Maladies orphelines

J Child Adolesc Psychopharmacol. 2026 May 13:10445463261451798. doi: 10.1177/10445463261451798. Online ahead of print.ABSTRACTOBJECTIVE: Anxiety and depressive disorders are common in individuals with Williams syndrome (WS), yet data regarding pharmacologic treatment in this population are limited. This study aimed to evaluate the effectiveness and safety of selective serotonin reuptake inhibitors (SSRIs) in individuals with WS treated for anxiety and/or depressive disorders.METHODS: We conducted a retrospective chart review of patients with a genetically confirmed diagnosis of WS treated with SSRIs between 2010 and 2025 at a clinic for individuals with WS. Fourteen children and adults (5 males and 9 females; mean age: 23.2 ± 11.9 years) met inclusion criteria, contributing 16 distinct SSRI treatment trials. Illness severity was assessed using the Clinical Global Impressions-Severity (CGI-S) scale at baseline and last follow-up and the Clinical Global Impressions-Improvement (CGI-I) scale.RESULTS: The CGI-S score decreased significantly from 4.62 ± 0.81 at baseline to 3.06 ± 1.12 at last follow-up (t(15) = 3.83, p = 0.002). Nine of 16 trials (56.2%) were rated as much or very much improved (CGI-I = 1 or 2). The mean duration of SSRI treatment was 3.95 ± 3.91 years (range: 0.75-16). Adverse events were documented in two trials (12.5%), and no treatment discontinuations due to adverse events occurred.CONCLUSIONS: SSRI treatment was effective and well tolerated in individuals with WS. Prospective controlled studies are required.PMID:42130028 | DOI:10.1177/10445463261451798

BMC Med Genomics. 2026 May 11. doi: 10.1186/s12920-026-02384-9. Online ahead of print.ABSTRACTBACKGROUND: Osteogenesis imperfecta (OI) is a rare genetic bone disorder for which treatment options remain limited. Disease-specific induced pluripotent stem cells (iPSCs) offer a valuable model to investigate its underlying pathological mechanisms.METHODS: Peripheral blood cells from two OI patients were reprogrammed into iPSCs. Transcriptomic sequencing and proteomic analysis were employed to systematically identify differentially expressed genes (DEGs) and proteins (DEPs) between OI-iPSCs and normal iPSCs. Bioinformatics approaches were subsequently applied for enrichment analysis and protein-protein interaction network investigation.RESULTS: OI-iPSCs were successfully established. Integrated multi-omics analysis identified 671 common DEGs and 636 common DEPs. These molecules were significantly enriched in metabolic pathways, with the oxidative phosphorylation pathway being particularly prominent. Further cross-omics screening revealed 22 genes that were differentially expressed at both the mRNA and protein levels. Among these, the focal adhesion protein VCL emerged as a central hub within the protein-protein interaction network.CONCLUSION: Through multi-omics analysis, this study revealed widespread dysregulation of metabolic pathways in OI-iPSCs, suggesting that targeted interventions on specific metabolic pathways may represent a novel therapeutic strategy for OI. VCL emerged as a key candidate molecule, warranting further functional validation in subsequent studies. These findings provide new insights into the mechanisms of OI and potential avenues for therapeutic development.PMID:42116115 | DOI:10.1186/s12920-026-02384-9

J AAPOS. 2026 May 6:104853. doi: 10.1016/j.jaapos.2026.104853. Online ahead of print.ABSTRACTPURPOSE: To present a comprehensive analysis of ocular features observed in pediatric patients diagnosed with Loeys-Dietz syndrome (LDS).METHODS: This prospective observational study included pediatric patients with a confirmed diagnosis of LDS who presented to the Eye Clinic at The Hospital for Sick Children, Toronto, Ontario, from January 2016 to September 2024. Comprehensive ophthalmic examinations were performed, including refraction, corneal imaging, and optic nerve evaluation. Genetic testing results were reviewed to correlate ocular findings with pathogenic variants in TGFBR1, TGFBR2, or TGFB2.RESULTS: Seventeen pediatric patients (34 eyes) were included, with a mean age of 10.6 ± 3.8 years (range, 4-17 years). The mean spherical equivalent was +0.79 ± 2.39 D. Retinal vascular tortuosity was observed in 18 patients (53%). The mean central corneal thickness was 511 ± 42 μm. Flat corneal curvature (mean K ≤ 42.00 D) was present in 21 eyes (66%). Supernumerary optic disk vessels were noted in 12 eyes (40%), and seven (23%) had an optic disk area >2.50 mm2. No lens abnormalities were identified. A single patient had significant myopia (> -1.00 D). No significant associations were found between genetic variants and ocular biometric parameters.CONCLUSIONS: In our small cohort of pediatric patients with LDS, ocular findings included retinal vascular tortuosity, reduced corneal thickness, and optic nerve anomalies. Lenticular abnormalities were absent, and significant myopia was nearly so.PMID:42103274 | DOI:10.1016/j.jaapos.2026.104853

