Isolated Ectopia Lentis Research Articles

Isolated ectopia lentis with partial anterior dislocation and pupillary block: a case report

BackgroundEctopia lentis is the dislocation of the natural crystalline lens and usually presents in the setting of trauma or other systemic diseases. Herein, we describe a case of an otherwise healthy four-year-old boy with isolated ectopia lentis whose partial lens dislocation was captured on a smartphone by the patient’s father several days prior.Case presentationA four-year-old boy with no past medical, developmental, or trauma history presented with bilateral partial anterior lens dislocation with pupillary block. Initial ophthalmic evaluation two months prior was notable for uncorrected visual acuity at 20/100 OD, 20/250 OS, bilateral iridodenesis, and partially dislocated lenses inferonasally OD and inferiorly OS on slit lamp. Genetic testing found no abnormalities. Ten months later, the patient developed sudden onset of left eye pain. A dislocated lens and temporarily dilated left pupil were captured on a smartphone by the patient’s father. He was evaluated 3 days later after a second episode and found to have hand motion vision OS, a fixed 8 mm left pupil with the crystalline lens subluxed into the pupil space and accompanying intraocular pressure OS of 40 mmHg. The lens was surgically removed with a limited anterior vitrectomy. Four and a half years after surgery, visual acuity was 20/125 OS with aphakic correction. The right eye eventually underwent prophylactic lensectomy and was 20/30 in aphakic correction.ConclusionsThis report presents a unique presentation of isolated ectopia lentis with anterior lens dislocation and pupillary block and illustrates the role of smartphone photography in assisting in the triage of eye emergencies.

Surgical management of bilateral isolated ectopia lentis – A case report

A 28-year-old female presented with diplopia for 3 years. The patient was a high myope with best corrected visual acuity (BCVA) of 6/18, N6 in the right eye (RE) and 5/60, N36 in the left eye (LE). RE showed mild inferotemporal ectopia lentis with zonular dialysis of 2 clock hours and LE showed moderate temporal ectopia lentis with zonular dialysis of 6 clock hours, with cataractous changes in both eyes. Systemic examination was unremarkable with no trauma history. Patient underwent phacoemulsification with intraocular lens (IOL) implantation with capsular tension ring in RE and lensectomy with pars plana vitrectomy and secondary IOL implantation (CM T-Flex IOL) in LE.

A novel ADAMTSL4 compound heterozygous mutation in isolated ectopia lentis: a case report and review of the literature

BackgroundCongenital ectopia lentis is characterized by dislocation of the lens caused by partial or complete abnormalities in the zonular fibers. It can be caused by either systemic diseases or isolated ocular diseases. Gene detection techniques can provide valuable information when an etiological diagnosis is challenging. Herein, we report the case of a six-year-old girl with a confirmed diagnosis of isolated ectopia lentis caused by a compound heterozygous ADAMTSL4 gene mutation.Case presentationThe patient was a 6-year-old Chinese Han girl with strabismus in the right eye. Slit lamp examination revealed that the lens in the right eye was opacified and dislocated, without an ectopic pupil. Gene detection demonstrated the presence of a compound heterozygous mutation in the ADAMTSL4 gene [c. 2270dupG (p.Gly758Trpfs *59) and c. 2110A > G (p.Ser704Gly)], and the diagnosis of isolated ectopia lentis was confirmed. She underwent lens extraction, and a sutured scleral-fixated posterior chamber intraocular lens (IOL) was placed in the right eye. The best-corrected visual acuity was 0.1 one month postoperatively.ConclusionGene detection plays a crucial role in diagnosing disorders with similar symptoms, such as isolated ectopia lentis and Marfan syndrome. In this study, we used whole exons sequencing to diagnose isolated ectopia lentis and identified the variant c.2110A > G (p.Ser704Gly), which may be associated with the development of ectopia lentis and early-onset cataract in the patient. These pathogenic gene mutations have significant implications for the genetic diagnosis of congenital ectopia lentis, treatment, surveillance, and hereditary and prenatal counseling for the patient and their family members.

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

We report 3 novel variants in fibrillin-1 (FBN1) and latent transforming growth factor-β-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. To explore the genetic mechanism in 3 families with isolated EL and secondary angle closure glaucoma. 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. 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. 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.

