Orphanet Journal of Rare Diseases最新文献

{"title":"Mapping the landscape of treatable inborn errors of metabolism: a systematic gene-level evaluation based on the ICIMD classification.","authors":"Tabeer Fatima, Jalal Khan, Fatma Al-Jasmi, Hiba Alblooshi","doi":"10.1186/s13023-026-04486-0","DOIUrl":"10.1186/s13023-026-04486-0","url":null,"abstract":"<p><strong>Background: </strong>Inborn errors of metabolism (IEMs) are among the most clinically actionable groups of rare genetic diseases, yet therapeutic knowledge remains distributed across multiple databases, complicating consistent identification of treatable IEMs.</p><p><strong>Methods: </strong>In this study, we performed a cross-database analysis to characterize the current therapeutic landscape of IEM genes using GeneReviews as a clinical reference. Gene symbols from GeneReviews, Metabolic Treatabolome, Treatable ID, and the Drug Database for Inborn Errors of Metabolism (DDIEM) were harmonized to HGNC nomenclature and mapped to the International Classification of Inherited Metabolic Disorders (ICIMD). IEM genes were categorized as associated with targeted or supportive treatment based on a GeneReviews-derived benchmark.</p><p><strong>Results: </strong>Among 656 ICIMD-defined IEM genes in GeneReviews, 155 (23.6%) were associated with targeted therapies and 501 (76.4%) with supportive treatment. Cross-database comparison demonstrated limited concordance, with only 36 genes associated with targeted therapy shared across Metabolic Treatabolome, Treatable ID, and DDIEM, reflecting heterogeneous representation of treatable IEMs across databases. Targeted therapies were more common in intermediary metabolic pathways, including fatty acid, tetrapyrrole, and vitamin/cofactor metabolism, whereas mitochondrial and complex cellular disorders were predominantly associated with supportive management. Moreover, 53% of the ICIMD-defined IEM genes remain unrepresented in structured databases.</p><p><strong>Conclusions: </strong>Our study defines a set of IEM genes for which targeted therapies are available and demonstrates that treatment information is largely fragmented across databases. This set of IEM genes may facilitate the interpretation of genomic findings and aid the prioritization of IEMs for genomic screening and clinical decision-making.</p>","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13637345/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148382543","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Real-world insights into neurodevelopmental outcomes amongst people with congenital hyperinsulinism.","authors":"Lauren N Lopez, Indraneel Banerjee, Diva D De Leon, Tai L S Pasquini, Marcia Roeper, Kristen E Rohli, Elizabeth Rosenfeld, Paul Thornton, Julie Raskin","doi":"10.1186/s13023-026-04471-7","DOIUrl":"10.1186/s13023-026-04471-7","url":null,"abstract":"<p><strong>Background: </strong>Congenital hyperinsulinism (HI) is a rare condition causing excessive insulin secretion, leading to severe hypoglycemia and high risk of neurological damage. Studies of neurodevelopmental outcomes in HI report prevalence ranging from less than one-quarter to about half of all people with HI. These studies largely focus on formal clinical assessments, but the real-world experiences of individuals with HI and their families are rarely published. The aim of this study was to describe the neurodevelopmental outcomes of a heterogenous cohort of individuals with HI directly from the perspective of the person with HI or their family, as shared through the HI Global Registry.</p><p><strong>Results: </strong>193 participants with HI from 34 countries were included in this analysis. Mean age at follow-up was 12.52 years (SD = 12.60). 66% of all participants, and 72% of participants aged ≥ 5 years at follow-up (n = 145), reported an adverse neurodevelopmental outcome. Of those aged ≥ 5 years at follow-up, 50% reported a diagnosed neurological, neurodevelopmental, or sensory disorder, 57% reported a history of developmental delay, and 18% reported a diagnosed mental health condition. Amongst participants ≥ 5 years of age with an adverse neurodevelopmental outcome, approximately half were capable of performing at peer level in domains of daily life. Participants added richness to the categorical data by providing free-text responses describing the problems faced in day-to-day life, with reported challenges in social, emotional, and behavioral issues.