting approvals with DoR as a secondary endpoint were SATs for 20 accelerated and 1 traditional approval. All approved drugs using DoR as an endpoint reported DoR in the label, with heterogenous metrics reported: 1 (3.8%) only DoR range reported, 1 (3.8%) median (mDoR) and range, 7 (26.9%) mDoR and 95% confidence interval (CI), 15 (57.7%) mDoR, 95% CI, and landmark(s), and 2 (7.7%) DoR range and landmark(s). For the 17 labels reporting landmark DoRs, 15 reported at 6 months, 3 reported at 9 months, 9 reported at 12 months, and 1 reported at 18 months. Only 4/26 (15.4%) labels where DoR was reported also reported follow-up duration and 6/26 (23.1%) did not report follow-up time anywhere in the review documents, despite its direct impact on DoR interpretation. Lastly, 10/26 (38.5%) of drugs with a DoR endpoint did not define or had incomplete definitions of DoR; within those with detailed definitions, there were discrepancies in how the start and end date for DoR were defined. Conclusions: DoR is a secondary endpoint in the majority of NSCLC approvals, especially in accelerated approvals. Most trials assessing DoR are SATs, in which time-to-event endpoints are known to be less interpretable. There was also significant variation in the metrics reported and definitions used, which can greatly impede endpoint interpretation. While DoR provides valuable context for ORR, these irregularities impede clinical interpretation. Further alignment of its appropriate use is needed.

This expert point of view discusses why allergen-specific immunotherapy (AIT) should be considered earlier in the management of allergic rhinitis and asthma, highlighting a shift from its traditional use as a last-line add-on therapy toward a more proactive, disease-modifying intervention in carefully selected patients. Large real-world datasets, including the REACT program and the EfficAPSI study, show that adding AIT to standard care in patients with allergic rhinitis, with or without mild-to-moderate asthma, is associated with sustained reductions in pharmacologic treatment needs, fewer severe asthma exacerbations, and lower healthcare utilization over long-term follow-up. Pediatric and adolescent analyses suggest that starting AIT earlier in life enhances these benefits, supporting the concept of a "window of opportunity" during which immune modulation may prevent or delay asthma onset and limit new sensitizations, in line with the notion of the allergic march. The accumulating real-world evidence that early AIT can alter the natural history of allergic airway disease provides a strong rationale to reposition AIT within clinical algorithms, moving it from a rescue option for pharmacologic failures to an earlier, integrated disease-modifying strategy. Earlier use of AIT, alongside optimized pharmacotherapy, may improve long-term control, reduce progression to severe asthma, with important implications for patients and health-care systems.

The expansion of precision medicine has shifted toward individualized care tailored to a patient's genetic profile. While randomized controlled trials (RCTs) remain the gold standard for establishing efficacy, they often struggle to reflect the phenotypic diversity of patients in routine clinical practice. This paper explores the role of Real-World Data (RWD) and Real-World Evidence (RWE) in bridging this translational gap. A structured literature search identified peer-reviewed articles examining RWE applications in identifying rare genetic targets, informing clinical trial design, and supporting U.S. Food and Drug Administration (FDA) regulatory decisions. This review synthesizes recent regulatory advances through early 2026, including frameworks supporting the use of aggregated RWD that expand large-scale, multi-institutional evidence generation. RWE provides a scalable mechanism for identifying rare genetic variants and validating biomarker-driven therapies across heterogeneous patient populations while enabling longitudinal assessment of natural disease history and treatment safety. Operational successes in oncology, transplant medicine, and rare diseases demonstrate regulatory acceptance of RWE alongside critical challenges in data standardization, interoperability, and bias mitigation through causal inference frameworks, including target trial emulation. RWD and RWE serve as necessary complements to RCTs, providing the hybrid evidentiary framework needed to realize precision medicine's potential.