Isolated Ectopia Lentis in Suspect of Weill-Marchesani Syndrome (WMS)

Introduction: The prevalence of Weill-Marchesani syndrome (WMS) is estimated to be 1:100.000 proportion of the population. Knowledge of the clinical and therapy of WMS is expected to improve the ability to diagnose this disease. In this case report, we will present a case of WMS in a tertiary hospital because our findings are rare and essential concerning the symptomatic treatment and visual rehabilitation. Case Presentation: A 7-year-old child presented with blurred vision in the left eye. The patient showed an abnormal facial appearance with short stature and brachydactyly on both hands. The patient had a history of Intracapsular cataract extraction (ICCE) surgery on the right eye with an indication of anterior lens subluxation. The patient then suffered aphakic glaucoma in the right eye after surgery. Anterior segment examination of the right eye found an aphakic lens, conjunctival sclerectasia, atrophic iris, and mid-dilation pupil. Anterior segment of the left eye found an atrophic iris and lens subluxation. From the clinical appearance and the ocular disturbance, such as brachydactyly and short stature, the patient was diagnosed with suspected WMS. The patient was treated with ICCE surgery on the left eye and micropulse transscleral cyclophotocoagulation (MP-TSCPC) surgery on the right eye. Conclusion: WMS is a rare disease. It is essential to make an early diagnosis of glaucoma and ectopia lentis in WMS patients because it will affect their vision.

Novel ADAMTSL4 gene mutations in Chinese patients with isolated ectopia lentis

BackgroundTo characterise the phenotype and genetic defects of isolated ectopia lentis (IEL) and to determine the ADAMTSL4 gene mutation frequencies in a Chinese congenital ectopia lentis (CEL) cohort.MethodsIn total, 127...

Genotype variant screening and phenotypic analysis of FBN1 in Chinese patients with isolated ectopia lentis.

Isolated ectopia lentis (IEL) can lead to blindness as result of severe complications, such as retinal detachment and secondary glaucoma. Pathogenic variants in the fibrillin 1 (FBN1) gene are a common cause of IEL. The aim of the present study was to investigate the frequency of pathogenic FBN1 variants in twelve probands with IEL and to evaluate their associated phenotypes. Systemic clinical examination of the twelve probands indicated that all had bilateral EL with a median age at diagnosis of three years. High myopia was the most common feature among the probands (83.3%; 10/12 cases). No extraocular symptoms (either cardiovascular or skeletal) were observed among these patients. Genomic DNA was extracted from peripheral blood leukocytes from all patients for targeted exome sequencing. Seven heterozygous missense variants in FBN1 were identified by bioinformatics analysis and further verified using Sanger sequencing. The seven variants were all classified as pathogenic after segregation analysis on available family members according to the American College of Medical Genetics and Genomics standards and guidelines. Of the seven variants, three were novel, namely c.2179T>C, c.2496T>G and c.3346G>C. The remaining four, namely c.184C>T, c.367T>C, c.1879C>T and c.4096G>A have been reported in previous studies. The seven pathogenic variants were identified in 8/12 (66.7%) probands with IEL. These results expand the variant spectrum of the FBN1 gene as well as the understanding of the molecular pathogenesis of IEL.

Novel p.G1344E mutation in FBN1 is associated with ectopia lentis

BackgroundEctopia lentis refers to dislocation or subluxation of the crystalline lens. Fibrillin-1, encoded by FBN1, is an important microfibrillar structural component that is specifically required for the suspensory ligament of...

Ectopia Lentis et Pupillae Caused by ADAMTSL4 Pathogenic Variants and an Algorithm for Work-up.

Ectopia lentis is displacement of the lens from its original position. It can be inherited or acquired with isolated or systemic findings. The authors describe a 4-year-old girl with isolated ectopia lentis et pupillae caused by pathogenic variants in the ADAMTSL4 gene and discuss the molecular genetic work-up of individuals with ectopia lentis. [J Pediatr Ophthalmol Strabismus. 2019;56:e45-e48.].

