Ocular Involvement and Treatment Pattern in Korean Patients with Marfan Syndrome: A Population-Based Study.

PURPOSE: This study aimed to investigate the incidence and prevalence of, and treatment patterns for ocular complications in Korean patients with Marfan syndrome. METHODS: Incidence and prevalence of Marfan syndrome was calculated from 2010 to 2018, based on data from the Korean National Health Insurance Service (KNHIS). Diagnosis codes (for cataract, ectopia lentis, retinal detachment, etc.) and surgery reimbursement codes (lensectomy, phacoemulsification, buckling, vitrectomy, etc.) in the patients with Marfan syndrome were retrieved by complete enumeration of the data. RESULTS: The annual prevalence of Marfan syndrome adjusted by age and sex was gradually increased from 2.44 per 100,000 in 2010 to 4.36 per 100,000 in 2018. The age group of 10-19 years showed the highest prevalence. The prevalence of ectopia lentis was 21.7%, of whom 43.0% underwent surgeries. Surgery for RD was performed in 253 (14.1%) of 2044 patients during the study period. CONCLUSION: Although the most prevalent ophthalmologic manifestation was ectopia lentis, total prevalence rate of RD was more than 10% in the study period; thus, regular fundus examination is recommended for the patients with Marfan syndrome.

Postoperative longitudinal refractive changes in children younger than 8 years with ectopia lentis and Marfan syndrome.

PURPOSE: To evaluate the postoperative longitudinal refractive changes in children younger than 8 years with ectopia lentis and Marfan syndrome (MFS). SETTING: Zhongshan ophthalmic center, Guangzhou, China. DESIGN: Retrospective cohort study. METHODS: Medical data of patients diagnosed with ectopia lentis and MFS that underwent surgery younger than 8 years were collected. Refractive errors and ocular biometric parameters were collected preoperatively and at each follow-up visit. Patients were stratified into groups according to age at surgery, and only the eye operated on first was selected. Multivariate analysis was performed to determine the association between refractive shift and potential risk factors. RESULTS: In total, 54 eyes of 54 patients were enrolled. The median age at surgery was 6.21 years (interquartile range [IQR], 5.25 to 6.85), and the median follow-up was 2.0 years (IQR, 1.2 to 2.8 years). At age 8 years, patients demonstrated a median myopic shift ranged from -1.75 diopters (D) (IQR, -2.75 to -1.00 D) for the 4-year-old group to -0.13 D (IQR, -0.50 to -0.06 D) for the 7-year-old group. Multivariate analysis showed that greater myopic shift was associated with younger age at surgery ( P = .004), male sex ( P = .026), and shorter preoperative axis length ( P = .005). CONCLUSIONS: A tendency toward increasing postoperative myopic was demonstrated in children with ectopia lentis and MFS, with the greatest myopic shift in the younger age groups. If the goal is to reach emmetropia by age 8 years, the immediate postoperative hypermetropic targets should be 1.75 D for age 4 years, 1 D for age 5 years, 0.5 D for age 6 years, and 0 to 0.25 D for age 7 years.

Uncovering the Hidden World of Aqueous Humor Proteins for Discovery of Biomarkers for Marfan Syndrome.

Ectopia lentis is a hallmark of Marfan syndrome (MFS), a genetic connective tissue disorder affecting 1/5000 to 1/10 000 individuals worldwide. Early detection in ophthalmology clinics and timely intervention of cardiovascular complications can be lifesaving. In this study, a modified proteomics workflow with liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based data-independent acquisition (DIA) and field asymmetric ion mobility spectrometry (FAIMS) to profile the proteomes of aqueous humor (AH) and lens tissue from MFS children with ectopia lentis is utilized. Over 2300 and 2938 comparable proteins are identified in AH and the lens capsule, respectively. Functional enrichment analyses uncovered dysregulation of complement and coagulation-related pathways, collagen binding, and cell adhesion in MFS. Through weighted correlation network analysis (WGCNA) and machine learning, distinct modules associated with clinical traits are constructed and a unique biomarker panel (Q14376, Q99972, P02760, Q07507; gene names: GALE, MYOC, AMBP, DPT) is defined. These biomarkers are further validated using advanced parallel reaction monitoring (PRM) in an independent patient cohort. The results provide novel insights into the proteome characterization of ectopia lentis and offer a promising approach for developing a valuable biomarker panel to aid in the early diagnosis of Marfan syndrome via AH proteome.

