Maladies orphelines

JACC Case Rep. 2026 Sep 23:110387. doi: 10.1016/j.jaccas.2026.110387. Online ahead of print.ABSTRACTBACKGROUND: Spontaneous coronary artery dissection is an uncommon cause of acute coronary syndromes, with rare reports in fragile X syndrome.CASE SUMMARY: A 44-year-old man with fragile X syndrome presented with ventricular fibrillation arrest and anterior ST-segment elevation. Angiography and intravascular ultrasound (IVUS) revealed extensive left anterior descending artery spontaneous coronary artery dissection with inadvertent false-lumen wiring. A dual-catheter technique was used, with live false-lumen IVUS-guided true-lumen wiring, hematoma fenestration, and ostial stenting, with postprocedural imaging confirming dissection sealing. Computed tomography angiography identified additional silent dissections of the celiac, superior mesenteric, and right femoral arteries.DISCUSSION: This case suggests systemic vascular fragility in fragile X syndrome and describes a novel IVUS-guided bailout strategy using live false-lumen imaging to facilitate true-lumen wiring and ostial stent positioning.TAKE-HOME MESSAGES: Acute coronary syndrome in fragile X syndrome should prompt consideration of systemic arteriopathy and multivessel dissection. Live false-lumen IVUS may facilitate true-lumen wiring when conventional techniques fail.PMID:42776114 | DOI:10.1016/j.jaccas.2026.110387

J Surg Res. 2026 Sep 23;327:203-215. doi: 10.1016/j.jss.2026.08.048. Online ahead of print.ABSTRACTINTRODUCTION: The purpose of this study is to evaluate the current body of literature describing abdominal wall reconstruction management and outcomes in patients with Ehlers-Danlos Syndrome (EDS) to guide future surgical recommendations for this vulnerable population.METHODS: In accordance with PRISMA-ScR guidelines, a scoping review was conducted in May 2026 using PubMed, Cochrane, Scopus, and Embase. We identified literature that discussed the operative management and postoperative outcomes of abdominal wall reconstruction in patients with EDS. Studies were screened and data were extracted by two independent reviewers. Data included study, patient, and operative characteristics, in addition to postoperative outcomes.RESULTS: Nine studies (six case reports and three case series) comprising 28 patients in total were included in this study. The most reported reconstructive technique was mesh reinforcement, primarily synthetic mesh, and most commonly retromuscular or sublay positioning. Other described techniques included oversized mesh reinforcement (mean 399 cm2 mesh surface area for a mean defect size of 3 × 5 cm, reported in a single case series of 14 patients), meticulous suture technique, component separation, multilayer fascial closure, and flap-based reconstruction (specifically when a contaminated defect was unsuitable for mesh use). Dehiscence was reported in six of the nine studies, representing the most commonly reported complication. Hernia recurrence was rarely reported, although statistical comparisons between postoperative outcomes were limited by small sample size.CONCLUSIONS: Oversized mesh augmentation and meticulous tissue handling were among the operative strategies described in the available literature on abdominal wall reconstruction for patients with EDS. This review is composed solely of case reports and case series. Future comparative studies are necessary to help generate algorithmic surgical approaches for the study population.PMID:42777436 | DOI:10.1016/j.jss.2026.08.048

Graefes Arch Clin Exp Ophthalmol. 2026 Sep 19. doi: 10.1007/s00417-026-07506-8. Online ahead of print.ABSTRACTPURPOSE: To systematically evaluate the anatomical and functional outcomes of surgical repair for retinal detachment (RD) in patients with Stickler syndrome, a condition that presents unique and complex surgical challenges due to abnormal vitreoretinal anatomy.METHODS: A systematic review and meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A comprehensive search of Cochrane, Web of Science, PubMed, EMBASE, and MEDLINE databases was performed up to November 2025 to identify studies reporting outcomes of surgical repair for retinal detachment in patients with Stickler syndrome. Primary outcomes included primary and final reattachment rates and changes in best-corrected visual acuity (BCVA).RESULTS: Ten multi-eye studies, comprising 217 eyes from 188 patients, were included after the exclusion of single-case reports. The pooled random-effects meta-analysis demonstrated a primary reattachment rate of 0.66 (95% Confidence Interval (CI): 0.50 to 0.78; I² = 65.8%, p = 0.0018; prediction interval 0.21 to 0.93). The pooled final reattachment rate, calculated from ten multi-eye studies (217 eyes), was 0.91 (95% CI: 0.79 to 0.96; I² = 55.5%, p = 0.0165; prediction interval 0.37 to 0.99), often requiring multiple surgeries. Proliferative vitreoretinopathy (PVR) and paediatric age were associated with lower primary reattachment rates. Combined PPV and SB procedures were utilised in multiple studies.CONCLUSION: Surgical intervention for RD in Stickler syndrome achieves a high rate of final anatomical success but is marked by a modest primary success rate that is lower than in idiopathic cases. The need for multiple interventions is common, especially in younger patients and those complicated by PVR.PMID:42760409 | DOI:10.1007/s00417-026-07506-8