</p><p><strong>Conclusions: </strong>This is the first study of neurodevelopmental outcomes in people with HI to focus on real-world data reported directly from people with HI and their families. Neurodevelopmental challenges were highly prevalent in people with HI and extended beyond formal clinical diagnoses into social, emotional, and behavioral problems. Proactive developmental assessments should be offered to all children with HI, and efforts should be made to develop multidisciplinary teams to support all medical and developmental aspects of care for people with HI. The real-world data on neurodevelopmental outcomes and experiences of individuals with HI and their families generated in this study will serve as a benchmark and help to quantify how future advances in diagnosis and treatment impact patient-centered neurodevelopmental outcomes.</p>","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13602634/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148382552","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Care of patients with Phenylketonuria (PKU) in Germany - a claims data analysis from 2013 to 2023.","authors":"Axel Boehnke, Lisa-Marie Müller, Constantin Heidecke, Alexa Benson, Aljoscha S Neubauer, Ania C Muntau","doi":"10.1186/s13023-026-04467-3","DOIUrl":"10.1186/s13023-026-04467-3","url":null,"abstract":"<p><strong>Background: </strong>Phenylketonuria (PKU) is a rare inherited metabolic disorder requiring lifelong management to prevent neurological, psychiatric, and physical complications. Although early detection through newborn screening has improved outcomes, real-world evidence on long-term care and healthcare utilisation remains limited. This study assessed the epidemiology, comorbidities, treatment practices, rehabilitation and healthcare resource utilisation (HCRU) of individuals with PKU in Germany, using nationwide statutory health insurance (SHI) claims data over ten years.</p><p><strong>Results: </strong>Based on anonymised claims data of 16 SHI funds (~ 4.4 million insured; 5% representative sample), 4,949-6,105 PKU patients were identified annually from 2013 to 2023, yielding a prevalence of 0.007%-0.008%. The five-year cumulative prevalence (2019-2023) was 0.010%, with a slight female predominance (52%). Compared to matched controls (1:10), PKU patients had higher odds of comorbidities, including intellectual disability (OR 16.0), other metabolic disorders (OR 9.2), osteoporosis (OR 3.4), hyperkinetic disorders (OR 2.1), and recurrent depressive disorders (OR 1.6), with the severity of cognitive impairment increasing with age. Less than 20% of the individuals received pharmacological treatment, with low incidences in patients older than 54 years. Nutritional therapy was common during childhood, adolescence and young adulthood (average 49% in ages 0-24) but declined with increasing age. Pregnancy terminations were documented in more than 15% of the 34 women with recorded pregnancy in the cohort. Rehabilitation care was overall higher than in the healthy population, especially among children aged 2-12 years (5.6% vs. 0.3% in controls), primarily for developmental disorders. Healthcare costs were considerably higher in the PKU cohort.</p><p><strong>Conclusions: </strong>PKU care in Germany exhibits age-dependent differences in documented treatment patterns and a high burden of comorbidities, highlighting a substantial unmet medical need and the importance of structured lifelong management strategies.</p>","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13332590/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148376242","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A lifespan pooled analysis of 832 cases: characterizing the lifespan profile of clinical presentations and comorbidities in congenital pulmonary airway malformation.","authors":"Xiao Cheng, Chao Meng, Lirong Nie, Zhiwen Li, Jufen Liu","doi":"10.1186/s13023-026-04464-6","DOIUrl":"10.1186/s13023-026-04464-6","url":null,"abstract":"<p><strong>Background: </strong>Congenital pulmonary airway malformation (CPAM) is a rare pulmonary developmental anomaly with heterogeneous clinical manifestations and associated comorbidities. While often diagnosed prenatally, its lifelong clinical spectrum and associated comorbidities remain poorly characterized, as existing evidence is fragmented across individual case reports and small series. To integrate and analyze individual patient data from published cases to delineate the age-stratified spectrum of comorbidities and clinical presentations of CPAM from fetal life to adulthood.