Initial screening for occult congenital ectopia lentis based on ocular biological parameters in preschool children.

BACKGROUND: This study aimed to identify an initial screening tool for congenital ectopia lentis (CEL) by comparing ocular biological parameters in children with myopia. METHODS: A retrospective case-control study was conducted at one tertiary referral centre, from October 2020 to June 2022. Axial length (AL), corneal curvature (CC), refractive astigmatism (RA), corneal astigmatism (CA), internal astigmatism (IA), the difference between the axis of RA and CA [AXIS(RA-CA)], white-to-white corneal diameter (WTW), and axial length-corneal radius ratio (AL/CR) were compared in 28 eyes of CEL patients, and 60 eyes of myopic patients matched for age and refraction. The spherical equivalent of each eye was < -3.00 D. Area under the curve (AUC) of the receiver operating characteristic curves were calculated. RESULTS: The differences in RA, AL, mean keratometry (Kmed), maximum keratometry (Kmax), minimum keratometry (Kmin), CA, IA, AXIS(RA-CA), WTW, and AL/CR between the CEL and myopic groups were statistically significant (p < 0.05; p < 0.001; p < 0.001; p < 0.001; p < 0.001; p < 0.05; p < 0.001; p < 0.001; p < 0.001; p < 0.001, respectively). In logistic regression analysis RA, IA, AXIS(RA-CA), and AL/CR were significantly associated with CEL (p < 0.05). AUCs for RA, IA, AXIS(RA-CA), and AL/CR were 0.694, 0.853, 0.814, and 0.960, respectively. AUCs for AL/CR in SE< -6.00 D subgroup was 0.970, and 0.990 in -6.00 D ≤ SE < -3.00 D group. An AL/CR < 3.024 was the optimal cut-off point differentiating the CEL and control groups (sensitivity, 92.9%; specificity, 88.30%). CONCLUSIONS: A smaller AL/CR could identify CEL in children with myopia. An AL/CR cut-off value of 3.024 may be the most sensitive and specific parameter for the differential diagnosis of CEL in patients with mild to high myopia.

[Endocapsular fixation of intraocular lens in patients with ectopia lentis and Marfan syndrome (case study)]. / Endokapsulyarnaya fiksatsiya intraokulyarnoi linzy pri ektopii khrustalika na fone sindroma Marfana (klinicheskoe nablyudenie).

Modern trends in advancement of phaco surgery techniques in patients with ectopia lentis (including patients with Marfan syndrome) are characterized by the transition from complete removal of the lens (lensectomy) to aspiration of the lens substance and attempts to preserve and reposition the capsular bag. This case study analyzes the results of surgical treatment of bilateral ectopia lentis in a 6-year-old patient with Marfan syndrome. The specifics of microinvasive phaco surgery consisted in capsular bag preservation and endocapsular fixation of the intraocular lens. The article presents the results of ophthalmological observation over a seven-year period.

Visual prognosis and complications of congenital ectopia lentis: study protocol for a hospital-based cohort in Zhongshan Ophthalmic Center.

INTRODUCTION: Congenital ectopia lentis (CEL) is a rare ocular disease characterised by the dislocation or displacement of the lens. Patients with mild lens dislocations can be treated with conservative methods (eg, corrective eyeglasses or contact lenses). In contrast, patients with severe CEL usually require surgical management. However, few studies have focused on the visual prognosis and complications in conservative and surgical management of patients. This study aims to investigate the prognosis and complications in patients with CEL with conservative and surgical management, which is vital for CEL management, especially the choice of surgical timing and surgical method. METHODS AND ANALYSIS: A cohort study will be conducted at Zhongshan Ophthalmic Center. We plan to recruit 604 participants diagnosed with CEL and aged ≥3 years old. Patients with mild lens subluxation and stable visual conditions will be included in the non-surgical group and follow-up at 1, 2 and 3 years after enrolment. Patients with severe lens subluxation who accept CEL surgery will be included in the surgical group. Different surgical techniques, including phacoemulsification, in-the-bag intraocular lens implantation (with or without capsular tension ring) and trans-scleral fixation, will be used depending on the severity of dislocation. Patients will be followed up at 3 months, and 1, 2 and 3 years postoperatively. Over a 5-year follow-up period, patients will receive a detailed ocular examination, including optometry, biological measurement, specular microscopy, ultrasound biomicroscopy, anterior segment and posterior segment optical coherence tomography (OCT), OCT angiography, echocardiography and questionnaires on vision-related quality of life. The primary outcome is the change of best-corrected visual acuity and the incidence of complications in both groups. ETHICS AND DISSEMINATION: Ethics approval was obtained from the ethics committee of the Zhongshan Ophthalmic Center (number: 2022KYPJ207). Study findings will be published in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: NCT05654025.