Extracting and standardizing phenotypic information from free-text medical reports remains a main challenge in biomedical natural language processing (NLP). Conceptual normalization, which maps textual mentions to standardized vocabularies such as the UMLS or HPO, is a key step for deep phenotyping. Dystrophic epidermolysis bullosa (DEB) is a rare severe and heterogeneous skin disorder causing skin and mucosal fragility that leads to early morbidity and mortality. To better understand the disease's natural history and severity spectrum, it is important to comprehensively identify DEB-related phenotypes. This study aimed to assess a pipeline for automatically mapping clinical terms from textual reports to the UMLS Metathesaurus and to evaluate how well the UMLS covers DEB-related phenotypes. The study was conducted at Necker-Enfants Malades Hospital in Paris, a reference center for rare diseases, using its "Dr Warehouse" database, containing more than 11 million clinical documents. It involved 198 patients with dystrophic epidermolysis bullosa (DEB). Phenotypes were automatically extracted from clinical texts using named entity recognition (NER) and then normalized using a cosine similarity method. Among the 198 DEB patients followed at Necker Hospital, 14,734 documents were analyzed, allowing the extraction of 33,347 phenotypes using an NER model. Of these phenotypes, 13,485 were correctly mapped to a UMLS or HPO concept, while 19,862 were not. A manual evaluation of 300 unmapped phenotypes revealed five main causes of failure: overly specific phenotypes (72%), missing synonyms in terminologies (30%), multiple phenotypes within a single extraction (15%), absence of a real phenotype (9%), missing concepts in terminologies (3%), or spelling/grammatical errors (3%). Despite the initial association failure, a significant proportion of overly specific or poorly formulated phenotypes actually corresponded to existing concepts. These results highlight the limitations of current ontologies and the challenges of automatic medical language processing.

The rising disease burden of inflammatory bowel disease (IBD) parallels the changing dietary landscape accompanying industrialization, underscoring the growing relevance of nutritional science in disease prevention and management. Precision nutrition has emerged as a promising approach to prevent and manage IBD through tailored dietary recommendations based on multidimensional individual characteristics, including demographics, disease natural history and multiomics traits. In this Review, we investigate the sources of heterogeneity in dietary responses and propose a stepwise framework for precision nutrition: phenotype-based precision nutrition, informed by general phenotypes in clinical and community settings; omics-based precision nutrition, targeting subgroups with shared biological features identified via omics and complementary approaches; and integrated precision nutrition, providing personalized dietary strategies informed by comprehensive, multidimensional phenotypes. Advances in large-scale longitudinal multiomics cohorts, biomarker detection and artificial intelligence are transforming data acquisition and interpretation, thereby facilitating both interventional research and real-world application of precision nutrition. Key considerations for implementing precision nutrition in IBD are discussed. This Review outlines a holistic and translational framework, aiming to advance both research and clinical practice in the prevention and management of IBD.

Calcium oxalate (CaOx) stones are the most prevalent form of nephrolithiasis and are characterized by a substantial risk of recurrence. Their pathogenesis arises through distinct etiological pathways, including idiopathic metabolic susceptibility, monogenic disorders such as primary hyperoxaluria, enteric hyperoxaluria, and toxicant-associated injury, and is shaped by two primary papillary mechanisms: Randall's plaque formation and ductal plugging. A central translational limitation is that most experimental systems, particularly chemically induced rodent models, rely on acute hyperoxaluria. These models capture crystal nucleation, aggregation, and deposition but do not adequately recapitulate the decades-long natural history of idiopathic CaOx stone disease in humans or the gradual formation of Randall's plaques. This review systematically evaluates CaOx stone models in mice, rats, Drosophila, pigs, dogs, and cats, with an emphasis on induction methods, analytical endpoints, strengths, limitations, and applications in mechanistic research, drug discovery, and surgical instrument evaluation. Particular attention is given to plaque-related models such as Abcc6 deficiency, etiologically aligned models of primary and enteric hyperoxaluria, and naturally occurring disease in companion animals. Finally, this review proposes a stepwise framework for selecting CaOx stone animal models according to research objectives, etiological relevances, pathological mechanisms, and translational applications.