Arch Clin Cases. 2026 May 5;13(1):19-25. doi: 10.22551/2026.50.1301.10336. eCollection 2026.ABSTRACTHomocystinuria (HCU) is a rare autosomal recessive metabolic disorder, characterized by a mutation in the enzyme cystathionine beta-synthase and abnormally high levels of homocysteine in the blood. HCU that runs in a family is rare; prior to this report, there have been only 150 familial cases described in the literature. Here, we describe a familial cluster of HCU in four children in "Family V," a consanguineous indigenous family from rural Honduras with a 10-year clinical follow up. We describe the diagnosis, presentation and progression of three patients who were diagnosed in 2015; critical findings include substantial vision loss in Patients 1 and 2, and a significant decline in language ability in Patient 3. We also describe the presentation of Patient 4, a grandchild who we diagnosed with probable HCU based on symptoms very similar to his siblings and highly suspicious for HCU. Additionally, we completed a narrative review of previously published familial HCU cases, using PubMed and Google Scholar, to highlight common phenotypic trends in familial HCU patients. In the reported familial cases, 57% had CNS complications, 48% had ocular complications, and 30% had cardiovascular complications.PMID:42111688 | PMC:PMC13154418 | DOI:10.22551/2026.50.1301.10336

Graefes Arch Clin Exp Ophthalmol. 2026 May 18. doi: 10.1007/s00417-026-07267-4. Online ahead of print.ABSTRACTPURPOSE: Stickler syndrome represents a group of rare, inherited genetic disorders and is the leading cause of inherited retinal detachment (RD). This study aimed to examine the ocular clinical characteristics and compare the surgical outcomes of Stickler syndrome.METHODS: This single-center, retrospective study included 86 patients diagnosed with Stickler syndrome (58 genetically confirmed) between 2012 and 2024. Patients with RD underwent one of two surgical procedures, and their anatomical and functional outcomes were compared. Patients without RD underwent ora serrata and peripheral retinal screening, with 360° prophylactic laser therapy applied to high-risk eyes exhibiting pathology.RESULTS: The pars plana vitrectomy (PPV) group exhibited more severe baseline clinical characteristics than the scleral buckle (SB) group. After surgery, the two groups showed no statistically significant differences in any outcomes except anatomical success rate and best-corrected visual acuity (BCVA). Preoperative BCVA, the presence of cataract, RD extent and status, proliferative vitreoretinopathy (PVR) grade, and silicone oil tamponade were significantly associated with worse postoperative BCVA. Patients at high risk of RD underwent ora serrata and peripheral retina screening, and 36 eyes received prophylactic laser treatment. Preoperative retinal breaks and ora serrata dialysis were independent risk factors for post-laser RD.CONCLUSION: Stickler syndrome is a progressive disorder associated with a high risk of RD. Early diagnosis and regular surveillance are crucial for initiating timely intervention. Further research is needed to understand the pathogenesis of Stickler syndrome better, develop more effective prophylactic and surgical strategies, and improve outcomes for affected individuals.PMID:42149213 | DOI:10.1007/s00417-026-07267-4

