Orphanet Journal of Rare Diseases最新文献

{"title":"Meeting Abstracts of the 1st Fragile X International Congress.","authors":"","doi":"10.1186/s13023-025-03574-x","DOIUrl":"https://doi.org/10.1186/s13023-025-03574-x","url":null,"abstract":"","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":"20 Suppl 1","pages":"173"},"PeriodicalIF":3.4,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12020033/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143985497","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":"Employment and work ability in individuals living with rare diseases: a systematic literature review.","authors":"Nicolas Bougas, Terhi Kangas, Katrien Vanthomme, Jose Joaquín Mira Solves, Gaël Brulé, Helene Mellerio, Hadewijch Vandenheede, Agnes Dumas","doi":"10.1186/s13023-025-03691-7","DOIUrl":"https://doi.org/10.1186/s13023-025-03691-7","url":null,"abstract":"<p><strong>Background: </strong>The socioeconomic impact of rare diseases has been mostly studied at the macrolevel, but evidence at the microlevel is lacking, which overshadows health-related social inequalities affecting people with rare diseases, namely, health selection effects.</p><p><strong>Aim: </strong>This study presents an overview of employment and work ability in individuals living with rare diseases, two factors related to health selection effects.</p><p><strong>Methods: </strong>A systematic literature review was conducted using the PRISMA checklist. Three electronic databases, PubMed, Embase, and Web of Science, were searched from 2013 to 2023. Eligible studies needed to investigate at least one work-related outcome measuring employment or work ability in individuals living with rare diseases and to compare it with a control group. Indeed, including only studies with matched or standardized control groups is essential for ensuring the reliability and validity of research findings.</p><p><strong>Results: </strong>Of the 7,694 abstracts identified, 44 studies, including 34 rare diseases, met the inclusion criteria. Administrative databases were used to collect work-related data in 48% of the studies, and 73% of the studies employed matching methods for comparison. Overall, 52% of the studies focused solely on employment, 14% focused solely on work ability and 34% included both categories. Individuals with rare diseases were less likely to be employed or more likely to be unemployed than controls in 68% of the studies and 87% of the studies reported that individuals with rare diseases were more likely to be work disabled. Regarding work ability, 90% of the studies reported more missed work time in cases than in controls, and more perceived impairment at work was found in 100% of the studies.</p><p><strong>Discussion/conclusion: </strong>These results show that individuals with rare diseases tend to have poor work outcomes, but methodological limitations hamper the understanding of health selection effects. Implications for future research and policy-making are discussed.</p>","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":"20 1","pages":"193"},"PeriodicalIF":3.4,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12020228/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144030344","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":"Enhancing the effects of nusinersen with cybernic treatment using Hybrid Assistive Limb (HAL) in spinal muscular atrophy: a real-world case series and exploratory cohort analysis.","authors":"Takashi Nakajima, Toshio Saito, Akihiro Hashiguchi, Taiki Nakabayashi, Kazuki Kodera, Kota Utsumi, Takeshi Kanayama, Haruka Urabe, Satoru Kinoshita","doi":"10.1186/s13023-025-03681-9","DOIUrl":"https://doi.org/10.1186/s13023-025-03681-9","url":null,"abstract":"<p><strong>Background: </strong>Nusinersen therapy for spinal muscular atrophy (SMA) provides significant functional improvement when initiated pre-symptomatically or early in life. However, challenges remain in diverse populations with longer disease duration. In Japan, innovative cybernic therapy with the Hybrid Assistive Limb (HAL) is gaining traction in treating neuromuscular diseases. This observational study investigated whether combining HAL therapy with nusinersen and conventional physiotherapy yields functional improvements in SMA, irrespective of disease duration or age. Functional improvement indicators included the Hammersmith Functional Motor Scale-Expanded (HFMSE) and Revised Upper Limb Module (RULM) scores, and the 2-minute walk test (2MWT), measured 15 months post-nusinersen initiation. A cohort analysis of a selected case series was conducted.</p><p><strong>Results: </strong>Twelve patients with SMA type 2 or 3 who met the criteria of being able to walk with a hoist and began nusinersen treatment > 40 months post-disease onset were selected for longitudinal clinical assessment. Cohort 1 (n = 5, mean age 36.0 years) underwent HAL therapy, while Cohort 2 (n = 7, 24.6 years) did not. Baseline characteristics, except mean age, were similar across cohorts. In Cohort 1, the period from baseline (nusinersen initiation) to HAL therapy ranged from 0 to 8.8 months. HFMSE scores improved in both cohorts at 15 months; the least squares mean (LSM) change from baseline (95% confidence interval [CI]) was 4.7 points (2.2, 7.3) in Cohort 1 and 2.9 points (0.7, 5.1) in Cohort 2. Clinically meaningful improvement of 3.0 points in HFSME was exceeded by four of five patients in Cohort 1 and three of seven in Cohort 2. The LSM change from baseline in RULM was 2.2 points (95% CI 1.0, 3.3) in Cohort 1, exceeding the minimal clinically important difference of 0.5-1.0 points, but remained unchanged in Cohort 2 due to ceiling effects (- 0.2; -1.5, 1.2; p = 0.016). The LSM change from baseline in the 2MWT had improved in Cohort 1 (34.57 m; 95% CI 4.57, 64.57), but not in Cohort 2 (- 3.86; -37.75, 30.03).