Search Results (99)

Background: Pulmonary arterial hypertension is a rare but life-threatening condition in children, with hereditary forms often being linked to mutations in genes such as bone morphogenetic protein receptor type 2 (BMPR2), caveolin 1 (CAV1), and potassium channel subfamily K member 3 (KCNK3). Among these, CAV1 mutations are associated with severe disease phenotypes, though cases resulting from de novo heterozygous CAV1 mutations with multi-system involvement remain rarely reported. The CAV1 mutation (c.424C > T, p.Q142X) disrupts caveolin-1 function, leading to dysregulated pulmonary vascular remodeling and multi-system abnormalities. Methods: This was a retrospective case study of a pediatric patient with hereditary PAH. The patient was followed at our hospital from initial presentation until death. Clinical data were collected from medical records, including physical examinations, laboratory tests, echocardiography, chest X-ray, computed tomography pulmonary angiography (CTPA), and genetic analysis. The patient was treated sequentially with various PAH-targeted medications. This report also includes a review of the relevant literature on CAV1-associated PAH. Results: A female aged 3 years and 11 months was diagnosed with hereditary PAH associated with a de novo heterozygous CAV1 mutation (c.424C > T, p.Q142X). Both parents underwent genetic testing and were negative for the mutation, confirming its de novo origin. Clinical manifestations included special facial features, congenital telangiectasia, cutis marmorata (marbled skin), congenital cataract, hereditary lipodystrophy, and severe PAH. The patient presented with progressive exercise intolerance, syncope, and worsening dyspnea over nine years. Echocardiography revealed pulmonary hypertension with an estimated pulmonary artery systolic pressure of 69–105 mmHg, right heart enlargement, right ventricular hypertrophy, and moderate tricuspid regurgitation. Blood and urine metabolic screenings were normal. A chest X-ray showed progressive enlargement of the cardiac silhouette and bulging of the pulmonary artery segment. CTPA demonstrated pulmonary hypertension, secondary right heart dysfunction, decompensated right ventricular function, and mosaic perfusion in both lungs, suggestive of small arterial branch occlusion. Right heart catheterization was declined by the parents. Thus, the diagnosis of PAH was established based on clinical, echocardiographic, CTPA, and genetic findings. The patient was hospitalized four times and lost to follow-up from 2017 to 2023. She received sequential treatment with digoxin, hydrochlorothiazide, tadalafil, ambrisentan, selexipag, and treprostinil. Despite these therapies, pulmonary artery pressure continued to rise with progressive clinical deterioration. The patient ultimately died at 13 years of age due to a pulmonary hypertensive crisis and multiple organ failure following a severe episode of gastroenteritis. Conclusions: Despite aggressive treatment with multiple targeted reduced pulmonary artery pressure drug therapies, managing hereditary PAH caused by CAV1 mutations in children remains a significant challenge, with a high mortality rate. Early genetic diagnosis, regular follow-up, and individualized treatment are crucial. It requires the joint efforts of patients, parents, and healthcare providers. Full article