</p><p><strong>Results: </strong>We performed a pooled analysis of individual case data extracted from 209 published articles during the period from 1992 to 2025. A total of 832 CPAM cases were stratified by age: fetus (n = 168), infant (n = 272), toddler (n = 70), child (n = 114), adolescent (n = 53), and adult (n = 155). In the 832 CPAM cases, a majority (66.6%; 95% CI 63.3%-69.8%) were asymptomatic at presentation, yet 37.4% (95% CI 34.1%-40.8%) had at least one documented comorbidity. Age-stratified analysis revealed significantly evolving profiles: malignant/pre-malignant lesions increased sharply with age (adults 23.9%; 95% CI 17.5%-31.3% vs. prenatal 2.9%; 95% CI 1.0%-6.9%, p < 0.001), while pulmonary sequestration was more frequent in fetal cases (9.5%). Asymptomatic presentation decreased from 89.4% prenatally to 48.4% in adulthood (p < 0.001), whereas infection-related symptoms, hemoptysis, and cough increased with age. Multivariate analysis identified symptomatic presentation at diagnosis as a strong, independent predictor of clinical outcome (aOR = 10.73, p = 0.004). Among the subset of 119 cases with genetic testing data, 63.0% (95% CI 53.7%-71.7%) harbored genetic findings of potential clinical significance.</p><p><strong>Conclusion: </strong>This large-scale pooled analysis demonstrates that CPAM exhibits a dynamic comorbidity and presentation spectrum across the lifespan, with increasing malignancy risk and symptomatic burden in adulthood. These findings challenge the perception of CPAM as solely a pediatric condition and argue for structured, lifelong follow-up. Specifically, we recommend: (1) age-stratified malignancy surveillance, with low-dose CT screening considered for adults with residual lesions; (2) transition from pediatric to adult care protocols that include patient education on symptom monitoring (e.g., new cough, hemoptysis); and (3) prioritized intervention and genetic counseling for symptomatic patients and those with identified genetic variants, given their higher risk of complications. Implementing these targeted strategies is crucial to optimize long-term outcomes.</p>","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13602632/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148369260","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitochondrial stress markers associate with phenotypic variability in Fabry disease.","authors":"Lucia Lavalle, Hibba Kurdi, David Moreno Martinez, Vincent Muczynski, Simon Heales, Derralynn Hughes","doi":"10.1186/s13023-026-04461-9","DOIUrl":"10.1186/s13023-026-04461-9","url":null,"abstract":"<p><strong>Background: </strong>Fabry disease (FD) exhibits marked clinical heterogeneity that cannot be fully explained by residual α-galactosidase A activity. Mitochondrial dysfunction has been reported in FD, but the role of mitochondrial stress remains unexplored.</p><p><strong>Objective: </strong>To investigate whether mitochondrial unfolded protein response (mtUPR) related markers associate with phenotypic variability and correlates with disease severity.</p><p><strong>Methods: </strong>We measured intracellular heat-shock protein 60 (Hsp60) expression by western blotting in fibroblasts and peripheral blood mononuclear cells (PBMCs). In the clinical cohort, intracellular Hsp60 was measured in PBMC whole-cell lysates from 27 FD patients (14 males, 13 females). Serum fibroblast growth-factor-21 and growth differentiation-factor-15 were measured in 35 patients. Clinical outcomes included Mainz Severity Score Index, Age-Adjusting Severity Score, estimated glomerular filtration rate, and left-ventricular mass index (LVMI).</p><p><strong>Results: </strong>Hsp60 showed variability, with sex-specific associations. In males, higher Hsp60 correlated with lower LVMI (r² = -0.82, p = 0.01) and preserved renal function in late-onset patients (r² = 0.89, p = 0.006). In females, higher Hsp60 associated with higher LVMI (r² = 0.66, p = 0.045) and greater clinical severity. Male patients had elevated growth differentiation-factor-15 vs controls (935 vs 559 pg/ml, p = 0.002). Both mitokines correlated with age and disease severity.</p><p><strong>Conclusions: </strong>mtUPR related markers exhibit sex- and genotype-specific patterns associated with disease severity, suggesting that mitochondrial stress contributes to phenotypic heterogeneity and support further longitudinal evaluation of Hsp60, FGF-21 and GDF-15 as candidate biomarkers of disease burden and treatment response.