</p><p><strong>Conclusions: </strong>In patients with SMA type 2 and 3, clinically meaningful improvements in multiple indicators were observed when HAL was combined with nusinersen, even when treatment commenced many years after disease onset.</p><p><strong>Registration: </strong>jRCT1090220400 ( https://jrct.niph.go.jp/en-latest-detail/jRCT1090220400 ).</p>","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":"20 1","pages":"194"},"PeriodicalIF":3.4,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12020134/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144030346","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":"Langerhans cell histiocytosis of the jaw: clinical analysis of 68 cases.","authors":"Jiale Li, Hao Wu, Zilin Wang, Jing Han, Jiannan Liu, Bing Han","doi":"10.1186/s13023-025-03680-w","DOIUrl":"https://doi.org/10.1186/s13023-025-03680-w","url":null,"abstract":"<p><strong>Background: </strong>This study aims to investigate the clinical characteristics, imaging features, treatment, and prognostic factors of jaw Langerhans cell histiocytosis (JLCH), providing valuable insights for its clinical diagnosis and management.</p><p><strong>Method: </strong>This study retrospectively analyzed the clinical and follow-up data of JLCH patients treated between January 2010 and January 2024. Data collected included gender, age, symptoms, imaging findings, treatment strategies, and outcomes. Univariate and multivariate Cox regression analyses were performed using SAS software to identify factors affecting treatment outcomes, with P ≤ 0.05 considered statistically significant.</p><p><strong>Results: </strong>A total of 68 patients (50 males, 18 females; median age 13.5 years) were included. Forty percent of patients were under 10 years old, and 71% had mandibular involvement. Disease classification included 49 cases of single-system unifocal (SS-s) disease, 10 cases of single-system multifocal (SS-m) disease, and 9 cases of multi-system (MS) disease. Common symptoms included jaw or tooth pain (28 cases), facial swelling (22), gingival ulceration (10), and loose teeth (9). Imaging revealed periodontal disease-like (7), cyst-like (17), and osteomyelitis-like (44) lesions. Univariate and multivariate Cox regression analyses identified that female patients had a lower risk of progression (P = 0.014, HR 0.071), while SS-m (P = 0.019, HR 4.992) and MS patients (P = 0.030, HR 4.182) exhibited higher progression risks compared to SS-s patients. Cyst-like (P = 0.001, HR 0.054) and osteomyelitis-like lesions (P < 0.001, HR 0.023) were associated with lower progression risks compared to alveolar lesions.</p><p><strong>Conclusion: </strong>JLCH can affect individuals of all ages, though it is more common in children. Factors such as gender, lesion multiplicity, and lesion type (alveolar) are significant in predicting disease progression. Complete surgical resection combined with radiotherapy offers the highest likelihood of cure for SS-type JLCH.</p>","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":"20 1","pages":"191"},"PeriodicalIF":3.4,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12013012/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144010781","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":"Extensive and persistent tongue ulceration is an early character of dyskeratosis congenita.","authors":"Xuefeng Zhang, Hongxia Dan, Yu Zhou, Wanxin Sun, Wanchun Yang, Xin Zeng","doi":"10.1186/s13023-025-03721-4","DOIUrl":"https://doi.org/10.1186/s13023-025-03721-4","url":null,"abstract":"<p><strong>Background: </strong>Dyskeratosis congenita (DC) is a rare and fatal disease, presenting with a classic triad of skin pigmentation, nail dystrophy and oral leukoplakia. However, diagnosing DC is challenging based solely on the protean manifestations and multisystemic involvement. Therefore, it is urgent to identify an early feature facilitating initial suspicion of DC.</p><p><strong>Results: </strong>In this study, we enrolled a cohort of six male children diagnosed with DC, all of whom exhibited erosions or ulcers on the tongue, while five of them did not display the complete classic triad. Strikingly, oral erosions or ulcers have never been included in any existing clinical diagnostic criteria for DC. Through a retrospective analysis, we further demonstrated that extensive and persistent tongue ulceration emerges as an early and practicable clinical marker, provoking suspicion of DC even in the absence of the classic triad.