Mol Aspects Med. 2026 Sep 15;112:101503. doi: 10.1016/j.mam.2026.101503. Online ahead of print.ABSTRACTFibrillin-1 is an extracellular matrix glycoprotein essential for microfibril integrity, mediating cell-matrix interactions, providing structural support to tissues, and serving as a scaffold for elastogenesis. Pathogenic variants in the fibrillin 1 gene (FBN1) give rise to a spectrum of autosomal dominant connective tissue disorders collectively termed type-1 fibrillinopathies, which include Marfan syndrome, geleophysic dysplasia 2, acromicric dysplasia, Weill-Marchesani syndrome 2, marfanoid-progeroid-lipodystrophy syndrome, stiff skin syndrome, MASS syndrome, and isolated ectopia lentis 1. These disorders predominantly manifest cardiovascular, skeletal, and ocular abnormalities. Among these, aortic and valvular lesions are the principal and most life-threatening complications and therefore warrant the greatest clinical attention. Skeletal anomalies are diverse and can even be diametrically opposed across different phenotypes, while ectopia lentis represents the hallmark of ocular conditions. Notably, mutant fibrillin-1 disrupts microfibril structure and/or function, leading to dysregulated transforming growth factor-β (TGF-β) signaling, which is widely recognized as a central mechanism underlying type-1 fibrillinopathies. Although numerous pathogenic FBN1 variants have been identified, the knowledge of genotype-phenotype correlations remains limited in some specific regions. This review synthesizes the current understanding of the FBN1-related molecular mechanisms linking aberrant TGF-β signaling to distinct phenotypic outcomes and discusses how genetically engineered animal models and human induced pluripotent stem cell models advance mechanistic insights and facilitate therapy development. Additionally, clinical manifestations and genetic characteristics across all phenotypes are elaborated to facilitate diagnosis, treatment, and management of these complex disorders.PMID:42743781 | DOI:10.1016/j.mam.2026.101503

Mol Genet Metab Rep. 2026 Sep 11;49:101355. doi: 10.1016/j.ymgmr.2026.101355. eCollection 2026 Dec.ABSTRACTNatural history data for homocystinuria is difficult to accurately obtain due to many factors related specifically to rare disorders. HCU Network America, a non-profit organization for this patient population, utilizes a patient-driven data collection program to support research. Patients and caregivers are asked to complete surveys through the collection program, and findings are provided as deidentified data. This report outlines the symptoms that enrolled participants identified as most impactful. Follow-up surveys were requested in those areas for specific symptomatology. Patients enrolled ranged from 1 to 74 years of age and encompass an international population from 23 countries and 35 US States.PMID:42756705 | PMC:PMC13583585 | DOI:10.1016/j.ymgmr.2026.101355

