Correlation between FBN1 mutations and ocular features with ectopia lentis in the setting of Marfan syndrome and related fibrillinopathies.

Mutations of fibrillin-1 (FBN1) have been associated with Marfan syndrome and pleiotropic connective tissue disorders, collectively termed as "type I fibrillinopathy". However, few genotype-phenotype correlations are known in the ocular system. Patients with congenital ectopia lentis (EL) received panel-based next-generation sequencing, complemented with multiplex ligation-dependent probe amplification. In a total of 125 probands, the ocular phenotypes were compared for different types of FBN1 mutations. Premature termination codons were associated with less severe EL and a thinner central corneal thickness (CCT) than the inframe mutations. The eyes of patients with mutations in the C-terminal region had a higher incidence of posterior staphyloma than those in the middle and N-terminal regions. Mutations in the TGF-ß-regulating sequence had larger horizontal corneal diameters (white-to-white [WTW]), higher incidence of posterior staphyloma, but less severe EL than those with mutations in other regions. Mutations in the neonatal region were associated with thinner CCT. Longer axial length (AL) was associated with mutations in the C-terminal region or TGF-ß regulating sequence after adjusting for age, EL severity, and corneal curvature radius. FBN1 genotype-phenotype correlations were established for some ocular features, including EL severity, AL, WTW, CCT, and so forth, providing novel perspectives and directions for further mechanistic studies.

Evaluation of the B/F Ratio Distribution of Cataract Patients Without Corneal Abnormalities and Its Effect on Ocular Parameters.

PURPOSE: To evaluate the distribution of the posterior-anterior corneal radius ratio (B/F ratio; posterior corneal radius/anterior corneal radius) in patients without corneal abnormalities, and to investigate which parameters affect this ratio. METHODS: Five thousand eyes from 5,000 patients who underwent cataract surgery were recruited to this study. We explored the linear relationship between B/F ratio and 13 variables using Principal Component-Multivariate Linear Regression Analysis. RESULTS: The B/F ratio was negatively correlated with the difference between simulated keratometry (SimK) and true net power (TNP), central corneal thickness, spherical aberration (SA), and posterior corneal astigmatism and positively correlated with posterior corneal radius, corneal posterior surface, axial length (AL) and anterior corneal radius. Several variables (central corneal thickness, difference between SimK and TNP and asphericity coefficient (Q-value) of the posterior corneal surface) had the highest loading on the final score. B/F ratio reflects the refractive state and anatomical structure of the cornea: thus, higher B/F ratios were associated with larger posterior corneal surface curvature radius, longer axial length, thinner central corneal thickness, lower high order aberrations of the cornea and SA, and the numerical difference between simK and TNP gradually reduced. In clinical practice, for patients with lower B/F ratio, special care should be taken in the choice of system used for intraocular lens (IOL) measurements.

Analysis of Axial Length in Young Patients with Marfan Syndrome and Bilateral Ectopia Lentis by Z-Scores.

INTRODUCTION: Marfan syndrome (MFS) is characterized by ectopia lentis (EL) and elongated axial length (AL). The characteristics of AL in young patients with MFS and bilateral EL before the lens surgery are not fully understood. METHODS: This study reviewed MFS patients under 20 years old with bilateral EL from January 2015 to October 2020. The Z-scores were introduced in terms of the number of standard deviations from the mean of age-matched normative data. Using Z-scores, the distribution of AL and influence factors were evaluated. The correlations between AL and other biometrics were analyzed. RESULTS: We reviewed 183 patients and enrolled both eyes. The mean age was 8.44 ± 4.69 years. About 36% of the patients were children under 6 years old. The median AL increased from 23.16 mm under 5 years old to 26.20 mm in the 16-20 age group, and when plotted, the trend presented a logarithmic curvature (R2 = 0.145, p < 0.001). The median Z-AL score was 1.24. One-third of eyes had Z-score <0. About 20% of the patients had AL difference over 1 mm between the right and left eyes, and the right one had longer Z-AL scores (p = 0.013). The eye complicated with megalocornea (10, 7.04%) had larger Z-AL scores (4.72 ± 3.51 vs. 1.10 ± 2.25, p = 0.002). A positive correlation was found between Z-AL and Z-corneal curvature radius (r = 0.265, p < 0.001). CONCLUSION: Young patients with bilateral EL but small AL should not be excluded from MFS without systematic examination. The age-adjusted Z-score will facilitate further study of the individual variations in AL across different ages.