</p><p><strong>Conclusions: </strong>Our findings challenge prevailing diagnostic criteria and advocates for an expanded consideration of tongue ulceration as a primary and indicative manifestation of DC, thereby affording a strategic advantage for early detection and intervention of this lethal disease.</p>","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":"20 1","pages":"192"},"PeriodicalIF":3.4,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12012981/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143984437","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":"The prediction of haemophilic arthropathy progression based on MRI findings and clinical characteristics.","authors":"Lu Zhang, Jinxia Guo, Shufang Wei, Jiajia Li, Yincong Dou, Tianming Cheng, Yinghui Ge, Tuo Zhang","doi":"10.1186/s13023-025-03716-1","DOIUrl":"https://doi.org/10.1186/s13023-025-03716-1","url":null,"abstract":"<p><strong>Objective: </strong>To identify magnetic resonance imaging (MRI) and clinical characteristics that are closely associated with the progression of haemophilic arthropathy (HA) after different therapies and to establish a prediction model for HA progression using Cox proportional hazards regression, thus facilitating the development of personalized clinical replacement therapy plans.</p><p><strong>Materials and methods: </strong>Retrospective clinical and imaging data were collected from HA patients registered at the Henan Provincial Registration Management Center of Haemophilia from December 2010 to May 2023. The inclusion criteria were joints with a history of haemorrhage and initial/posttreatment reevaluation with X-ray and MRI. Joints with severe damage (i.e., a Pettersson score > 6) were excluded. Joint disease progression was defined as a > 1-point increase in the Pettersson score. Progression-free survival (PFS) was the primary outcome. MRI observations revealed joint effusion, synovial hypertrophy, haemosiderin deposition, bone destruction or cystic degeneration at the joint margins, and cartilage destruction. Age, body mass index (BMI), factor VIII (FVIII) activity, activated partial thromboplastin time (APTT), prothrombin time (PT), therapy type, annual joint bleeding rate (AJBR), and the Haemophilia Joint Health Score (HJHS) were also assessed. Subsequently, univariate and multivariate Cox proportional hazards regression models were employed to analyse the clinical and imaging characteristics influencing HA progression. Factors with a P < 0.15 in univariate analysis were subsequently included in the multivariate analysis. The impact of various imaging and clinical characteristics on PFS was assessed via Kaplan‒Meier (K-M) survival curves.</p><p><strong>Results: </strong>This study included 98 joints across 65 patients. During the follow-up period, 63 joints exhibited progression. Both univariate and multivariate Cox analyses revealed that MRI-detected synovial hypertrophy (MRI-SP) was an independent risk factor for HA progression. Incorporating BMI into the model improved its predictive performance (Model 1: c-index = 0.671, P < 0.01). Spearman's correlation analysis revealed strong correlations between baseline MRI-SP and detected haemosiderin deposition (r = 0.73) as well as AJBRs (r = 0.66). K-M survival curves indicated that patients receiving prophylactic treatment and those with less severe MRI-SP had better progression-free survival.</p><p><strong>Conclusion: </strong>MRI-detected synovial hypertrophy is an independent risk factor for HA progression. The predictive model, which includes BMI as a covariate for assessing the risk of HA progression, can serve as an auxiliary tool for developing personalized treatment plans for HA patients.</p>","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":"20 1","pages":"190"},"PeriodicalIF":3.4,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12008956/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143992186","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":"Distinct features of three clinical subtypes in 533 patients with primary hypertrophic osteoarthropathy.","authors":"Xilei Cai, Xiujuan Yang, Pengyue Zhang, Ziyue Dou, Zilian Chen, Chongzhi Zhu, Weiwei Xu, Xinchen Wang, Xiaodan Hong, Zhenhua Zhang","doi":"10.1186/s13023-025-03722-3","DOIUrl":"https://doi.org/10.1186/s13023-025-03722-3","url":null,"abstract":"<p><strong>Background: </strong>Primary hypertrophic osteoarthropathy (PHO) is a rare genetic disorder classified into clinical subtypes and genetic subtypes. Previous clinical studies have primarily focused on case reports and family analyses, largely characterizing the genetic subtypes. However, there remains a long-standing gap in understanding the characteristics of the different clinical subtypes of PHO. This study aimed to determine the distribution of the three clinical subtypes of PHO and compare their clinical characteristics using a large global sample.</p><p><strong>Methods: </strong>A systematic literature search was conducted in multiple databases to categorize cases into complete form (CO), incomplete form (IN), and fruste form (FR). Statistical analyses were performed to assess clinical differences in a retrospective study design.