Dev Neurosci. 2026 Aug 27:1. doi: 10.1159/dne/aclag004. Online ahead of print.ABSTRACTINTRODUCTION: Atypical sensory processing, particularly auditory hypersensitivity, is a common and debilitating phenotype of Fragile X Syndrome (FXS). Electrophysiology studies in the FMR1-knockout (KO) mice previously observed hyperexcitability at the auditory cortex (AC), with enhanced neuronal firing to auditory stimuli. Prepulse inhibition (PPI), a behavioral measure of sensorimotor gating, is robustly impaired in FXS individuals. Interestingly, a related paradigm called gap-induced inhibition of the acoustic startle (GPIAS) is mediated by the AC, and a previous study observed decreased GPIAS in mature FMR1-KO mice. Further, habituation is also an important sensory filtering mechanism, which has been reported to be impaired in mature FMR1-KO mice. However, not much is known about GPIAS and habituation in the FMR1-KO mice during early development.METHODS: We evaluated GPIAS in male and female FMR1-KO mice at post-natal days 15 (P15), 20 (P20) and 30 (P30). The paradigm consisted of a prepulse stimulus (gap in continuous background noise) followed by a startle stimulus, at inter-stimulus intervals of 50 and 100 ms. Habituation was assessed prior to the GPIAS trials, with a series of startle only stimulus.RESULTS: We observed a trend for genotype difference in acoustic startle response (ASR) magnitude, particularly in the female mice at P30. No significant genotype differences were noted in GPIAS or latency of ASR. Response duration was significantly increased in the male FMR1-KO mice compared to their WT counterparts during early development. Significant genotype differences were also observed in habituation and sensitization. In terms of development, we observed a significant increase in GPIAS with maturation. Furthermore, we also observed significant changes in the magnitude, response latency and duration of ASR with maturation. Finally, significant sex differences were observed in ASR magnitude and duration.CONCLUSION: Our findings suggest that behavioral responses to auditory stimuli are dynamic during development and differ between females and males. This is an important consideration for future study designs and highlights the need for mechanistic studies to further understand the development- and sex-related differences. Additionally, the FMR1-KO mice display habituation deficits during early development, which could be an ideal window for addressing auditory […]

Diabet Med. 2026 Sep 3:e70466. doi: 10.1111/dme.70466. Online ahead of print.ABSTRACTAIM: Deep intronic variants can disrupt splicing and cause monogenic disease but are missed by routine genetic testing. This study assessed the contribution of deep intronic variants to Wolcott-Rallison syndrome (WRS), a recessive disorder characterized by early-onset diabetes and progressive multisystem disease caused by loss-of-function EIF2AK3 variants.METHODS: We investigated a cohort of 116 individuals referred to the Exeter Genomics Laboratory for genetic testing who had diabetes diagnosed at ≤2 years and at least one additional feature consistent with WRS: hepatic dysfunction, skeletal abnormalities or developmental delay. No genetic cause had been identified after testing all known early-onset diabetes genes. We screened genome-sequencing data for rare homozygous intronic EIF2AK3 variants. Candidate variants predicted to affect splicing by SpliceAI were assessed using a minigene exon-trapping assay.RESULTS: We identified two rare homozygous intronic EIF2AK3 variants in two siblings. Only one variant, c.1651-180G>T, was predicted to disrupt splicing in silico. The two children, born to consanguineous parents, were diagnosed with early-onset diabetes (diagnosed at 1 year and 21 weeks), hepatic dysfunction, skeletal abnormalities, developmental delay, thyroid dysfunction, hip dysplasia and gait abnormalities. The minigene assay showed that c.1651-180G>T creates a cryptic donor splice site within intron 9, resulting in inclusion of a 79-nucleotide pseudoexon, causing a frameshift and premature stop codon. Using this evidence, the variant was reclassified as likely pathogenic according to ACMG/ACGS guidelines.CONCLUSIONS: We report the first deep intronic EIF2AK3 variant causing WRS, highlighting the need to consider systematic intronic analysis in unresolved cases.PMID:42689758 | DOI:10.1111/dme.70466

Br J Dev Psychol. 2026 Aug 26. doi: 10.1111/bjdp.70065. Online ahead of print.ABSTRACTResearch on genetic syndromes is vital to our understanding of how development unfolds, but the rarity of genetic syndromes can mean that studies are carried out with small sample sizes. Small sample sizes can reduce the statistical power of a study to produce reliable and replicable results. Here, we review all UK journal articles on three target genetic syndromes published from 2013 to 2022. There were 368 eligible articles. The median sample size of genetic syndrome groups was N = 30, and only 6.5% of articles reported a power analysis. Power analysis was performed on the 123 articles classed as 'Cognitive' research, as a test case. This demonstrated an average power of only 54% for a medium effect size and an alpha of 0.05. This is well below the recommended threshold of 80% power. The low power of UK genetic syndrome research has consequences for the replicability of the field due to the risk of Type II errors and reduced precision in effect size estimates, as well as implications for the communities that this research seeks to serve. We provide suggestions for researchers, journal editors and funders for improving the replicability of the field of genetic syndrome research.PMID:42644592 | DOI:10.1111/bjdp.70065