</p>","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13587467/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148361750","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Preclinical modeling of Loeys-Dietz syndrome: insights into mechanisms and therapy.","authors":"Amira Bousbaa, Ivanna Fedoryshchenko, Ilse Luyckx, Bart Loeys, Aline Verstraeten","doi":"10.1186/s13023-026-04431-1","DOIUrl":"10.1186/s13023-026-04431-1","url":null,"abstract":"<p><strong>Background: </strong>Loeys-Dietz syndrome (LDS) is a rare multisystemic connective tissue disorder characterized by aggressive aortopathy, skeletal, craniofacial, cutaneous and gastrointestinal manifestations. It is caused by pathogenic variants in genes encoding components of the transforming growth factor-beta (TGF-β) signaling pathway, including TGFBR1, TGFBR2, SMAD2, SMAD3, TGFB2 and TGFB3.</p><p><strong>Main body: </strong>Preclinical modeling has been instrumental in elucidating LDS pathogenesis and informing therapeutic strategies. In this review, a comprehensive overview of available in vivo and in vitro models used to study LDS is presented. We critically evaluate the extent to which each model recapitulates the diverse LDS phenotypes and discuss their respective advantages and limitations. Attention is given to experimental design and variables that influence phenotype expression, including mouse genetic background, sex differences and variant-specific effects. We further synthetize insights gained from these models into the molecular and cellular mechanisms driving LDS, such as the TGF-β paradox, extracellular matrix dysregulation and immune activation. Lastly, we discuss current and emerging therapeutic strategies.</p><p><strong>Conclusion: </strong>The models described here highlight the critical role of preclinical modeling in advancing our understanding of LDS pathophysiology and therapy, outlining key considerations for future model development and translational application.</p>","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13602759/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148361784","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mortality trends and socioeconomic inequalities in sickle cell disease in Colombia, 2012-2023: a population-based study.","authors":"Uriel Palacios-Barahona, Juan Felipe Combariza","doi":"10.1186/s13023-026-04475-3","DOIUrl":"10.1186/s13023-026-04475-3","url":null,"abstract":"<p><strong>Background: </strong>Sickle cell disease (SCD) is one of the most common monogenic disorders worldwide and remains associated with substantial mortality in low- and middle-income countries. In Colombia, population-level evidence on long-term mortality trends and socioeconomic inequalities in SCD is limited.</p><p><strong>Methods: </strong>We conducted an ecological time-series study using death certificate data from the Colombian National Administrative Department of Statistics (DANE). Age-standardized mortality rates (ASMRs) were calculated using the WHO world standard population. Temporal trends were assessed using joinpoint regression and mixed-effects Poisson models. Departments were classified into tertiles of socioeconomic development using the Multidimensional Poverty Index. Additional analyses examined differences by sex and urban-rural residence, and interrupted time-series and excess mortality analyses assessed the COVID-19 period (2020-2021).</p><p><strong>Results: </strong>A total of 675 SCD-related deaths were recorded between 2012 and 2023. The national ASMR increased from 0.055 per 100,000 in 2012 to 0.143 per 100,000 in 2023. In mixed-effects Poisson models, mortality increased (rate ratio [RR] per year = 1.03; 95% CI: 1.01-1.06; p = 0.002). Joinpoint analysis showed a rising trend among males (AAPC = + 8.20%; 95% CI: 0.98 to 15.24; p = 0.029). Mortality varied across departments, with the highest rates in Caribbean regions. Departments with low socioeconomic development had higher mortality than those with high development (RR = 3.00; 95% CI: 1.19-7.61; p = 0.020), and this association strengthened after adjustment for sex and area of residence (RR = 4.00; 95% CI: 1.60-9.97; p = 0.003). During 2020-2021, observed deaths were lower than expected based on pre-pandemic trends (standardized mortality ratio = 0.80; 95% CI: 0.68-0.95).