The green and sustainable radiology department.

As manmade climate change threatens the health of the planet, it is important that we understand and address the contribution of healthcare to global emissions. Medical imaging is a significant contributor to overall emissions. This article aims to highlight key issues and examples of sustainable practices, in order to empower radiologists to make a change within their department.

Combination of Panel-based Next-Generation Sequencing and Clinical Findings in Congenital Ectopia Lentis Diagnosed in Chinese Patients.

PURPOSE: To evaluate the diagnostic yield of congenital ectopia lentis (EL) in a Chinese cohort by combining panel-based next-generation sequencing with clinical findings. DESIGN: A cohort study. METHODS: In total, 175 patients with congenital EL and their available family members (n = 338) were enrolled. All patients with congenital EL underwent genetic testing. Genotype-phenotype analyses were conducted to assess the biometric and structural ocular manifestations of congenital EL. RESULTS: In total, 175 patients with congenital EL and 338 of their relatives were included in this study. In these patients, 92.57% (162 of 175) of disease-related variants were detected in FBN1 (83.43%), CPAMD8 (1.71%), COL4A5 (0.57%), ADAMTSL4 (3.43%), LTBP2 (1.71%), and CBS (2.29%). Based on genetic and clinical findings, the primary diagnostic rate was increased to 40.57% from 19.43% with the exception of the 91 diagnoses of potential Marfan syndrome, with a new diagnostic strategy for congenital EL, thus having been developed. Within this group of patients harboring FBN1 mutations, 16.44% (19 of 141) probands were diagnosed with EL syndrome and 2.13% (3 of 141) were diagnosed with Marfan syndrome. CONCLUSIONS: The results of this cohort study expand the genomic landscape associated with congenital EL in Chinese cohorts. FBN1 mutations represent the most common cause of congenital EL in this population, and we have developed a new diagnostic strategy for congenital EL subtypes via the use of a well-designed panel-based next-generation sequencing that can be used to efficiently and precisely diagnose patients with congenital EL in a cost-effective manner.

Fibrillin-1 gene mutations in a Chinese cohort with congenital ectopia lentis: spectrum and genotype-phenotype analysis.

AIMS: To identify the mutation spectrum and genotype-phenotype correlations of fibrillin-1 (FBN1) mutations in a Chinese cohort with congenital ectopia lentis (EL). METHODS: Patients clinically suspected of congenital zonulopathy were screened using panel-based next-generation sequencing followed by multiplex ligation-dependent probe amplification. All the probands were subjected to thorough ocular examinations. Molecular and clinical data were integrated in pursuit of genotype-phenotype correlation. RESULTS: A total of 131 probands of FBN1 mutations from unrelated families were recruited. Around 65% of the probands were children younger than 9 years old. Overall, 110 distinct FBN1 mutations were identified, including 39 novel ones. The most at-risk regions were exons 13, 2, 6, 15, 24 and 33 in descending order of mutation frequency. The most prevalent mutation was c.184C>T (seven, 5.34%) in the coding sequence and c.5788+5G>A (three, 2.29%) in introns. Missense mutations were the most frequent type (103, 78.63%); half of which were distributed in the N-terminal regions (53, 51.46%). The majority of missense mutations were detected in one of the calcium-binding epidermal growth factor-like domains (62, 60.19%), and 39 (62.90%) of them were substitutions of conserved cysteine residues. Microspherophakia (MSP) was found in 15 patients (11.45%). Mutations in the middle region (exons 22-42), especially exon 26, had higher risks of combined MSP (OR, 5.51 (95% CI 1.364 to 22.274), p=0.017). CONCLUSIONS: This study extended the knowledge of the FBN1 mutation spectrum and provided novel insights into its clinical correlation regarding EL and MSP in the Chinese population.

Accuracy of IOL power calculation formulas in Marfan lens subluxation patients with in-the-bag IOLs and implantation of scleral-sutured single-eyelet modified capsular tension rings.