Clin Case Rep. 2026 Aug 21;14(8):e73301. doi: 10.1002/ccr3.73301. eCollection 2026 Aug.ABSTRACTCentral precocious puberty (CPP) is an increasingly recognized endocrine comorbidity in girls with Williams syndrome (WS), but its diagnosis and management may be complicated by the short stature and atypical growth pattern associated with WS. We report two girls with genetically confirmed WS and CPP who showed different clinical presentations and treatment courses. Both patients presented with advanced pubertal development and markedly advanced bone age. In Case 1, pubertal growth acceleration was not readily apparent on standard population-based growth charts but became evident when assessed using WS-specific growth charts. Gonadotropin-releasing hormone agonist (GnRHa) therapy initially achieved sustained pubertal suppression, but the improvement in predicted adult height (PAH) was limited. Recombinant human growth hormone (GH) was subsequently added, and PAH progressively increased. In Case 2, rapid progression from breast development to menstrual bleeding prompted early combined treatment with GnRHa and GH. During follow-up, bone-age advancement remained limited and PAH increased above the mid-parental height, allowing planned discontinuation of GnRHa and continuation of GH. These cases highlight the value of WS-specific growth charts for recognizing abnormal growth acceleration and support individualized treatment strategies guided by pubertal progression, bone age advancement, growth velocity, and serial PAH assessment.PMID:42632986 | PMC:PMC13498749 | DOI:10.1002/ccr3.73301

Radiol Case Rep. 2026 Aug 13;21(11):5372-5379. doi: 10.1016/j.radcr.2026.07.058. eCollection 2026 Nov.ABSTRACTWilliams-Beuren syndrome is a rare chromosomal microdeletion (7q11.23) associated with psychomotor delay, a characteristic dysmorphic profile, neurocognitive disorders, and, especially, an increased risk of cardiovascular and renal complications leading to hypertension. We report a case of severe hypertensive emergency in a child with this syndrome. Our patient is a 7-year-old boy who presented with headaches, morning projectile vomiting, and polyuria over the past month. On admission, the blood pressure was 180/120 mmHg, and the cardiovascular examination revealed no cardiac or vascular murmurs. The physical examination revealed a distinctive facial phenotype suggestive of Williams-Beuren syndrome. The biological assessment showed normal renal function without electrolyte abnormalities. The abdominal ultrasound showed kidneys of normal size, and the renal Doppler revealed bilateral stenosis of the proximal renal arteries. The thoraco-abdominal angioscanner identified severe stenoses of the bilateral renal arteries at the ostial and postostial levels. The echocardiography revealed left ventricular hypertrophy without aortic stenosis. Angioplasty with dilation of both arteries was performed, with good clinical progress, and the patient was discharged on 2 antihypertensives. Arterial hypertension is a classic complication of Williams-Beuren syndrome, secondary to renal artery stenosis or supravalvular aortic stenosis. It may present with neurological manifestations (headaches, vomiting) or urinary symptoms. The diagnosis is based on vascular imaging and nephrological monitoring. This case highlights the importance of systematic blood pressure screening and nephrocardiological monitoring in children with Williams-Beuren syndrome. Early identification and proper treatment of hypertension can avert enduring cardiovascular and renal complications.PMID:42633204 | PMC:PMC13499177 | DOI:10.1016/j.radcr.2026.07.058