Zonule-Associated Gene Variants in Isolated Ectopia Lentis and Glaucoma.

PRCIS: We report 3 novel variants in fibrillin-1 (FBN1) and latent transforming growth factor-ß-binding protein 2 (LTBP2) in 3 families with isolated ectopia lentis (EL), which shed new light on the diagnosis and genetic counseling of EL and secondary glaucoma in clinical settings. PURPOSE: To explore the genetic mechanism in 3 families with isolated EL and secondary angle closure glaucoma. METHODS: Three Han Chinese families with EL and glaucoma were recruited. All of the participants underwent complete ocular and general physical examinations and DNA samples were extracted from peripheral venous blood and screened for disease-causing variants using whole exome and Sanger sequencing. In silico analyses were performed to predict the structural and functional changes in gene variants and abnormal proteins. RESULTS: All 3 probands presented with EL and pupillary-blocking glaucoma. Genetic testing showed that all the patients have zonule-related gene mutations, with the proband (II:1), as well as his mother (I:2) and daughters (III:1 and III:2) from family 1 carrying a heterozygous mutation in FBN1 gene (c.6493G>T:p.(V2165L)); the proband (II:1) from family 2 carrying a heterozygous mutation in FBN1 gene (c.2543C>A:p.(T848N)), and the proband (II:1) from family 3 carrying a pair of compound heterozygous mutations in LTBP2 gene (c.4825T>A:p.(C1609S) / c.529T>C:p.(W177R)). No other genetic variants were found to be associated with the phenotypes of patients and other family members in this study. All variants are predicted to affect the structure and function of proteins as risk factors for EL based on bioinformatics analysis. CONCLUSION: Four novel mutations were identified in 3 families with EL, suggesting an intimate link between specific mutations in FBN1 and LTBP2 and isolated EL and angle closure glaucoma. Our results expanded the variant spectrum of zonule-related genes and helped explore the underlying molecular pathology of these disorders.

Predicting axial length in patients with Marfan syndrome and ectopia lentis after modified capsular tension ring and intraocular lens implantation.

PURPOSE: To predict the growth of axial length (AL) in patients with Marfan syndrome (MFS) and ectopia lentis (EL). SETTING: Eye and ENT Hospital of Fudan University, Shanghai, China. DESIGN: Consecutive retrospective case series. METHODS: Eyes were evaluated that had modified capsular tension ring and intraocular lens (IOL) implantation. The rate of AL growth (RALG) was calculated using AL divided by log10-transformed age. A multivariate linear regression model of RALG was developed after validation. RESULTS: 128 patients with MFS and EL were enrolled with a median follow-up duration of about 3 years. RALG was independent of age between 3 years and 15 years old ( P = .799) and decreased to 0 thereafter ( P = .878). Preoperative AL was associated with RALG in patients under 15 years old ( P = .003). Beta values for the final model of RALG were as below: intercept (-9.794) and preoperative AL (0.664). The postoperative AL was predicted as: postAL = preAL + RALG × log 10 ([postAge + 0.6]/[preAge + 0.6]). The mean prediction error was -0.003 (95% CI, -0.386 to 0.3791) mm and the mean absolute percentage error was 1.93% (95% CI, 0.73% to 3.14%). A Python-based calculator was developed to use the predicted AL in selecting IOL power and setting undercorrection. CONCLUSIONS: The AL growth of patients with MFS followed a logarithmic pattern and ceased at about age 15. A prediction model of postoperative AL was established for individual MFS patients between 3 and 15 years old, which could potentially optimize the IOL power selection.