Background:The natural history of steatotic liver disease (SLD)—including major adverse liver outcomes (MALO), major adverse cardiovascular events (MACE), and all-cause mortality—remains inadequately defined in population-based settings.Aims:We sought to quantify their incidence and compare risks across SLD subtypes.Methods:We evaluated 244,760 UK Biobank participants, assessing metabolic dysfunction–associated SLD (MASLD), metabolic dysfunction and alcohol-associated liver disease (MetALD), or alcohol-associated liver disease (ALD), and examined outcomes across these subtypes.Results:Among the cohort, 47,949 (19.6%) had MASLD, 23,000 (9.4%) had MetALD, and 8,085 (3.3%) had ALD. Of the 79,034 individuals with SLD (mean age 57.2; 72.4% female; 98.0% White), the incidence rates of MALO (per 1,000 person-years) were 1.91 for MASLD, 2.35 for MetALD, and 5.80 for ALD during a median follow-up of 13.5 years. Corresponding rates for MACE were 14.88, 15.48, and 19.36, and for all-cause mortality were 12.99, 13.59, and 20.93. After adjustment, ALD (hazard ratio [HR], 2.95; 95% CI, 2.64–3.29) and MetALD (HR, 1.23; 95% CI, 1.11–1.36) were associated with higher MALO risk than MASLD. ALD also showed higher risks of MACE and mortality than MetALD (MACE: HR, 1.17; 95% CI, 1.10–1.24; mortality: HR, 1.49; 95% CI, 1.41–1.58) or MASLD (MACE: HR, 1.17; 95% CI, 1.11–1.24; mortality: HR, 1.52; 95% CI, 1.44–1.60), whereas MetALD and MASLD showed no differences.Conclusions:In the United Kingdom, ALD exhibited the highest liver, cardiovascular, and mortality risks, while MASLD and MetALD had similar cardiovascular and survival profiles but differed in liver-related risk.

Association between cardiovascular-kidney-metabolic syndrome and clinical outcomes in patients with atrial fibrillation: Insights from COOL-AF registry.

Intravenous immunoglobulin (IVIg) is the standard of care for the treatment of Kawasaki disease (KD) and should be administered within 10 days of the onset of fever. Management guidelines for children with KD who defervesce spontaneously are not clear. In this study, we analysed patients with KD diagnosed between 1994 and 2024 at our centre who had defervesced spontaneously, had normal acute-phase reactants, and underwent echocardiographic examination, and in whom IVIg had not been administered. We reviewed the records of patients with KD from January 1994 - December 2024. The diagnosis of KD was based on standard guidelines. Patients with KD were said to be in spontaneous defervescence when they remained afebrile for ≥ 48 h, had normal acute-phase reactants [C-reactive protein (CRP), Erythrocyte sedimentation rate (ESR)] and no coronary artery abnormalities (CAAs) on echocardiography at presentation, and when IVIg was not administered. Patients with spontaneous defervescence were subdivided into (i) early defervescence (Ed-KD), if the interval between onset of symptoms and defervescence was < 10 days, and (ii) late defervescence (Ld-KD), if the duration between onset of symptoms and defervescence was ≥ 10 days, respectively. Details of the clinical profile, laboratory investigations, and echocardiography findings were obtained from the records. Of the 1499 patients with KD enrolled during the study period, 115 patients (7.7%; 86 boys) defervesced spontaneously. The median age at disease onset was 6 years (mean, 5.6 years; range, 0.8-15 years). The median duration of fever, defined as the total duration of the febrile episode before spontaneous defervescence, was 5 days (range, 1-21 days). The median interval between illness onset (defined as fever onset) and diagnosis of KD was 15 days (range, 4-40 days), indicating that diagnosis was often made after fever had already subsided. The most common clinical feature was periungual desquamation, followed by rash, oral-mucosal changes, cervical lymphadenopathy, and conjunctival injection. Incomplete presentation was noted in 73.9% (n = 85/115) of patients. No patient has developed CAAs or other cardiac sequelae over a median follow-up of 9 months (range 2 months-156 months). The cumulative follow-up for the cohort was 235 patient-years. The 'low-risk' subgroup of patients with KD who defervesce spontaneously, and have normal acute phase reactants with no CAAs at presentation, have good clinical and coronary outcomes.