Int Heart J. 2026 Sep 11. doi: 10.1536/ihj.26-162. Online ahead of print.ABSTRACTAn increased incidence of ventricular fibrillation (VF) has been reported in patients with Marfan syndrome (MFS) compared with the general population. Although reduced left ventricular systolic function and severe valvular disease are recognized as major risk factors for ventricular arrhythmias (VAs) in MFS, we report a case of VF that developed despite the absence of these risk factors.A 22-year-old man with MFS who had previously undergone a valve-sparing aortic root replacement with the David procedure, lost consciousness and was diagnosed with VF. After resuscitation, no new abnormal findings were observed except for mild QT prolongation (QTc 471 msec) and a slightly elevated B-type natriuretic peptide level (89.0 pg/mL). An echocardiogram revealed no significant changes compared with the previous examination. It showed that the ejection fraction was preserved and that there was mild aortic valve regurgitation and mild-to-moderate mitral valve regurgitation. Whole-exome sequencing analysis revealed no pathogenic variants, except for an FBN1 variant that was already known to be present. He was diagnosed with idiopathic VF and was implanted a subcutaneous implantable cardioverter-defibrillator.This case underscores the risk of VAs in MFS even in the absence of ventricular dysfunction or severe valvular diseases. A combination of various factors, such as subtle depolarization abnormalities, moderate valvular abnormalities, and underlying myocardial damage, may contribute to the development of VF. More careful surveillance and precise identification of risk factors for arrhythmias are warranted.PMID:42732934 | DOI:10.1536/ihj.26-162

Int Ophthalmol. 2026 Sep 10;46(1):391. doi: 10.1007/s10792-026-04265-7.ABSTRACTPURPOSE: To evaluate corneal subbasal nerve plexus alterations in genetically confirmed FBN1-related Marfan syndrome (MFS) using in vivo confocal microscopy (IVCM).METHODS: This cross-sectional case-control study included patients with genetically confirmed FBN1-related MFS and healthy controls. Corneal imaging was performed using IVCM, and six representative images of the subbasal nerve plexus were analyzed with ACCMetrics software. Quantitative parameters included corneal nerve fiber length (CNFL), corneal nerve fiber density (CNFD), corneal nerve branch density (CNBD), corneal nerve total branch density (CTBD), corneal nerve fiber area (CNFA), corneal nerve fiber width (CNFW), and corneal nerve fractal dimension (CNFraD). Between-group differences were assessed using the Mann-Whitney U test. Age-stratified analyses and interaction models adjusted for sex were used to examine the consistency of group effects across age categories.RESULTS: 49 participants were included (30 MFS, 19 controls). Compared with controls, patients with MFS showed significantly reduced CNFL, CNFD, CNBD, CTBD, CNFA, and CNFraD (all P < 0.001), while CNFW did not differ between groups (P = 0.33). Similar reductions were observed in both <18 and ≥18 years subgroups, with no significant group-by-age interaction. Qualitative abnormalities included reduced corneal nerve density with simplified branching, microneuroma-like terminal enlargements, and hyper-reflective deposits adjacent to nerve fibers and the epithelial basement membrane.CONCLUSIONS: FBN1-related MFS is associated with significant quantitative and morphological alterations of the corneal subbasal nerve plexus. Corneal nerve assessment using IVCM may provide a noninvasive marker of microstructural involvement in this systemic connective tissue disorder.PMID:42722916 | DOI:10.1007/s10792-026-04265-7

Cardiovasc Drugs Ther. 2026 Sep 17. doi: 10.1007/s10557-026-07954-8. Online ahead of print.ABSTRACTMarfan syndrome (MFS), a multisystemic connective tissue disorder, shows intra- and interfamilial aortopathy variability. More than 3,000 mutations have been reported in the FBN1 gene, which encodes fibrillin-1, a component of microfibrils and elastic fibres. Aortic dilatation mainly affects the aortic root and the ascending aorta. However, dissection of the aortic wall can occur either before or after the aortic arch (type A and type B dissections, respectively). There is no doubt that progress in aortic surgery has significantly improved patients' life expectancy, but conversely, current medical treatment based on beta-blockers (BBs) and angiotensin receptor blockers (ARBs) only slightly slows aortic growth. Aortopathy is the result of multiple defects in cellular and subcellular processes that affect aortic wall cells and extracellular matrix homeostasis and organisation. Pathomechanisms include dysregulated cell signalling, altered mechanotransduction, and oxidative stress. Therefore, it is reasonable to consider a multi-target strategy for medical treatment. Here, we suggest the concurrent administration of allopurinol with current medical treatment. Allopurinol's mode of action is based on its strong antioxidant effects, demonstrated in preclinical assays in different MFS mouse models. Allopurinol is a widely used compound in medical practice for gout, and has been proven safe, economical and effective in other cardiovascular diseases. The recent approval of allopurinol as an orphan drug for the treatment of MFS by the European Medicines Agency (EMA) adds further value to its potential inclusion in standard medical therapy in the near future.PMID:42752801 | DOI:10.1007/s10557-026-07954-8