PURPOSE: To investigate the accuracy of intraocular lens (IOL) formulas for the prediction of postoperative refraction in lens subluxation in Marfan syndrome. SETTING: Eye and ENT Hospital of Fudan University, Shanghai, China. DESIGN: Consecutive retrospective clinical observational case series. METHODS: 60 eligible eyes with lens subluxation from 39 young patients with Marfan syndrome (8.53 ± 4.38 years) underwent phacoemulsification combined with single-eyelet modified capsular tension ring (MCTR) and IOL implantation. The prediction error values with mean zero out (relative prediction error) and their absolute values (AE) were calculated. RESULTS: Generally, the SRK/T formula with Wang-Koch (WK) adjustment had the lowest median AE at 0.418 diopters (D), and the Holladay 1 with WK adjustment had the lowest mean AE at 0.499 D. The median AE of the other 10 formulas, in order from lowest to highest, were Haigis with WK (0.494 D), Holladay 1 with WK (0.495 D), Hoffer Q with WK (0.508 D), Haigis (0.525 D), T2 (0.542 D), Hoffer Q (0.624 D), SRK/T and Holladay 1 (0.660 D), Super (0.680 D), and Barrett Universal II (0.714 D) formulas. Haigis formula was found to be statistically significantly different from SRK/T, Holladay 1, and Barrett Universal II (all 3 P < .001) but not Hoffer Q (P = .236) formula. CONCLUSIONS: The Haigis formula was recommended for young Marfan lens subluxation patients with in-the-bag IOLs and scleral-sutured single-eyelet MCTR implantation. WK adjustments were successful in those cases where the axial length was longer than 25.0 mm.

Surgical outcomes of modified capsular tension ring and intraocular lens implantation in Marfan syndrome with ectopia lentis.

OBJECTIVE: To evaluate surgical outcomes of modified capsular tension ring (MCTR) and intraocular lens (IOL) implantation in eyes of Marfan syndrome (MFS). METHODS: This retrospective case series included MFS patients receiving MCTR transscleral fixation and IOL in-the-bag implantation. The MCTR was sutured to the sclera through a sulcus by 9-0 polypropylene with the modified knotless Z-suture technique. Main outcomes were visual acuity and postoperative complications. RESULTS: A total of 109 MFS patients (187 eyes) had the surgery. Patients were 15.47 ± 14.36 years old and followed up for 10.07 ± 8.99 months. MCTR and IOL implantations were performed in 174 eyes (93.05%). The postoperative BCVA (LogMAR) was 0.24 ± 0.24 (1 month), 0.26 ± 0.20 (3 months), 0.22 ± 0.20 (6 months), 0.20 ± 0.19 (12 months) and 0.25 ± 0.32 (over 12 months), which was significantly better than preoperatively (0.63 ± 0.35) (p < 0.001). Major complications included posterior capsular opacification (PCO) in 41 eyes (23.56%) and decentered anterior capsular opacification (ACO) in 15 eyes (8.62%). The mean occurrence time was 9.44 ± 7.08 and 8.87 ± 15.08 months respectively. Other complications included transient intraocular pressure elevation in seven eyes (4.02%), retinal detachment in two eyes (1.15%), cystoid macula edema in one eye (0.57%), and endophthalmitis in one eye (0.57%). No eye had suture breakage or IOL dislocation. CONCLUSIONS: The visual improvement is significant in eyes of MFS undergoing MCTR transscleral fixation and IOL in-the-bag implantation. The long-term monitoring of complications is warranted, especially in the first-two years.

Visual outcomes of lens subluxation surgery with Cionni modified capsular tension rings in Marfan syndrome.

Marfan syndrome (MFS) is a hereditary disease with an incidence of 0.3% in the general population. Approximately 60% of MFS patients with FBN1 gene mutation will suffer ectopia lentis (EL) from the age of 3. With the development of EL, severe loss of vision will accrue because of lens tilt and glaucoma. Cionni modified capsular tension rings (MCTR) has been applied in the surgery for EL in MFS patients. To evaluate visual acuity and safety of using MCTR during lens subluxation surgery in MFS patients, 66 MFS patients (110 eyes) were included in our study, with the mean duration of follow-up of 4.7 months (SD 1.76 months). The capsular bags were preserved in 101 eyes (91.81%) with MCTR implantation. There was an overall significant improvement in BCVA at 1-month follow-up which was maintained at 3 months. Multivariable linear regression revealed that older age at first visit was associated with greater postoperative BCVA at the 1-month follow-up (P = 0.007). A significant difference was found between different degrees of lens subluxation and the length of surgical time and complications. At follow-up, only two eyes (1.98%) were identified to have developed retinal detachments. In conclusion, better visual outcomes can be achieved when patients received an early operation with MCTR implantation.