Surgical treatment and pedigree analysis of FBN1 mutation for a Chinese family with isolated ectopia lentis

Surgical treatment and pedigree analysis of FBN1 mutation for a Chinese family with isolated ectopia lentis

Hereditäre Linsenluxation

If not due to trauma, ectopia lentis is usually caused genetically. It is a main symptom of several syndromal disorders such as Marfan syndrome or homocystinuria. Also other connective tissue disorders convey an elevated risk for ectopia lentis. Isolated ectopia lentis is frequently caused by genetic alterations as well, most commonly due to mutations in ADAMTSL4. Depending on the molecular basis, the consequences for the management of patients may differ significantly: On the one hand, possible accompanying symptoms may require a specific surveillance and treatment. Also, the risk for other family members to develop ectopia lentis or accompanying symptoms can only be determined if the genetic cause and thus inheritance pattern are known. This review describes the different types and genetic causes of syndromal and isolated ectopia lentis as well as possible consequences for the patients; also it presents a sensible algorithm for the molecular diagnostic approach.

The revised ghent nosology; reclassifying isolated ectopia lentis

Inherited ectopia lentis (EL) is most commonly caused by Marfan syndrome (MFS), a multisystemic disorder caused by mutations in FBN1. Historically the diagnosis for patients with EL who have no systemic features of MFS is isolated EL (IEL). However, the Ghent nosology for MFS was updated in 2010 and made some important alterations. In particular, patients with EL and a FBN1 mutation are now categorically diagnosed with MFS, if their mutation has previously been described with aortic dilation/dissection. This carries significant systemic implications, as many patients previously diagnosed with IEL are now reclassified. We provide a review of all published cases of IEL caused by FBN1 mutations over the last 20 years to assess what impact the new Ghent nosology has on these. Indeed, 57/123 probands (46.3%) are now classified as MFS according to the revised Ghent nosology and 37/96 mutations (38.5%) reported to cause isolated EL have also been found in patients with aortic dilation/dissection. These findings suggest that EL caused by mutations in FBN1 is actually part of a spectrum of fibrillinopathies with MFS, and the term 'IEL' should be avoided in such cases.

Gene expression and protein distribution of ADAMTSL-4 in human iris, choroid and retina

BackgroundMutations in ADAMTSL4 have recently been shown to be the major cause of autosomal recessive isolated ectopia lentis (IEL). However, the function and ocular localisation of the protein is yet...

Ophthalmic findings in a family with early-onset isolated ectopia lentis and the p.Arg62Cys mutation of the fibrillin-1 gene (FBN1)

Purpose: The purpose of this paper is to describe ophthalmic findings in a family with isolated ectopia lentis (EL) caused by a specific FBN1 mutation.Methods: Detailed family histories and clinical data were recorded for six isolated EL patients of 11 family members. The ophthalmological and systematic examinations were performed on patients and unaffected members of the investigated family. The detailed ocular examinations included visual acuity, anterior chamber depth, pupil size, lens location, optometry, central corneal thickness, keratometry, slitlamp examination, fundus examination, axial length, ocular B-ultrasound, gonioscope checking, ultrasound biomicroscopy (UBM) and intraocular pressure (IOP; Goldmann applanation tonometer). Systematic examinations included the measurement of echocardiogram, height, arm span, skull, face, jaw, tooth, breast bone, spinal column, and skin. Genomic DNA was extracted using the phenol-chloroform extraction method for all subjects, and sequencing was carried out on an ABI Prism 3730 Genetic Analyzer.Results: A heterozygous mutation, c.184C>T (p.Arg62Cys) in exon 2 of FBN1 was identified in all affected members but was not found in any unaffected member of the family. Our study presented detailed clinical manifestations, including some novel ophthalmic findings, such as pupillary abnormality, different types of glaucoma, and progressive hyperopia.Conclusions: Ophthalmic findings and the p.Arg62Cys mutation of FBN1 gene were reported in a family with early-onset isolated ectopia lentis.