</p><p><strong>Results: </strong>Males predominated across all subtypes, whereas females were most prevalent in IN patients (51.1%). IN patients had the highest family history rate (62.1%). Age at onset peaked in adolescence for CO and FR patients, while IN patients exhibited bimodal peaks in early childhood and adolescence. Congenital diseases were more frequent in IN patients (7.8%, P = 0.021), while CO patients had a higher prevalence of digestive system diseases (12.2%, P = 0.007). Urinary prostaglandin E2 (PGE2) and PGE Metabolite (PGEM) were consistently elevated in CO and FR patients. In IN patients, urinary PGE2 levels were also increased, but the urinary PGEM levels showed equal proportions of elevation and reduction. Genetic analysis revealed that solute carrier organic anion transporter family member 2A1 (SLCO2A1) mutations were predominant in CO (95 cases, 73.1%) and FR (22 cases, 57.9%) patients, whereas hydroxyprostaglandin dehydrogenase (HPGD) mutations were most frequently associated with IN (25 cases, 73.5%).</p><p><strong>Conclusions: </strong>The three clinical subtypes of PHO exhibited distinct characteristics with no clear correlation between clinical and genetic subtypes. These findings highlighted the clinical significance of PHO typing and provided valuable insights for diagnosis, differential diagnosis and subtype-specific management strategies.</p>","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":"20 1","pages":"188"},"PeriodicalIF":3.4,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12007382/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144037397","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":"Novel homozygous frameshift mutation of ITGB3 in the Glanzmann thrombasthenia patient with abnormal bone metabolism and congenital bone defects.","authors":"Yujiao Luo, Nina Guo, Yewei Wang, Ji Li","doi":"10.1186/s13023-025-03700-9","DOIUrl":"https://doi.org/10.1186/s13023-025-03700-9","url":null,"abstract":"<p><strong>Background: </strong>Glanzmann thrombasthenia (GT) is a rare inherited bleeding disorder caused by dysfunction of the integrin αIIbβ3 in platelets. The subunit β3, encoded by ITGB3 also plays a significant role in bone metabolism. Whether GT patients with β3 deficiency also suffer from bone pathology remains unclear.</p><p><strong>Method: </strong>The 21-year-old female patient presenting with bleeding diathesis and multiple congenital bone defects in her right hand, and her seven family members were included in the study. Whole exome sequencing as well as Sanger sequencing were conducted to identify GT-associated mutations within the family. The platelet function of the family was detected by the platelet aggregation test and thromboelastography (TEG). The expression levels of CD41 (αIIb) and CD61 (β3) on the platelet surface and total in platelet were detected by flow cytometry and Western blot. Bioinformatics analysis was used to evaluate the pathogenicity of mutation sites and their effects on protein structure and function. X-ray imaging, bone densitometry and bone metabolism index were performed to evaluate bone development and metabolism.</p><p><strong>Result: </strong>A novel homozygous frameshift mutation c.2143_2158delinsCT (p.Lys715Leufs*36) of ITGB3 was found in the proband. Platelet aggregation by ADP, collagen, epinephrine, and arachidonic acid was absent, TEG showed hypocoagulability and decreased platelet function, and the expression levels of αIIb and β3 on the platelet surface and total in platelet were significantly reduced (< 5%) in the proband. The parents, second elder sister and grandmother of proband were heterozygous carriers without bleeding symptoms and had normal platelet aggregation function and αIIb/β3 protein expression. Structural modeling strongly suggested that the mutation creates a truncation in cytoplasmic domains of β3, resulting in the mutant β3/αIIbβ3 inactivated and low expression. The proband was born with partial absence of phalanges in digits 2-4 and the deformity of fingers 1 and 5 in her right hand, bone densitometry indicated significant osteopenia and increased risk of fracture in her right radius, and no other gene mutations related to bone pathology were identified.</p><p><strong>Conclusion: </strong>A novel mutation of ITGB3 which results in GT was identified. This is the third reported case of GT combined with bone defect. Our work expands ITGB3 mutation spectrum and provide further insights into the potential association between GT and bone development and metabolism.</p>","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":"20 1","pages":"189"},"PeriodicalIF":3.4,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12007121/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144004331","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":"The clinical diversity and molecular etiology in 46, XY disorders of sex development patients without uterus.","authors":"Leilei Ding, Min Luo, Shan Deng, Duoduo Zhang, Qinjie Tian","doi":"10.1186/s13023-025-03719-y","DOIUrl":"https://doi.org/10.1186/s13023-025-03719-y","url":null,"abstract":"<p><strong>Background: </strong>Disorders of sexual development (DSDs) are a group of rare conditions with a discordance of chromosomal, gonadal, or phenotypic features of the internal and/or external genitalia, which accounts for 0.5% of the population. The precise diagnosis of 46, XY DSDs without uterus is often obscure because of the similar clinical manifestations. Reverse phenotyping based on specific genetic variants helps to identify the cause of these diseases and reduces misdiagnosis caused by limitations in serum tests and imaging.