Arch Cardiol Mex. 2026 May 18. doi: 10.24875/ACM.25000200. Online ahead of print.ABSTRACTOBJECTIVE: To compare the strength of correlation between the aortic root, pulmonary artery, and body surface area in pediatric and young patients with Marfan syndrome.METHOD: Cross-sectional study using secondary data from 1371 records of Marfan syndrome patients from the A100 form of the Pediatric Heart Network Marfan Study. Variables included maximum diameters of the aortic root and pulmonary artery (bidimensional echocardiography), body surface area (Mosteller formula), sex, and age. Normality was assessed using the Kolmogorov-Smirnov test; Spearman correlation was applied due to non-normal distribution. Analyses were stratified by age and sex.RESULTS: The correlations between aortic root diameter, main pulmonary artery, and body surface area were significant across all groups, though stronger in patients ≤ 14 years (ρ= 0.616-0.786) compared to those aged 15-26 years (ρ = 0.295-0.442). By sex, the associations were high and comparable ble, both in females (ρ = 0.697-0.812) and in males (ρ = 0.622-0.792), indicating a closer vascular morphometric relationship at younger ages and a trend toward greater structural concordance by sex.CONCLUSIONS: The aortic-pulmonary relationship depends on age, with greater strength during periods of accelerated growth.PMID:42150605 | DOI:10.24875/ACM.25000200

J Neurodev Disord. 2026 May 20. doi: 10.1186/s11689-026-09697-x. Online ahead of print.ABSTRACTBACKGROUND: Individuals with fragile X syndrome (FXS) and Down syndrome (DS) have significant and pervasive challenges in language (and more specifically grammar) and executive functions (EFs). While these aspects of development are linked in autism and developmental language disorder, there has not been an investigation into this in FXS and DS. Thus, the purpose of this study was: 1) to evaluate the feasibility of experimental tasks for language and EFs, 2) to test if there are differences in language and EFs in DS and FXS, and 3) to test if EFs are related to grammatical abilities in DS and FXS within and between groups.METHODS: Participants included 21 boys with FXS and 25 participants with DS (n = 9 females) between 9-17 years of age; groups were matched on chronological age (variance ratio = 1.13; d = 0.04, p = 0.897) and were similar on nonverbal IQ and vocabulary. Participants completed lab-based assessments including standardized assessments of nonverbal IQ and vocabulary, experimental measures of grammar (i.e., grammatical judgment and sentence imitation), three experimental executive function tasks, and a parent report of executive functions.RESULTS: While there were participants who could not complete the tasks, overall the feasibility was high (72-91% participants completed the tasks). Wilcoxon rank-sum tests revealed no significant group differences in experimental grammar or EF tasks. In contrast, large differences emerged on parent-reported EFs, with greater impairment in FXS for shifting and inhibition. We used generalized linear regression models with Gaussian and binomial distributions to examine the relationships between EFs and grammatical abilities. We found that only working memory significantly predicted grammatical judgment.CONCLUSIONS: Participants with DS and FXS showed similar grammatical production and comprehension skills, contrasting with prior studies that relied on standardized testing and found more impaired production skills for children and adolescents with DS. Our sentence imitation task highlighted expressive grammar skills in DS, while grammaticality judgment posed challenges as a measure of grammar comprehension. Feasbility was good for all tasks, but there was a range, and younger participants in particular seemed to struggle with some of the tasks. The contrast in group differences between experimental and parent-reports […]

Am J Med Genet A. 2026 May 12:e70178. doi: 10.1002/ajmg.a.70178. Online ahead of print.ABSTRACTVascular Ehlers-Danlos syndrome (vEDS) is a hereditary connective tissue disorder caused by heterozygous pathogenic variants in COL3A1. European studies have shown that celiprolol may reduce the risk of life-threatening vascular events, but outcomes in non-European populations and the therapy's psychological impact remain unclear. We conducted a retrospective cohort study of individuals aged ≥ 20 years with genetically confirmed vEDS in a single referral center in Japan between 2000 and 2024. Clinical, molecular, and treatment data were obtained from medical records, and semi-structured interviews were conducted with a subset of participants to assess patient experiences. Twenty-six patients were included. The mean age at celiprolol initiation was 36.9 years, with a mean follow-up of 96.6 months. All patients received celiprolol, and 61.5% reached the target dose (400 mg/day). One patient died of hepatic artery rupture; vascular events occurred in 11, while 14 remained event-free. No significant associations were observed between vascular event occurrence and genotype or celiprolol dose. Interviews with 11 patients revealed that celiprolol use provided emotional reassurance and promoted a more proactive approach to disease management. Celiprolol therapy may reduce fatal vascular events in vEDS and have a positive psychological impact, though nonfatal vascular complications remain frequent.PMID:42124361 | DOI:10.1002/ajmg.a.70178