A Genotype-Phenotype Comparison ofADAMTSL4andFBN1in Isolated Ectopia Lentis

To describe the genotype-phenotype relationship of a cohort of consecutive patients with isolated ectopia lentis (EL) secondary to ADAMTSL4 and FBN1 mutations.Patients underwent detailed ocular, cardiovascular, and skeletal examination. This was correlated with Sanger sequencing of ADAMTSL4 and FBN1 genes.Seventeen patients were examined, including one with ectopia lentis et pupillae. Echocardiography and skeletal examination revealed no sign of systemic disorders associated with EL, in particular Marfan syndrome (MFS). Nine patients (52.9%) were found to have mutations in ADAMTSL4, including four novel nonsense mutations. Four patients (25%) were found to have novel FBN1 mutations, not previously reported as causing classical Marfan syndrome. One additional patient was found to have an FBN1 mutation previously reported in classical MFS. Four patients (25%) were found to have no mutations in either gene. Median age of diagnosis of EL was 35 years in patients with FBN1 mutations and 2 years in patients with ADAMTSL4 mutations (P < 0.01). Mean axial length was 22.74 mm (95% confidence interval [CI]: 21.3-24.2) (FBN1) and 27.54 mm (95% CI: 24.2-30.9) (ADAMTSL4) (P < 0.01). Other ophthalmic features, including corneal thickness and power, foveal thickness, visual acuity, and direction of lens displacement, were similar for both groups.ADAMTSL4 is the most important known causative gene in isolated EL. Mutations in ADAMTSL4 appear to cause earlier manifestation of EL and are associated with increased axial length as compared to FBN1. We suggest that ADAMTSL4 be screened in all patients with isolated EL and that physicians be vigilant for the more severe ocular phenotype associated with mutations in this gene.

LTBP2 mutations cause Weill-Marchesani and Weill-Marchesani-like syndrome and affect disruptions in the extracellular matrix

Latent transforming growth factor (TGF) beta-binding protein 2 (LTBP2) is an extracellular matrix (ECM) protein that associates with fibrillin-1 containing microfibrils. Various factors prompted considering LTBP2 in the etiology of isolated ectopia lentis and associated conditions such as Weill-Marchesani syndrome (WMS) and Marfan syndrome (MFS). LTBP2 was screened in 30 unrelated Iranian patients. Mutations were found only in one WMS proband and one MFS proband. Homozygous c.3529G>A (p.Val1177Met) was shown to cause autosomal recessive WMS or WM-like syndrome by several approaches, including homozygosity mapping. Light, fluorescent, and electron microscopy evidenced disruptions of the microfibrillar network in the ECM of the proband's skin. In conjunction with recent findings regarding other ECM proteins, the results presented strongly support the contention that anomalies in WMS patients are due to disruptions in the ECM. Heterozygous c.1642C >T (p.Arg548*) possibly contributed to MFS-related phenotypes, including ocular manifestations, mitral valve prolapse, and pectus excavatum, but was not cause of MFS.

ADAMTSL4, a Secreted Glycoprotein Widely Distributed in the Eye, Binds Fibrillin-1 Microfibrils and Accelerates Microfibril Biogenesis

ADAMTSL4 mutations cause autosomal recessive isolated ectopia lentis (IEL) and ectopia lentis et pupillae. Dominant FBN1 mutations cause IEL or syndromic ectopia lentis (Marfan syndrome and Weill-Marchesani syndrome). The authors sought to characterize recombinant ADAMTSL4 and the ocular distribution of ADAMTSL4 and to investigate whether ADAMTSL4 influences the biogenesis of fibrillin-1 microfibrils, which compose the zonule. ADAMTSL4 was expressed by the transfection of HEK293F cells. Protein extracts and paraffin sections from human eyes were analyzed by Western blot analysis and by immunoperoxidase staining, respectively. Immunofluorescence was used to evaluate fibrillin-1 deposition in the ECM of fetal bovine nuchal ligament cells after culture in ADAMTSL4-conditioned medium or control medium. Confocal microscopy was performed to investigate ADAMTSL4 and fibrillin-1 colocalization in these cultures. Western blot analysis identified ADAMTSL4 as a glycoprotein in HEK293F cells and as a major band of 150 kDa in ocular tissues including ciliary body, sclera, cornea, and retina. Immunoperoxidase staining showed a broad ocular distribution of ADAMTSL4, associated with both cells and fibrillar ECM. When cultured in ADAMTSL4-containing medium, fetal bovine nuchal ligament cells showed accelerated fibrillin-1 deposition in ECM. ADAMTSL4 colocalized with fibrillin-1 microfibrils in the ECM of these cells. ADAMTSL4 is a secreted glycoprotein that is widely distributed in the human eye. Enhanced fibrillin-1 deposition in the presence of ADAMTSL4 and colocalization of ADAMTSL4 with fibrillin-1 in the ECM of cultured fibroblasts suggest a potential role for ADAMTSL4 in the formation or maintenance of the zonule.