JBMR Plus. 2026 Aug 22;10(10):ziag142. doi: 10.1093/jbmrpl/ziag142. eCollection 2026 Oct.ABSTRACTOsteogenesis imperfecta (OI) is a heterogeneous group of inherited connective tissue disorders primarily caused by dominant mutations in COL1A1 or COL1A2 that impair type I procollagen folding and secretion. Misfolded collagen accumulates in the endoplasmic reticulum (ER), triggering ER stress and osteoblast dysfunction, and bone fragility. Current pharmacologic therapy focuses on inhibiting bone resorption but has limited efficacy and does not address the underlying biology of the disease. The epigenetic regulator polycomb-repressive complex 2 (PRC2) has emerged as an important regulator of bone formation. Genetic and pharmacologic disruption of PRC2 enhanced osteogenic differentiation in WT cells. Here, we demonstrate that inhibition of the PRC2 through targeting its essential component embryonic ectoderm development (EED) enhances osteogenic differentiation, improves bone architecture in male Col1a2 +/G610C OI mouse models, modulates the integrated stress response (ISR), and improves ER morphology in OI cells. These findings identify EED inhibition as a novel epigenetic strategy to restore collagen homeostasis and improve skeletal integrity in OI.PMID:42708099 | PMC:PMC13549438 | DOI:10.1093/jbmrpl/ziag142

Bone. 2026 Sep 7:118085. doi: 10.1016/j.bone.2026.118085. Online ahead of print.ABSTRACTBACKGROUND: Sclerostin inhibition is a potential anabolic therapy for osteogenesis imperfecta (OI). We systematically evaluated whether anti-sclerostin therapy improves bone quantity, bone quality, mechanical performance, and fracture-related outcomes in preclinical and clinical studies of OI.METHODS: PubMed, Embase, and Web of Science were searched for randomized controlled trials and controlled animal studies investigating sclerostin inhibition in OI. 3 reviewers independently screened studies, extracted data using a standardized template, and assessed methodological quality with Joanna Briggs Institute appraisal tools.RESULTS: 18 studies were included:15 controlled experimental studies in mouse models of OI and 2 clinical trials in adults with OI, plus one ancillary iliac crest biopsy study derived from a trial cohort. Across murine models, anti-sclerostin consistently increased bone quantity (e.g., trabecular bone volume, cortical thickness, bone mineral density), often increased whole-bone strength, and sometimes reduced fracture incidence. However, efficacy varied by genotypes, ages, skeletal sites, or outcome levels. In several collagen-related murine OI models (e.g. Brtl/+, Crtap-deficient and the severe Col1a1Jrt/+ model), tissue-level material properties such as elastic modulus, hardness and mineralization indices remained abnormal despite structural gains. Clinical studies in adults with OI similarly demonstrated increases in areal bone mineral density, whereas microarchitectural and biopsy-based matrix-level outcomes were more variable and frequently failed to normalize.CONCLUSIONS: Anti-sclerostin therapy elicits an anabolic response in OI, improving overall bone mass and whole-bone strength. However, it does not consistently restore intrinsic tissue-level material properties. Current clinical evidence supports skeletal responses in adults with COL1A1/COL1A2-related OI types I, III, and IV, without a demonstrated difference between type I and pooled types III/IV; it does not identify a preferentially responsive individual genotype or an optimal pediatric age. Future trials should prespecify molecular and skeletal-maturity strata and prioritize fractures and whole-bone strength, supported by axial DXA, weight-bearing-site HR-pQCT/microFE, and tissue-level bone-quality outcomes.PMID:42705406 | DOI:10.1016/j.bone.2026.118085