Background: Cataract is a progressive lens opacity. According to the World Health Organization, about 45 million people in the world are blind, with about half of these cases attributable to cataracts. Due to the complexity of cataract disease, current research on cataracts is far from sufficient, so it is especially important to understand the development process and the pathogenic factors of cataracts. Myodes rufocanus (M. rufocanus) is an animal of the M. rufocanus of the hamster family Volinae. In developing M. rufocanus, we found an individual of M. rufocanus with a congenital cataract phenotype. We confirmed the symptoms of cataract under natural light and using a slit lamp. Methods: Therefore, we analyzed the mechanism of congenital cataract in M. rufocanus from the aspects of pathological histology, physiology and biochemistry, and gene level, aiming to explore the feasibility of its development into an animal model of cataract. Cataract is a progressive lens opacity and a leading cause of visual impairment. Understanding its pathogenesis requires appropriate animal models. In a laboratory-bred colony of M. rufocanus, we identified individuals with a spontaneous congenital cataract phenotype, confirmed by gross observation and slit lamp examination. To characterize this phenotype and explore its potential as an animal model, we performed pathological, physiological, biochemical, and transcriptomic analyses using three cataract-affected and three normal age-matched male individuals (8 weeks old per group). Results: Blood tests revealed significantly lower white blood cell and lymphocyte counts in the cataract group, while blood glucose and other biochemical parameters showed no significant differences. Histologically, cataractous lenses exhibited eosinophilic aggregation in the nuclear region with disorganized fiber cells. Transcriptome analysis identified 6544 differentially expressed genes, including downregulation of crystallin genes (CRYBB2, CRYBA4, CRYGS) known to be associated with congenital cataract. KEGG pathway enrichment analysis highlighted retinol metabolism, tyrosine metabolism, and cytochrome P450-related pathways. RT-qPCR confirmed reduced CRYBB2 expression in cataractous eyes. Conclusions: This study provides the first transcriptome dataset for M. rufocanus ocular tissues and offers preliminary evidence that this naturally occurring cataract phenotype may serve as a potential model for congenital cataract research. Full article

MAF encodes a transcription factor involved in T-helper-2 (Th2) cell differentiation. Heterozygous pathogenic variants in MAF have been observed in both isolated and syndromic congenital cataract cases; genotype–phenotype correlations are based on the location of the variant within the gene. Variants in the N-terminus domain of MAF are associated with cataracts as part of Aymé-Gripp syndrome. The purpose of this report is to expand the ocular phenotypic spectrum of Aymé-Gripp syndrome by describing a patient with MAF variant c.185C>G, p.Thr62Arg, and the traditional systemic findings and congenital cataracts as well as an unusual feature of pigmentary retinopathy, which has not been previously reported in Aymé-Gripp syndrome. Additionally, a comprehensive review of the literature was completed to report ocular genotype–phenotype data on previously reported patients with MAF-associated Aymé-Gripp syndrome. Full article

Background/Objectives: Paediatric cataract is among the most common treatable causes of childhood blindness, caused by a genetically diverse disorder with variable clinical features. Although genetic factors significantly contribute to the development of paediatric cataracts, recent data on their genetic makeup and genotype–phenotype relationships in Saudi Arabia is limited. This study aims to investigate the genetic spectrum, inheritance patterns, and genotype–phenotype correlations of paediatric cataract in a Saudi population over twenty years. Methods: We conducted a retrospective cohort study of children diagnosed with congenital or juvenile cataracts between 2000 and 2019 at two major referral centres in Riyadh. Clinical, ocular, and systemic data were collected through multidisciplinary evaluations. Genetic analysis involved whole-exome and whole-genome sequencing performed at College of American Pathologists (CAP)-accredited laboratories. Variant interpretation was supported by bioinformatic and Artificial Intelligence (AI) prediction tools. Genotype–phenotype relationships were systematically analysed. Results: The study included 28 cases of genetically confirmed paediatric cataracts. Variants classified as pathogenic or likely pathogenic were identified in 13 genes. Autosomal recessive inheritance was predominant, with many patients exhibiting homozygous variants, often due to consanguinity. Two novel variants were identified in the Collagen Type XVIII Alpha 1 Chain (COL18A1) and the RAB3 GTPase-activating protein catalytic subunit 2 (RAB3GAP2) genes. Considerable phenotypic variability was observed, even among patients with the same mutation, particularly those with the recurrent CRYBB1 c.171del (p.Asn58fs) mutation. Syndromic cataracts were more frequently associated with loss-of-function variants and multisystem features. Conclusions: This study offers updated insights into the genetics and clinical presentation of paediatric cataract in Saudi Arabia. It highlights high genetic diversity, unique inheritance patterns, and notable genotype–phenotype variability, emphasising the importance of early genetic testing and multidisciplinary assessment for improved diagnosis, management, and counselling. Full article