JAMA. 2026 May 14. doi: 10.1001/jama.2026.6889. Online ahead of print.ABSTRACTIMPORTANCE: Osteogenesis imperfecta causes multiple fractures throughout life, causing substantial morbidity.OBJECTIVE: To determine whether the parathyroid hormone analogue teriparatide followed by zoledronic acid reduces the risk of fractures in adults with osteogenesis imperfecta.DESIGN, SETTING, AND PARTICIPANTS: Multicenter open-label, parallel-group, randomized clinical trial, conducted between May 17, 2017, and March 21, 2025, in adults attending one of 27 referral centers with a clinical diagnosis of osteogenesis imperfecta. Bone mineral density (BMD) was measured by dual x-ray absorptiometry and bone turnover by serum procollagen type 1 N-terminal propeptide and C-terminal telopeptide of type 1 collagen. Fractures were confirmed by skeletal imaging. Several measures of health-related quality of life were assessed.INTERVENTIONS: Those in the active group received 20 μg of teriparatide daily by subcutaneous injection for 2 years followed by an infusion of 5 mg of zoledronic acid. In the standard care group, bisphosphonates and other bone-targeted medicines could be used but teriparatide and other bone anabolic drugs were prohibited.MAIN OUTCOMES AND MEASURES: The primary end point was the number of participants with imaging-proven incident fractures adjudicated by reviewers blinded to treatment allocation. Secondary end points included the total number of fractures, changes in BMD, biochemical markers of bone turnover, and health-related quality of life.RESULTS: Of the 350 individuals randomized, 176 were allocated to receive teriparatide plus zoledronic acid, 174 to standard care, and 1 withdrew, leaving 349 evaluable participants. The mean age was 43.7 years (188 females [53.9%]). Most had type I osteogenesis imperfecta caused by pathogenic variants in the type 1 collagen genes. In the teriparatide plus zoledronic acid group 65 of 176 (36.9%) had incident fractures compared with 63 of 173 (36.4%) in the standard care group (absolute risk reduction, -1.57%; 95% CI, -9.90% to 5.89%; hazard ratio, 0.97; 95% CI, 0.68 to 1.38). Lumbar spine and total hip BMD increased significantly more with teriparatide plus zoledronic acid than standard care. Several quality-of-life measures favored teriparatide plus zoledronic acid. Adverse events were similar in both groups.CONCLUSIONS AND RELEVANCE: This randomized clinical trial among adults with osteogenesis imperfecta found that […]

Heart. 2026 May 8:heartjnl-2025-327408. doi: 10.1136/heartjnl-2025-327408. Online ahead of print.ABSTRACTBACKGROUND: The prevalence and clinical correlates of extra-aortic vascular disease in Marfan syndrome remain incompletely defined, and current surveillance strategies primarily target the thoracic aorta.METHODS: We conducted a multicentre retrospective cohort study of 783 patients with Marfan syndrome across three tertiary centres, with systematic chart and imaging adjudication to define aneurysm and dissection distribution.RESULTS: Extra-aortic aneurysms were identified in 32% of patients, most commonly involving the iliac, carotid and subclavian arteries. Extra-aortic dissections occurred in 5.2%. Extra-aortic aneurysms clustered strongly with markers of advanced aortic disease, including abdominal aortic aneurysm (adjusted OR 3.48), prior aortic dissection (OR 3.39) and extra-aortic dissection (OR 4.44), as well as age >40 years and male sex. Genetic confirmation status was not associated with extra-aortic aneurysm presence.CONCLUSIONS: Extra-aortic vascular involvement is common in Marfan syndrome and closely linked to advanced aortic pathology. These findings support risk-stratified vascular imaging beyond the thoracic aorta in higher-risk patients.PMID:42103457 | DOI:10.1136/heartjnl-2025-327408