Identification and phenotypic analysis of novel LTBP2 mutations in a Chinese cohort with congenital ectopia lentis.

Purpose: To evaluate the frequency of LTBP2 mutations and to elaborate on LTBP2-related clinical phenotypes in a Chinese congenital ectopia lentis (CEL) cohort. Methods: In total, 145 Chinese probands with CEL were recruited for this study and underwent ocular and systemic examinations. Whole-exome sequencing was used to identify mutations, and Sanger sequencing and bioinformatics analysis were further performed to verify pathogenic mutations. Results: Overall, biallelic mutations in LTBP2 involving eight novel mutations (c.4370-7_4370-9delTCT, c.4370-5C>G, c.3452G>A, c.2253delG, c.4114T>C, c.1251G>A, c.4760G>A, and c.620G>A) were identified in four CEL probands (4/145, 2.76%). Patients with LTBP2 mutations were characterized by a megalocornea, spherophakia, high myopia, and glaucoma instead of a flat cornea, high corneal astigmatism, cardiovascular and skeletal abnormalities that were reported in other gene mutations. A novel homozygous frameshift mutation was detected, and this type of mutation was found to cause more complicated ocular symptoms than others, ranging from the anterior segment to the fundus. Conclusion: This study reported the mutation frequency of the LTBP2 gene in a Chinese CEL cohort and provided novel insight into LTBP2-related genotype-phenotype associations in CEL.

Kissing microvitreoretinal blade technique: A novel approach for safe and effective endocapsular lens aspiration in microspherophakia.

We herein describe the kissing MVR technique in cases of microspherophakia for safe and effective endocapsular lens aspiration. Microspherophakia is associated with abnormally lax and broken zonules, which pose a great challenge to the operating surgeon, especially while creating the openings in the capsular bag. In this novel technique, simultaneous use of two 23 G MVR blades reduces the above problem associated with the severely mobile lens. Here, one MVR blade stabilizes the capsular bag and, at the same time, provides counter-traction for the opposite MVR blade while puncturing the capsular bag. Furthermore, the creation of openings in the lens at the equator or just posterior to it is beneficial as the capsule is relatively thicker and stronger at this location. This also minimizes the risk of premature extension to the anterior or posterior capsule, thereby avoiding complications like dropped lens matter, vitreous prolapse, and vitreous traction.

The phenotypic spectrum of ADAMTSL4-associated ectopia lentis: Additional cases, complications, and review of literature.

Purpose: ADAMTSL4-associated ectopia lentis is a rare autosomal recessive condition that is primarily associated with crystalline lens displacement. However, the prevalence of other ocular and systemic manifestations of this condition is poorly understood. In this study, we summarize the ocular and systemic phenotypic spectrum of this condition. Methods: A cross-sectional case study series of four individuals with biallelic pathogenic or likely pathogenic ADAMTSL4 variants was performed alongside a literature review of individuals with ADAMTSL4-associated ectopia lentis on September 29, 2021. Ocular and systemic findings, complications, and genetic findings of all four individuals were collected and summarized. Results: The phenotypic spectrum across 91 individuals sourced from literature and four individuals from this case study series was highly variable. The main ocular phenotypes included ectopia lentis (95/95, 100%), ectopia lentis et pupillae (18/95, 19%), iris transillumination (13/95, 14%), iridodonesis (12/95, 13%), persistent pupillary membrane (12/95, 13%), and early-onset cataract or lens opacities (12/95, 13%). Anterior segment features other than ectopia lentis appeared to be exclusively associated with biallelic loss of function variants (p<0.001). Pupillary block glaucoma had a prevalence of 1%. Post-lensectomy complications included retinal detachment (6/41, 15%), elevated intraocular pressure (4/41, 10%), and aphakic glaucoma (1/41, 2%). Most individuals were not reported to have had systemic features (69/95, 73%). Conclusions: The clinical phenotype of ADAMTSL4-associated ectopia lentis was summarized and expanded. Clinicians should be aware of the varied ocular phenotype and the risks of retinal detachment, ocular hypertension, and glaucoma in the diagnosis and management of this condition.