Background: Marinesco–Sjögren syndrome (MSS, MIM #248800) is a condition that is characterized by biallelic pathogenic variants in the SIL1 gene. Manifestations include congenital cataracts, cerebellar ataxia, progressive muscle weakness and skeletal deformities, delay in psychomotor development, hypergonadotropic hypogonadism and short stature. Muscular involvement has been extensively discussed as a clinical finding but there is little literature on muscle imaging. The aim of this paper is to systematically review muscular imaging techniques in MSS reported in the literature, and to describe the clinical and imaging features of two pediatric subjects with MSS. Methods: Having searched through three electronic databases (PubMed, Scopus and Web of Science) two articles, written in English, describing twelve patients with MSS mutations on whom muscle MRI imaging was performed, were selected. In addition, two paediatric cases (brother and sister) with Marinesco–Sjögren syndrome (MSS) and MRI muscle findings were added. Data on type of study, cohort characteristics, type of mutation, neuromuscular signs and symptoms, imaging assessment, electrophysiological findings, biopsies, CNS symptoms, ocular signs and muscle imaging data were collected and stored in a table. Results: Of the 239 articles examined, only 3 used a muscle imaging technique to describe myopathy in MSS; one used a CT while another a muscle MRI. All 14 patients showed signs of fatty replacement. The infiltration mainly affected the lower limbs, but involvement in the upper limb was described in some adult patients. Conclusions: Performing a muscle MRI in MSS can lead to the early identification of muscle involvement and may be a useful biomarker to monitor disease progression. Full article

Background and Objectives: Predicting postoperative refractive development after paediatric intraocular lens (IOL) implantation remains challenging due to continued ocular growth and interindividual variability. This scoping review maps current evidence on demographic, biometric, and surgical factors influencing postoperative myopic shift in children undergoing cataract surgery with IOL implantation. Methods and Materials: A systematic literature search was conducted in PubMed and Scopus from the last ten years through October 2025. Eligible studies included children (≤18 years) with congenital or developmental cataract undergoing primary or secondary IOL implantation that reported postoperative refractive change and its predictors. Titles, abstracts, and full texts were screened according to PRISMA-ScR guidelines. Data were charted on study design, age at surgery, follow-up duration, refractive and biometric outcomes, and associated predictors. Results: Twelve studies met the inclusion criteria. Younger age at surgery, shorter preoperative axial length, and unilateral cataract consistently predicted greater postoperative myopic shift. Reported myopic change ranged from approximately −1.8 D after 2 years to −11.6 D after 15 years of follow-up, correlating with the rate of axial elongation. Optical biometry and modern formulas (e.g., Holladay 1) showed lower absolute prediction error than manual A-scan or SRK-II calculations. Postoperative complications, especially glaucoma and visual axis opacification, were associated with greater refractive change. Conclusions: Postoperative myopic shift is a predictable, age-dependent feature of paediatric pseudophakia driven primarily by ocular growth dynamics. Standardised biometry, age-stratified refractive targeting, and integration of longitudinal growth models into IOL calculation algorithms may improve refractive predictability and visual outcomes in children. Full article

Congenital Cataracts, Facial Dysmorphism, and Neuropathy (CCFDN) syndrome is a rare autosomal recessive disorder predominantly found among Vlax Roma populations, caused by a deep intronic founder variant in the CTDP1 gene. This review synthesizes recent advances in understanding the molecular mechanisms of CTDP1 dysfunction, highlighting its central role in transcriptional regulation, RNA splicing, DNA repair, and genome integrity. The unique splicing defect caused by the founder disease-causing variant in the Roma population results in a multisystem phenotype with early-onset neuropathy, congenital cataracts, and characteristic facial dysmorphism. Beyond its genetic homogeneity, CCFDN displays variable clinical severity and presents diagnostic challenges due to overlapping syndromic features. We discuss the emerging therapeutic landscape, focusing on antisense oligonucleotides, small molecule modulators, gene replacement, and genome or transcriptome editing strategies, while emphasizing the challenges in targeted delivery and efficacy. Ongoing insights into CTDP1’s broader biological functions and population genetics inform new directions for diagnosis, genetic counselling, and the development of effective therapies for this severe yet underrecognized disorder. Full article