Am J Med Genet A. 2026 Apr 29. doi: 10.1002/ajmg.a.70176. Online ahead of print.ABSTRACTHypermobile Ehlers-Danlos syndrome (hEDS), while generally free from severe vascular complications, may occasionally present with cardiac and vascular abnormalities that warrant specific investigation. While studies have been conducted on the prevalence of cardiac involvement, none have focused on vascular aspects. This retrospective study was performed to investigate the prevalence of aneurysms in patients diagnosed with hEDS based on the 2017 International diagnostic criteria, to evaluate the need for systematic vascular screening. Fifty-five patients with hEDS were included. All patients had undergone computed tomography angiography of the chest, abdomen, pelvis, and sometimes the head during their initial assessment. The images were analyzed to determine the prevalence of aneurysms, and a potential link to cardiovascular risk factors was examined. Aneurysms were identified in four patients (7.3%). These were located in the thoracic aorta, splenic artery, or the circle of Willis. There was no significant association with cardiovascular risk factors. While this study provides an initial evaluation of the prevalence of aneurysms in hEDS, its results should be interpreted with caution. Our findings highlight the need for larger-scale studies with rigorous methodology to accurately characterize the vascular abnormalities associated with hEDS and determine their clinical significance.PMID:42057351 | DOI:10.1002/ajmg.a.70176

JACC Basic Transl Sci. 2026 Apr 22;11(5):101543. doi: 10.1016/j.jacbts.2026.101543. Online ahead of print.ABSTRACTFibrillin defects lead to severe cardiovascular complications in Marfan syndrome (MFS), including aortic dilation, dissection, and rupture. To model MFS, zebrafish mutants lacking various fibrillin genes were generated. Among these mutant lines, only fibrillin-3-deficient zebrafish exhibited cardiovascular phenotypes mimicking human disease. Multimodal imaging revealed early cardiac defects, bulbus arteriosus dilation, and valve abnormalities. Transcriptomic analysis identified altered regulation of pathways related to extracellular matrix homeostasis and immune system activation. This zebrafish model, recapitulating key cardiovascular features of MFS, provides a valuable platform to investigate disease mechanisms and identify novel treatment strategies.PMID:42025244 | DOI:10.1016/j.jacbts.2026.101543

J Intellect Disabil Res. 2026 Apr 24. doi: 10.1111/jir.70106. Online ahead of print.ABSTRACTBACKGROUND: Fragile X syndrome (FXS) is a monogenic X-linked cause of intellectual disability and autism. Individuals with FXS often have high levels of anxiety and sometimes display challenging behaviours. Autonomic dysfunction has been suggested to be one physiological mechanism that may contribute to these. Therefore, the objective of this review is to systematically examine existing evidence on autonomic function in FXS.METHOD: An electronic literature search was conducted on OVID platforms (Medline, Embase and PsycINFO) and Web of Knowledge databases for references published before 22 April 2025, which physiologically measured autonomic function in FXS. A preregistered search strategy was designed to gather literature on the autonomic nervous system in FXS.RESULTS: A total of 1426 articles were identified, and 28 studies met the inclusion criteria. Samples comprised individuals across the lifespan (ages < 1-71 years), with most studies utilising a case control design to examine indices of autonomic function; 75% of studies found a between-group difference in autonomic function metrics. Of these studies, hyperarousal in the FXS group was present in 86% (N = 18) of studies. Although some studies reported associations of autonomic function with clinical characteristics, findings varied considerably between studies. There was some evidence of potential differences between genders, although more research in female populations is required. Of the 28 included studies, 64% (N = 18) further examined links between autonomic function and clinical characteristics associated with FXS, demonstrating links between relevant clinical symptoms, that is, autistic traits and hyperarousal, as well as potential gender differences in autonomic function.CONCLUSIONS: The findings demonstrate evidence for autonomic hyperarousal as a clinical phenotype in FXS across the lifespan. Future work is required to define whether overactivation of the sympathetic nervous system, as indicated by hyperarousal in FXS, can be linked to clinical symptoms. Variations in sample demographics as well as in methodological approaches to measuring autonomic function both hinder accurate comparison of the results from included studies.PMID:42028919 | DOI:10.1111/jir.70106