Evaluation of axial length/total corneal refractive power ratio as a potential marker for ocular diagnosis of Marfan's syndrome in children.

AIM: To investigate whether the axial length (AL)/total corneal refractive power (TCRP) ratio is a sensitive and simple factor that can be used for the early diagnosis of Marfan's syndrome (MFS) in children. METHODS: The relationship between the AL/TCRP ratio and the diagnosis of MFS for 192 eyes in 97 children were evaluate. The biological characteristics, including age, sex, AL, and TCRP, were collected from medical records. Receiver operating characteristic (ROC) curve analysis was performed to investigate whether the AL/TCRP ratio effectively distinguishes MFS from other subjects. The Youden index was used to re-divide the whole population into two groups according to an AL/TCRP ratio of 0.59. RESULTS: Of 96 subjects (mean age 7.46±3.28y) evaluated, 56 (110 eyes) had a definite diagnosis of MFS in childhood based on the revised Ghent criteria, 41 (82 eyes) with diagnosis of congenital ectopia lentis (EL) were included as a control group. AL was negatively correlated with TCRP, with a linear regression coefficient of -0.36 (R 2=0.08). A significant correlation was found between age and the AL/TCRP ratio (P=0.023). ROC curve analysis showed that the AL/TCRP ratio distinguished MFS from the other patients at a threshold of 0.59. MFS patients were present in 24/58 (41.38%) patients with an AL/TCRP ratio of ≤0.59 and in 34/39 (87.18%) patients with an AL/TCRP ratio of >0.59. CONCLUSION: An AL/TCRP ratio of >0.59 is significantly associated with the risk of MFS. The AL/TCRP ratio should be measured as a promising marker for the prognosis of children MFS. Changes in the AL/TCRP ratio should be monitored over time.

Eyes of Aniso-Axial Length Individuals Share Generally Similar Corneal Biometrics with Normal Eyes in Cataract Population.

AIMS: To determine the characteristics of corneal biometrics in eyes from aniso-axial length cataract patients compared with eyes from non-aniso-axial length individuals. METHODS: This is a retrospective case series. Cataract patients with preoperative binocular measurements were recruited. A binocular axial difference of ≥1 mm was considered to indicate aniso-axial length. The anterior segmental biometrics were measured using Pentacam HR (Oculus, Wetzlar, Germany) and IOLMaster 500 (Carl Zeiss Meditec, Jena, Germany). Comparisons of biometrics were made among 4 eye conditions: the longer eyes from aniso-axial length patients, the shorter eyes from aniso-axial length patients, the longer eyes from non-aniso-axial length patients, and the shorter eyes from non-aniso-axial length patients. The aniso-axial length eyes were also stratified into 8 subgroups with axial length (AL) increments of 1 mm, and the biometrics of the subgroups were compared. RESULTS: There was smaller anterior corneal astigmatism in the shorter aniso-axial length group than those in the longer aniso-axial length group (1.01 ± 0.70 D vs 1.12 ± 0.76 D, P=0.031). The longer aniso-axial length eyes had greater anterior corneal steep curvature (44.13 ± 1.69 D vs 43.87 ± 1.69 D, P=0.009) and anterior corneal astigmatism (1.12 ± 0.76 D vs 1.02 ± 0.69 D, P=0.023) compared with longer non-aniso-axial length subjects. Other corneal biometrics were similar between the aniso-axial length eyes and the non-aniso-axial length eyes. In the longer aniso-axial length group, the posterior corneal aberrations of eyes in the ≥5 mm subgroups were greater than those in the <5 mm subgroups (0.879 ± 0.183 µm vs 0.768 ± 0.178 µm for total aberrations, P < 0.001; 0.228 ± 0.086 µm vs 0.196 ± 0.043 µm for high-order aberrations, P=0.036; 0.847 ± 0.173 µm vs 0.741 ± 0.179 µm for low-order aberrations, P=0.001). CONCLUSION: Eyes of aniso-axial length individuals share generally similar corneal biometrics with normal eyes in cataract population. Anterior corneal astigmatism of the longer eyes from the aniso-axial length cataract patients was higher than that of the longer eyes from the non-aniso-axial length individuals. Total posterior corneal aberrations of the longer aniso-axial length eyes increased when the binocular axial difference was over 5 mm.