Marinesco–Sjögren syndrome (MSS) is a rare autosomal recessive disorder characterized by cerebellar ataxia, congenital cataracts, developmental delay, hypotonia, and progressive myopathy. Most reported cases are linked to pathogenic variants in SIL1, a gene encoding a co-chaperone essential for protein folding in the endoplasmic reticulum. Here, we present a comprehensive case study of a Turkish pediatric patient diagnosed with MSS, supported by genetic, bioinformatic, and structural modeling analyses. Whole-exome sequencing revealed a homozygous splice-site variant (SIL1 c.453+1G>T), confirmed by Sanger sequencing and segregation analysis. In silico annotation using Genomize, InterVar, Franklin, VarSome, ClinVar, OMIM, and PubMed classified the variant as pathogenic according to ACMG guidelines. Structural modeling by Phyre2 and I-TASSER demonstrated that the variant abolishes the intron 5 donor site, leading to truncation of the wild-type 461-amino-acid protein into a shortened ~189-amino-acid polypeptide. This truncation results in the loss of critical Armadillo (ARM) repeats required for HSPA5 interaction, explaining the observed instability and impaired chaperone function. Clinically, the patient presented with congenital cataracts, ataxia, developmental delay, and progressive muscle weakness, consistent with previously reported MSS cases. Comparison with the literature confirmed that splice-site variants frequently correlate with severe phenotypes, including early-onset ataxia and cataracts. This report highlights the importance of integrating genomic, structural, and clinical data to better understand genotype–phenotype correlations in MSS. Our findings expand the mutational spectrum of SIL1, reinforce the role of splicing defects in disease pathogenesis, and emphasize the necessity of comprehensive molecular diagnostics for rare neurogenetic syndromes. Full article

Background: Hereditary hyperferritinemia-cataract syndrome (HHCS) is a rare autosomal dominant disorder characterized by persistently elevated serum ferritin and early-onset bilateral cataracts in the absence of systemic iron overload. It is caused by pathogenic variants in the iron-responsive element (IRE) of the FTL gene, leading to dysregulated L-ferritin synthesis. Methods: We evaluated a 12-year-old Czech girl with markedly elevated serum ferritin identified incidentally during workup for abdominal pain. Clinical assessment included biochemical, radiological, ophthalmological, and genetic testing of the proband and available family members. Results: Magnetic resonance imaging excluded systemic iron overload, while ophthalmological evaluation revealed bilateral cataracts. Family history indicated multiple affected relatives across three generations. Genetic testing confirmed a heterozygous FTL c.-168G>C variant. Additional screening for common HFE variants revealed heterozygous H63D in several family members, with no impact on ferritin or hepcidin levels. Beyond this case, we provide a comprehensive review of HHCS, including molecular mechanisms, an updated overview of reported FTL mutations, and ophthalmological features that distinguish HHCS cataracts from other congenital cataracts. Conclusions: This report underscores the translational relevance of combining molecular diagnostics, clinical evaluation, and family screening to improve recognition and management of HHCS, and to prevent misdiagnosis and unnecessary iron-depletion therapy. Full article

Objectives: To develop a proof-of-concept machine learning (ML) neural network model to predict post-operative visual outcomes in children with congenital cataracts undergoing intraocular lens (IOL) implantation, thereby guiding the optimal timing for IOL insertion. Determining the ideal timing and predicting outcomes for IOL implantation in children remains clinically complex due to variability in eye development and measurement accuracy. Methods: Retrospective analysis using a publicly available dataset from 110 children diagnosed with congenital cataracts, who underwent IOL implantation at the Eye and ENT Hospital of Fudan University. A neural network model with a hidden layer of 10 nodes was developed in MATLAB 2024a using the scaled conjugate gradient algorithm. Input variables included demographic and clinical features; the target was achieving visual acuity greater than 20/40. Performance metrics were evaluated using cross-entropy loss, sensitivity, specificity, and accuracy. Results: Training completed after 14 epochs with the test set reaching the highest performance metrics: 88.2% accuracy, 88.9% sensitivity, and 87.5% specificity. ROC curve analysis showed AUC values of 0.942 (training), 0.920 (validation), 0.885 (test), and 0.917 (overall). Conclusions: The neural network effectively predicted post-operative visual outcomes, offering potential clinical utility in guiding IOL implantation decisions. Despite limitations in dataset diversity, this study lays the foundation for future development of personalized strategies in pediatric cataract care. Full article