Prospective analysis of Artisan aphakia intraocular lens implantation for nontraumatic ectopia lentis in children.

PURPOSE: To report long-term outcomes of iris claw aphakia intraocular lens (IOL) implantation for nontraumatic ectopia lentis (EL) in children. METHODS: In this prospective study, children who underwent Artisan Aphakia IOL placement were included if they have a minimum of 1-year follow-up after implantation. Main outcome measures were: best-corrected distance visual acuity, reoperations, change in central corneal thickness (CCT), and corneal endothelial cell counts (ECC). RESULTS: The Artisan Aphakia IOL was implanted in a total of 76 eyes of 43 patients (68 eyes of 34 patients with EL). 56 eyes of 28 patients have been followed long enough to meet the inclusion criteria for this report. The average age at Artisan Aphakia IOL implantation was 11.1 years (range of 2-20 years). Average follow-up was 3.59 years, and 23% of patients have >5 years' follow-up. Mean best-corrected visual acuity improved from 0.36 (20/46) to logMAR 0.18 (20/30) after implantation (P = 0.02). Five reoperations were needed in 4 patients, 3 (7%) related to post-implantation trauma. Average preoperative CCT was 580 µm; estimated mean increase in CCT at the 5-year postoperative visit was 11.9 µm higher (P = 0.047). Average preoperative ECC was 3178 cells/mm2; estimated mean loss of ECC at the 5-year postoperative visit was not significantly different from zero (187.7 cells/mm2 [P = 0.102]). CONCLUSIONS: The Artisan Aphakia IOL, used in the absence of capsular support, had an acceptable safety profile in our patients.

Ectopia lentis surgery in Marfan's syndrome: from "couching" to the use of intracapsular tension rings.

In the course of time, correction of the ectopia lentis in Marfan's syndrome has been approached through quite many surgical techniques. They addressed the iris, or the lens and aimed at increasing the aphakic zone, the opacification or removal of the lens. Although associated to many complications, the first techniques proved the courage and imagination of pioneer surgeons and are worth mentioning. They were steps towards the invention of current techniques and devices that make surgery of ectopia lentis safe, easy, and having a favorable prognosis.

Next-generation sequencing panel analysis in 24 Chinese patients with congenital ectopia lentis.

BACKGROUND: Congenital ectopia lentis (CEL) is a rare but serious disease. We use next-generation sequencing to detect genes associated with lens abnormalities in 24 patients with bilateral CEL and search for pathogenic genes and mutation sites. MATERIALS AND METHODS: A total of 24 patients diagnosed with CEL from January 2019 to November 2019 were enrolled in this study, and their clinical data were collected and genome-wide deoxyribonucleic acid was extracted from peripheral venous blood. Targeted gene capture technology was used to obtain 188 exons of lens abnormality-related genes, which were sequenced using a high-throughput method. The mutation sites were determined through data analysis and verified by the Sanger method. According to the data from previous studies, the association between the genotype and clinical phenotype was analysed. RESULT: Of the 24 patients, 23 had mutations in the fibrillin-1 (FBN1) gene, and 20 were diagnosed with Marfan syndrome. The 23 cases of FBN1 mutations were all heterozygous mutations, including 17 missense mutations, 3 splicing variants, 2 exon deletion mutations, 1 codon mutation, and 9 new mutations. A total of 17 mutations were located in the calcium-binding epidermal growth factor domain, including 16 mutations that contained missense mutations of cysteine. In addition, a heterozygous mutation of the gap junction protein alpha 8 (GJA8) gene was detected in one patient. CONCLUSION: In this study, we identified 23 FBN1 gene mutations and 1 GJA8 gene mutation in 24 patients with CEL. Of these, 9 new FBN1 mutations and 14 known mutations were found. The results expanded the mutation spectrum of the FBN1 gene, suggesting that FBN1 mutation may be the main cause of CEL in Chinese patients.

Clinical profile and outcome of ocular manifestation in Marfans syndrome in India.