Correlations of Corneal Spherical Aberration with Astigmatism and Axial Length in Cataract Patients.

PURPOSE: To clarify the distribution of corneal spherical aberrations (SAs) in cataract patients with different corneal astigmatism and axial length. SETTING: Department of Ophthalmology and Vision Science of the Eye and ENT Hospital of Fudan University, Shanghai, China. DESIGN: Retrospective case series. METHODS: The axial length, corneal SAs, and other corneal biometrics were collected in cataract patients with Pentacam HR and IOLMaster 500. The statistical analysis of the corneal SAs was based on the stratification of axial length and anterior corneal astigmatism. RESULTS: In total, 6747 eyes of 6747 patients were recruited, with 2416 eyes (58.17 ± 16.81 years old) in the astigmatism group (anterior corneal astigmatism ≥1 D) and others (61.82 ± 12.64 years old) in the control group. In patients with astigmatism <2 D, the total and anterior SAs decreased as the axial length increased (P < 0.001). The total corneal SAs of patients with astigmatism of 2-3 D stabilized at around 0.29 µm, whereas those of patients with anterior corneal astigmatism ≥3 D tended to be variable. Age and anterior corneal astigmatism had positive and negative effects, respectively, on SA in the regression model. CONCLUSIONS: Axial length has a negative effect on the anterior and total corneal SAs, which stabled around 0.33 µm and 0.30 µm in patients with axial length of ≥26 mm, respectively. Individualized SA adjustments are essential for patients undergoing aspheric toric IOL implantation with preoperative anterior corneal astigmatism of 1-2 D or ≥3 D. Toric IOLs with a negative SA of -0.20 µm are recommended for patients with anterior corneal astigmatism of 2-3 D if no customized therapy is warranted.

Expression level is a key determinant of E2F1-mediated cell fate.

The Rb/E2F network has a critical role in regulating cell cycle progression and cell fate decisions. It is dysfunctional in virtually all human cancers, because of genetic lesions that cause overexpression of activators, inactivation of repressors, or both. Paradoxically, the downstream target of this network, E2F1, is rarely strongly overexpressed in cancer. E2F1 can induce both proliferation and apoptosis but the factors governing these critical cell fate decisions remain unclear. Previous studies have focused on qualitative mechanisms such as differential cofactors, posttranslational modification or state of other signaling pathways as modifiers of the cell fate decisions downstream of E2F1 activation. In contrast, the importance of the expression levels of E2F1 itself in dictating the downstream phenotypes has not been rigorously studied, partly due to the limited resolution of traditional population-level measurements. Here, through single-cell quantitative analysis, we demonstrate that E2F1 expression levels have a critical role in determining the fate of individual cells. Low levels of exogenous E2F1 promote proliferation, moderate levels induce G1, G2 and mitotic cell cycle arrest, and very high levels promote apoptosis. These multiple anti-proliferative mechanisms result in a strong selection pressure leading to rapid elimination of E2F1-overexpressing cells from the population. RNA-sequencing and RT-PCR revealed that low levels of E2F1 are sufficient to induce numerous cell cycle-promoting genes, intermediate levels induce growth arrest genes (i.e., p18, p19 and p27), whereas higher levels are necessary to induce key apoptotic E2F1 targets APAF1, PUMA, HRK and BIM. Finally, treatment of a lung cancer cell line with a proteasome inhibitor, MLN2238, resulted in an E2F1-dependent mitotic arrest and apoptosis, confirming the role of endogenous E2F1 levels in these phenotypes. The strong anti-proliferative activity of moderately overexpressed E2F1 in multiple cancer types suggests that targeting E2F1 for upregulation may represent an attractive therapeutic strategy in cancer.