Congenital eye malformations like microphthalmia–anophthalmia–coloboma (MAC), anterior segment dysgenesis (ASD), primary congenital glaucoma (PCG) and congenital cataracts (CC) are significant causes of childhood visual impairment. Phenotypic heterogeneity often complicates diagnosis. The goal of this study was to optimize the diagnostic strategy for next-generation sequencing (NGS)-based procedures, thereby aiming to identify genetic causes of congenital eye malformations. Forty patients with congenital eye malformations were included. A primary diagnostic testing (PD) of a limited number of genes was followed by multigene panel (MGP) testing, including 186 eye-related genes, and exome sequencing. Causative variants were identified in 17 patients (43%) and clinically relevant variants of uncertain significance (VUS) in 6 patients (15%). PD had a diagnostic yield (DY) of 15%, MGP of 29% and exome sequencing of 4%, leading to a cumulative DY of 43%. Diagnostic rates were highest in CC (75%), bilateral cases (46%), complex ocular phenotypes (78%), patients with extraocular manifestations (55%) and positive family history (70%). Rare and possible new genotype–phenotype correlations and candidate genes (FAT1, POGZ) could be identified. In total, eight (likely) pathogenic variants in six genes (CYP1B1, ADAMTS18, MAB21L2, NHS, MFRP, CRYBB1) were not yet reported. A stepwise genetic testing approach starting with a broad multigene panel followed by exome sequencing provides higher diagnostic yield than limited phenotype-specific testing. Comprehensive genetic diagnosis is essential for prognosis, treatment and genetic counseling, underscoring the need for routine genetic testing and interdisciplinary collaboration in managing congenital eye malformations. Full article

Background/Objectives: Neurodevelopmental disorders (NDDs) are genetically heterogeneous conditions with a complex molecular etiology involving numerous genes. Biallelic pathogenic variants in INTS1 cause a rare autosomal recessive NDD characterized by congenital cataracts, growth retardation, facial dysmorphism, and global developmental delay. To date, the clinical description of this disorder has been based solely on individual case reports, and its phenotypic spectrum remains incompletely defined. Methods: A 9-year-old female proband was evaluated for developmental delay, multiple congenital anomalies, and distinctive craniofacial features. Whole-exome sequencing (WES) was performed, followed by Sanger validation and segregation analysis. Variant pathogenicity was assessed using in silico prediction tools and 3D protein structural modeling. Results: Whole-exome sequencing identified two novel compound heterozygous missense variants in INTS1, c.1145G>A (p.Arg382Gln) and c.1195G>A (p.Gly399Ser), both located in exon 9. Segregation analysis showed that c.1145G>A was inherited from the father and c.1195G>A from the mother, and both variants are extremely rare in population databases. Conclusions: We report a patient carrying novel biallelic INTS1 variants, whose clinical presentation differs from previously reported cases, including those with milder phenotypes characterized by preserved speech development and absence of intellectual disability. This observation broadens the clinical spectrum of INTS1-related disease and underscores its phenotypic heterogeneity. Full article