</p><p><strong>Conclusions: </strong>SCD mortality in Colombia increased between 2012 and 2023, marked by territorial and socioeconomic inequalities. The apparent decline during the COVID-19 period likely reflects under-registration rather than a true reduction in mortality.</p>","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13587389/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148361786","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fatigue and pain in children with multiple osteochondromas: a cross-sectional study.","authors":"Ihsane Amajjar, Nienke W Willigenburg, Rob J E M Smeets, S John Ham","doi":"10.1186/s13023-026-04476-2","DOIUrl":"10.1186/s13023-026-04476-2","url":null,"abstract":"<p><strong>Background: </strong>Multiple osteochondromas (MO) is a rare, inherited disorder characterized by multiple benign bone tumors. Although pain and fatigue are commonly encountered in clinical practice, their impact on children with MO remains largely unaddressed in literature. This study aimed to (1) assess fatigue and pain levels in children with MO, (2) compare fatigue severity with healthy peers, and (3) identify variables associated with fatigue and pain.</p><p><strong>Methods: </strong>In this cross-sectional study, 230 children (4-18yrs.) with MO were invited to complete validated, age-specific online questionnaires addressing fatigue (Checklist Individual Strength [CIS], visual analogue scale [VAS-fatigue]), pain (VAS), and psychosocial factors. Fatigue scores were compared to reference data from healthy peers using one-sample t-tests. The International Classification of Functioning, disability and health framework was used for a-priori selection of potential independent variables for multivariable regression analysis.</p><p><strong>Results: </strong>A total of 134 children participated. Fatigue was reported by 89.6% (VAS-fatigue = 3.17 ± 2.63), with CIS scores significantly higher than healthy controls (CIS-MO = 66.32 ± 24.63 vs. CIS-healthy peers = 55.07 ± 20.99, p = 0.012). Pain was reported by 75.4% (VAS = 2.41 ± 2.42). For fatigue, both CIS and VAS-fatigue were associated with pain and emotional/behavioral problems (CIS-model adj. R2 = 0.524, p < 0.001; VAS-fatigue model adj. R2 = 0.576, p < 0.001). CIS was also associated with depressive symptoms (CDI, p = 0.019). The pain regression model explained 45% of the variance (p < 0.001), and pain was significantly associated with functional disability and VAS-fatigue (p < 0.001).</p><p><strong>Conclusion: </strong>Fatigue, alongside pain, is highly prevalent and significantly increased in children with MO compared to healthy peers. Psychosocial factors are closely associated with both fatigue and pain, underscoring the importance of multidisciplinary disease management.</p><p><strong>Clinical trial number: </strong>Not applicable.</p>","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-06-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13587480/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148353080","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Refining the diagnosis of 46,XY disorders of sex development: insight from whole-exome sequencing.","authors":"Ewa Błaszczyk, Małgorzata Więcek, Aleksandra Jazela-Stanek, Grzegorz Kudela, Tomasz Koszutski, Karolina Kowalczyk, Jagoda Sikora, Agnieszka Wiernik, Małgorzata Żarczyńska, Wiktoria Kempińska, Agnieszka Bielska-Brodziak, Aneta Gawlik-Starzyk","doi":"10.1186/s13023-026-04453-9","DOIUrl":"10.1186/s13023-026-04453-9","url":null,"abstract":"<p><strong>Introduction: </strong>Differences in sex development (DSD) with 46,XY karyotype are a group of rare congenital conditions affecting the structure and function of the urogenital system. Published data indicate, that despite the increasingly widespread use of genetic testing, the etiology remains unclear in approximately half of cases.</p><p><strong>Aim of the study: </strong>To clarify the molecular causes of 46,XY DSD by performing whole-exome sequencing (WES) in a precisely phenotyped and clinically comprehensively evaluated group of patients.</p><p><strong>Patients and methods: </strong>WES was performed in a consecutive cohort of 39 children diagnosed in our center as 46,XY DSD (aged 0.2-17.9 years). 32 were assigned male, 6 female, and 1 was a transgender boy. All patients underwent detailed clinical, hormonal and biochemical evaluation prior to genetic testing.