Metabolic (dysfunction)-associated fatty liver disease (MAFLD) or metabolic (dysfunction)-associated steatotic liver disease (MASLD) is the most common and fastest growing cause of chronic liver disease worldwide. There has been a substantial increase in the epidemiological research regarding MASLD/MAFLD originating from Australia since 2020. This narrative review summarises these pivotal epidemiological studies investigating the disease prevalence, natural history, prognostication and management of this condition. The Australian literature demonstrates the prevalence to be between one-third and two-fifths of adults affected, depending on nomenclature, with a heightened risk of cardiovascular disease irrespective of terminology. Current local data support guideline-based disease staging with non-invasive tests of fibrosis and the management continues to centre on diet and lifestyle interventions, with directed therapy on the horizon.

X-linked Emery-Dreifuss muscular dystrophy (EDMD1) is a rare early-onset myopathy, affecting 1/400.000 individuals, characterized by humeroperoneal weakness, contractures and cardiac involvement. EDMD1 natural history has been poorly investigated, with most of the studies including only a few patients. The aim of the study was to investigate the clinical and molecular features in a large Italian cohort of EDMD1. We retrospectively collected data of 38 genetically defined EDMD1 males (16 members of 6 families, and 22 sporadic cases) and 10 female carriers, from 14 referral neuromuscular centers in Italy. Patients were included only if showing detectable muscle weakness or contractures at the neurological examination. Mean age at onset of patients was 12.0 ± 3.4years (range 2-61). Among them 32 (84.2%) presented with muscle weakness or contractures and 6 (15.8%) with cardiac symptoms. Twenty-nine (76.3%) patients had heart involvement, with a mean age at onset of 24.2 ± 13.1years. Age at disease onset was significantly different (p = 0.0011) between patients with cardiac onset and those with muscular onset. Moreover, patients with muscular onset had worse (p = 0.0163) motor performance at last follow-up (LFU), according to Gardner-Medwin-Walton Scale (GMWS). Loss of walking ability was observed in 3/38 (7.9%) patients, after a disease duration of 35, 49 and 35years, respectively. Most of the remaining patients showed a mild disease severity, scoring 1-3 at the GMWS at LFU. Ten EMD mutations were novel and unreported in the literature. Our data provide further insight in the field of EDMD1 and suggest that the disease natural history is dominated by heart involvement, while skeletal muscle weakness slowly progresses over the years.

Gastrointestinal Disorders in Scleroderma

Introduction: The hyperinsulinism/hyperammonemia (HI/HA) syndrome manifests with fasting and protein-induced hypoglycemia, hyperammonemia, and neurodevelopmental features including epilepsy. There is a paucity of information describing the natural history of the HI/HA syndrome. Methods: A retrospective review of patients with HI/HA syndrome evaluated at the Congenital Hyperinsulinism Centers at the Children’s Hospital of Philadelphia or Cook Children’s Medical Center or who contributed to the Congenital Hyperinsulinism International HI Global Registry (HIGR) was conducted to describe the natural history of the HI/HA syndrome with particular focus on treatment and neurodevelopmental outcomes. Results: A total of 66 patients (36 female) from the medical record review and 15 patients (7 female, 3 sex not reported) from HIGR were included. Median age at last follow-up was 13.1 years (IQR, 6.8–19.0 years) in the medical record cohort and median age at survey completion was 11.6 years (IQR, 5.5–18.0 years) among HIGR participants. Eighty percent of the medical record cohort and 82% of HIGR participants were treated with diazoxide and most continued treatment over the follow-up period. Epilepsy (29% of medical record cohort, 33% HIGR participants) and neurodevelopmental issues (64% medical record cohort, 73% HIGR participants) were common. Conclusion: Our findings underscore the importance of longitudinal endocrine and neuropsychological follow-up for patients with HI/HA syndrome and demonstrate the potential value of patient-driven registry data to address persistent knowledge gaps in the natural history of rare diseases.