Congenital cataracts (CCs) are a leading cause of preventable childhood blindness, with genetic factors playing a crucial role in their etiology. Nance–Horan syndrome (NHS) is a rare X-linked dominant disorder associated with CCs but is often underdiagnosed due to variable expressivity, particularly in female carriers. Objective: This study aimed to explore the genetic landscape of CCs in a Swiss cohort, focusing on two novel NHS and one novel GJA8 variants and their phenotypic presentation. Methods: Whole-exome sequencing (WES) was conducted on 20 unrelated Swiss families diagnosed with CCs. Variants were analyzed for pathogenicity using genetic databases, and segregation analysis was performed. Clinical data, including cataract phenotype and associated systemic anomalies, were assessed to establish genotype–phenotype correlations. Results: Potentially pathogenic DNA sequence variants were identified in 10 families, including three novel variants, one in GJA8 (c.584T>C) and two NHS variants (c.250_252insA and c.484del). Additional previously reported variants were detected in CRYBA1, CRYGC, CRYAA, MIP, EPHA2, and MAF, reflecting genetic heterogeneity in the cohort. Notably, NHS variants displayed significant phenotypic variability, suggesting dose-dependent effects and X-chromosome inactivation in female carriers. Conclusions: NHS remains underdiagnosed due to its variable expressivity and the late manifestation of systemic features, often leading to misclassification as isolated CC. This study highlights the importance of genetic testing in unexplained CC cases to improve early detection of syndromic forms. The identification of novel NHS and GJA8 variants provides new insights into the genetic complexity of CCs, emphasizing the need for further research on genotype–phenotype correlations. Full article

Background: Cataract is the leading cause of severe, non-traumatic vision loss worldwide, leading to multiple adverse outcomes in mental health, including depression, anxiety, and cognitive decline; however, the relationship to psychotic symptoms remains unclear. While congenital vision loss appears protective against psychosis, acquired vision loss or acute deprivation are inducing psychotic symptoms. Methods: This study of 200 consecutive cataract patients, with severe vision loss, compares Paranoid Ideation and Psychoticism symptoms pre surgery, measured with the SCL-90-R scale, to those symptoms that persisted two months post-surgery. Results: The results confirm the hypothesis that cataract surgery is associated with a reduction in those symptoms (Wilcoxon Z = 5.425, p < 0.001 for Paranoid Ideation and Wilcoxon Z = 6.478, p < 0.001 for Psychoticism). Higher improvement in those variables was associated with higher improvement in visual acuity while controlling for age, gender and stressful life events during the past six months. Conclusions: Those results point to the importance of addressing loss of visual function especially in patients with pre-existing psychotic symptoms or signs of cognitive decline. Full article

Purpose: To review the current literature on the combined use of cataract surgery (or lensectomy) and vitrectomy in pediatric patients, with a focus on clinical indications, surgical techniques, outcomes, and complications across various pediatric ocular pathologies. Methods: A narrative review of published studies addressing the use of combined lensectomy and vitrectomy (LV) in pediatric patients was conducted. Conditions discussed include congenital cataracts, ectopia lentis, retinopathy of prematurity (ROP), retinal detachment (RD), and persistent fetal vasculature (PFV). Key surgical considerations, visual and anatomical outcomes, and postoperative complications were examined. Results: The literature search yielded a total of 160 articles, of which 43 met the inclusion criteria and were included in this review. Although lens-sparing vitrectomy (LSV) is preferred in many pediatric cases to preserve accommodation and reduce complications, combined LV is often necessary in advanced or complex diseases. Studies have shown that combined LV can achieve favorable anatomical outcomes, but functional visual recovery remains variable and is affected by factors such as patient age, baseline ocular anatomy, and disease severity. Postoperative complications such as glaucoma, visual axis opacification (VAO), and intraocular lens (IOL) dislocation are more frequent with combined procedures and require long-term follow-up and rehabilitation. Conclusions: Combined cataract surgery (or lensectomy) and vitrectomy may represent a valuable strategy in the management of complex pediatric ocular conditions, particularly when individualized to the clinical context. Tailored surgical approaches are essential to optimize anatomic and functional outcomes. Further prospective studies and harmonized multicenter registries are needed to develop evidence-based principles that can guide individualized surgical decision-making in this unique patient population. Full article