PURPOSE: Marfan syndrome (MFS) is a genetic disorder associated with considerable morbidity and mortality. Presently, well-documented information on this condition is not available in India. METHODS: In this retrospective cohort study, we recruited patients with clinically diagnosed MFS who presented to the outpatient department using revised Ghent nosology. We retrieved complete ophthalmic information, including vision, anterior and posterior segments, exported from electronic medical records, and relevant investigations, surgical details, and follow-up data were obtained in a specific, pretested format. RESULTS: Our cohort consisted of 86 eyes of 43 patients and had a male preponderance. The prevalence was 20.5 per 100,000 individuals. The mean age of the patients was 23.9 years. All eyes were treated either optically with refraction or surgically using lensectomy and vitrectomy with suture supported scleral fixated intraocular lens (IOL), which significantly affected the visual outcome (P = 0.000). CONCLUSION: Although considered a rare disease, MFS is commonly found in the ophthalmological setting. Refraction and surgery (lensectomy with scleral fixated IOL) may improve the vision significantly.

Technique of using Cionni capsular tension ring in the management of of ectopia lentis cases.

BACKGROUND: Ectopia lentis is a condition that compromises vision in childhood by inducing either double vision or aphakic visual axis. Correction of lens status is of prime importance to prevent amblyopia or sensory strabismus. PURPOSE: Placing an intraocular lens (IOL) in the bag in such cases will maintain aqueous vitreous barrier but it is a difficult task.This video demonstrates the method of placing modified Cionni capsular tension ring (CTR) and placement of IOL in children. SYNOPSIS: This video shows the management of multiple cases of ectopia lentis with more than 180 degree subluxation. Making intact rhexis is crucial and technically difficult in such cases. The way of making a proper capsulorhexis is shown. After making capsulorhexis, all the cases were managed with single loop Cionni CTR. Cionni CTR has a loop with a anterior offset of 0.4 mm to override the anterior capsule. It has two designs - right and left design, based on the position of islet in the CTR. Since the offset of the hook is tiny, there are high chances to flip the Cionni CTR. If the Cionni CTR is placed in a flipped manner, it would not give effective pull of the bag, when fixated to sclera. And also, it could be traumatic to explant and place in correct manner. Hence it is vital to place the Cionni CTR in correct orientation, so that anterior offset will orient anteriorly. This video gives guidance to the viewers about the correct way of placing different designs of Cionni CTR in different types of subluxation.Timing of passing sutures through sclera may be done either before or after placing the Cionni CTR in the bag. Both the ways are demonstrated in different cases. HIGHLIGHTS: Different technique of doing Cionni CTR fixation with IOL placement are demonstrated. Surgeons who wish to try this procedure can choose the option that they feel comfortable with. We conclude that choice of Cionni CTR design and technique of placement depends on surgeon's choice and not based on the type of subluxation. VIDEO LINK: https://youtu.be/zbdpP0lhykw.

Molecular characterization and investigation of the role of genetic variation in phenotypic variability and response to treatment in a large pediatric Marfan syndrome cohort.

PURPOSE: In a large cohort of 373 pediatric patients with Marfan syndrome (MFS) with a severe cardiovascular phenotype, we explored the proportion of patients with MFS with a pathogenic FBN1 variant and analyzed whether the type/location of FBN1 variants was associated with specific clinical characteristics and response to treatment. Patients were recruited on the basis of the following criteria: aortic root z-score > 3, age 6 months to 25 years, no prior or planned surgery, and aortic root diameter < 5 cm. METHODS: Targeted resequencing and deletion/duplication testing of FBN1 and related genes were performed. RESULTS: We identified (likely) pathogenic FBN1 variants in 91% of patients. Ectopia lentis was more frequent in patients with dominant-negative (DN) variants (61%) than in those with haploinsufficient variants (27%). For DN FBN1 variants, the prevalence of ectopia lentis was highest in the N-terminal region (84%) and lowest in the C-terminal region (17%). The association with a more severe cardiovascular phenotype was not restricted to DN variants in the neonatal FBN1 region (exon 25-33) but was also seen in the variants in exons 26 to 49. No difference in the therapeutic response was detected between genotypes. CONCLUSION: Important novel genotype-phenotype associations involving both cardiovascular and extra-cardiovascular manifestations were identified, and existing ones were confirmed. These findings have implications for prognostic counseling of families with MFS.