</p><p><strong>Results: </strong>A genetic cause explaining DSD phenotype was identified in 8 children. Pathogenic variants were detected in 3 patients, including variants in the AR and DHX37 genes. Likely pathogenic variants were found in 5 patients, affecting the AR and HSD17B3 genes. Variants of uncertain significance (VUSs) were identified in 7 patients, involving genes with well-established relevance to DSD- NR5A1, DHX37, AR, MAMLD1, SOS2andFAM111A. Although classified as VUSs these variants represent plausible contributors to the patients' phenotypes. In the remaining children, no variants currently known or suspected to be associated with 46,XY DSD were identified. The most common confirmed etiology in the cohort was androgen insensitivity syndrome (AIS). In addition, pathogenic variants in genes not linked to DSD were identified in 7 patients, demonstrating the broader clinical utility of WES.</p><p><strong>Conclusions: </strong>Our findings confirm that even a broad, high-throughput method such as WES fails to establish the molecular cause of 46,XY DSD in a substantial proportion of well-phenotyped patients, while at the same time enabling the identification of pathogenic variants in genes unrelated to DSD. We observed frequent genotype-phenotype discordance: similar clinical phenotypes could be associated with different genotypes, whereas the same gene variant could present with variable clinical expression. Re-analysis of WES data after 12-24 months should be considered in patients without a definitive diagnosis or in those who develop additional clinical features.</p>","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13322092/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148339530","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Management of pregnancy in women with rare multisystemic vascular diseases: a qualitative survey analysis.","authors":"Gloria Somalo-Barranco, Alexandra Benachi, Laurence M Boon, Petra Borgards, Janine Dickinson, Freya Droege, Olivier Dupuis, Michael Frank, Guillaume Jondeau, Robert M Kauling, Diana Marinello, Edit Nagy, Jolien W Roos-Hesselink, Meike Rybczynski, Pernille Mathiesen Torring, Carine van der Vleuten, Aline Verstraeten, Liesbeth Wildero Van Wouwe, Dina Zucchi, Julie De Backer","doi":"10.1186/s13023-026-04472-6","DOIUrl":"10.1186/s13023-026-04472-6","url":null,"abstract":"<p><strong>Background: </strong>Pregnancy in women with rare vascular diseases is highly challenging, as it can be associated with significant maternal and foetal risks, requiring complex and multidisciplinary management. Care across countries remains insufficiently characterized, and both patients and healthcare providers across Europe highlight the need for better structures and organization to support this critical and potentially life-threatening phase.</p><p><strong>Objective: </strong>To describe current practices, perspectives, and challenges faced by patients and healthcare professionals in the management of pregnancy in women with rare vascular diseases.</p><p><strong>Methods: </strong>A survey developed by the European Reference Networks (ERN) pregnancy working group was extended with VASCERN-specific questions, resulting in a 13-item questionnaire. The survey was distributed to healthcare providers and patient representatives (ePAGs). Qualitative data from open-ended responses were analysed using an inductive thematic approach.</p><p><strong>Results: </strong>36 responses were collected from 145 invited VASCERN members, resulting in a 25% response rate and representing 10 European countries. Most respondents were healthcare providers (83%). 17% were patient representatives. Thematic analysis identified five recurring themes, including the need for coordinated and collaborative multidisciplinary approaches, variability in the practices regarding preconception and genetic counselling, limited access to specialised centres for pregnancy monitoring, and the importance of structured delivery planning and postnatal follow-up.</p><p><strong>Conclusions: </strong>This survey clearly shows that there are common concerns about pregnancy in women with rare vascular diseases. Improvement actions mainly involve better education and drawing up multidisciplinary care pathways and guidelines that will lead to better access and organisation of care. Initiatives in this direction have already been taken within VASCERN.</p>","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13587322/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148339359","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}