</p><p><strong>Methods: </strong>Patients with 46, XY DSDs without uterus were enrolled from the Department of Obstetrics and Gynecology, Reproductive Endocrinology and Infertility Center of the Peking Union Medical College Hospital between 2022 and 2023. Comprehensive clinical data, including the social gender, chief complaint, physical examination results and laboratory tests related to sexual development, and surgical information were collected from medical records. Whole exome sequencing (WES) was performed on all patients and the etiological diagnoses were made based on the results. Targeted Sanger sequencing for the candidate gene was performed in the parents.</p><p><strong>Results: </strong>A total of twenty-one patients with 46, XY DSDs without uterus were included. Twenty-two variants from six genes associated with sex development were identified, including 14 recurrent variants and 8 novel variants. Based on the ACMG guidelines, 17 variants were classified as pathogenic (P) or likely pathogenic (LP), and 5 were defined as variants of uncertain significance (VUS). The genes LH/HCG receptor (LHCGR) (2/22), CYP17A1 (4/22), SRD5A2 (3/22), and AR (10/22) were involved in steroid hormone synthesis and androgen receptor action, while NR5A1(2/22) was associated with gonadal development. Furthermore, a DHX37 variant instead of an AR variant was identified in a patient clinically diagnosed with complete androgen insensitivity syndrome. Trio-WES revealed three de novo variants.</p><p><strong>Conclusion: </strong>This study identified several novel variants broadening the mutation spectrum of 46, XY DSD without uterus. The etiology of 46, XY DSDs is complex. Reverse phenotyping helps differentiate the abnormalities and explore the molecular etiology more accurately.</p>","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":"20 1","pages":"187"},"PeriodicalIF":3.4,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12007265/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144010711","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":"Applying artificial intelligence to rare diseases: a literature review highlighting lessons from Fabry disease.","authors":"Dominique P Germain, David Gruson, Marie Malcles, Nicolas Garcelon","doi":"10.1186/s13023-025-03655-x","DOIUrl":"https://doi.org/10.1186/s13023-025-03655-x","url":null,"abstract":"<p><strong>Background: </strong>Use of artificial intelligence (AI) in rare diseases has grown rapidly in recent years. In this review we have outlined the most common machine-learning and deep-learning methods currently being used to classify and analyse large amounts of data, such as standardized images or specific text in electronic health records. To illustrate how these methods have been adapted or developed for use with rare diseases, we have focused on Fabry disease, an X-linked genetic disorder caused by lysosomal α-galactosidase. A deficiency that can result in multiple organ damage.</p><p><strong>Methods: </strong>We searched PubMed for articles focusing on AI, rare diseases, and Fabry disease published anytime up to 08 January 2025. Further searches, limited to articles published between 01 January 2021 and 31 December 2023, were also performed using double combinations of keywords related to AI and each organ affected in Fabry disease, and AI and rare diseases.</p><p><strong>Results: </strong>In total, 20 articles on AI and Fabry disease were included. In the rare disease field, AI methods may be applied prospectively to large populations to identify specific patients, or retrospectively to large data sets to diagnose a previously overlooked rare disease. Different AI methods may facilitate Fabry disease diagnosis, help monitor progression in affected organs, and potentially contribute to personalized therapy development. The implementation of AI methods in general healthcare and medical imaging centres may help raise awareness of rare diseases and prompt general practitioners to consider these conditions earlier in the diagnostic pathway, while chatbots and telemedicine may accelerate patient referral to rare disease experts. The use of AI technologies in healthcare may generate specific ethical risks, prompting new AI regulatory frameworks aimed at addressing these issues to be established in Europe and the United States.</p><p><strong>Conclusion: </strong>AI-based methods will lead to substantial improvements in the diagnosis and management of rare diseases. The need for a human guarantee of AI is a key issue in pursuing innovation while ensuring that human involvement remains at the centre of patient care during this technological revolution.</p>","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":"20 1","pages":"186"},"PeriodicalIF":3.4,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12007257/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143976234","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}