Alternative diagnoses with ectopia lentis

Sir, We read with great interest the case presented by Moore et al,1 suggesting a correlation between Sturge–Weber syndrome and ectopia lentis. As the authors discuss, the ophthalmic features of Sturge–Weber syndrome do not classically include ectopia lentis, with only two previous reports of such an association.2, 3 The first of these reports is over 35-years old,2 whereas the second may have been attributable to trauma.3 Moore et al therefore seem to be presenting the first case of ectopia lentis associated with Sturge–Weber syndrome in the era of modern genetic analysis. The most common cause of spontaneous ectopia lentis is Marfan syndrome, which the authors excluded on clinical grounds in this case, although no family history is discussed. Although normal mentation is mentioned, other syndromes associated with ectopia lentis have not been explicitly discussed by the authors. Nevertheless, if all associated syndromes are excluded, the condition of isolated ectopia lentis (IEL) must be considered. IEL has been established for over 30 years, with both dominant and recessive inheritance reported.4, 5 This can occur with marked asymmetry (Chandra A. ARVO Abstract (2766)(2011)) and indeed be unilateral.6 Although estimates of IEL prevalence and incidence are yet to be established, up to 31% of congenital ectopia lentis in a national study were not associated with a nosological classification.7 These may thus be termed IEL, suggesting that the condition of IEL is far more common than an association with Sturge–Weber syndrome, which Moore et al are reporting. We have previously shown that mutations in FBN1 and ADAMTSL4 have been associated with IEL.8 Other genetic mutations have also been associated with ectopia lentis.9 Although we do not deny that the association suggested in this case by Moore et al may be true, it is important to exclude more common causes of ectopia lentis beyond Marfan syndrome, including IEL. Interrogation for known genetic mutations would be an important and crucial step before such an association can be suggested.

Response to ‘Alternative diagnoses with ectopia lentis’

Sir, Chandra and colleagues1 rightly wonder about other possible causes for ectopia lentis seen in our patient with Sturge–Weber syndrome (SWS).2 Because of space constraints, we did not report on the full differential diagnosis of ectopia lentis.3 As we noted, our patient denied even a remote history of trauma; her normal mentation and body habitus, and her ocular examination and the unilaterality of her condition made several possible diagnoses unlikely, including ectopia lentis and pupillae, homocystinuria, Weill–Marchesani syndrome, sulfite oxidase deficiency, and hyperlysinemia. In addition to the investigations included in our report, she reported no family history of Marfan syndrome, nor of any other family members with her condition, including her two school-aged children. In addition, no clinical evidence of pseudoexfoliation, retinitis pigmentosa, buphthalmos, megalocornea, chronic uveitis (other than that associated with her condition), or ocular syphilis, nor aniridia was seen. To our regret, we did not perform any genetic studies, and our patient may have separate mutations resulting in both SWS and isolated ectopia lentis. Indeed, that is likely, given the paucity of reports associating ectopia lentis and SWS. However, reports of unilateral isolated ectopia lentis are similarly rare;4 this entity is usually familial and bilateral, at least those due to known genetic mutations.5 We welcome further research into the pathogenetic mechanisms of ectopia lentis.

Genetic and functional linkage between ADAMTS superfamily proteins and fibrillin-1: a novel mechanism influencing microfibril assembly and function.

Tissue microfibrils contain fibrillin-1 as a major constituent. Microfibrils regulate bioavailability of TGFβ superfamily growth factors and are structurally crucial in the ocular zonule. FBN1 mutations typically cause the Marfan syndrome, an autosomal dominant disorder manifesting with skeletal overgrowth, aortic aneurysm, and lens dislocation (ectopia lentis). Infrequently, FBN1 mutations cause dominantly inherited Weill-Marchesani syndrome (WMS), isolated ectopia lentis (IEL), or the fibrotic condition, geleophysic dysplasia (GD). Intriguingly, mutations in ADAMTS [a disintegrin-like and metalloprotease (reprolysin-type) with thrombospondin type 1 motif] family members phenocopy these disorders, leading to recessive WMS (ADAMTS10), WMS-like syndrome (ADAMTS17), IEL (ADAMTSL4 and ADAMTS17) and GD (ADAMTSL2). An ADAMTSL2 founder mutation causes Musladin-Lueke syndrome, a fibrotic disorder in beagle dogs. The overlapping disease spectra resulting from fibrillin-1 and ADAMTS mutations, interaction of ADAMTS10 and ADAMTSL2 with fibrillin-1, and evidence that these ADAMTS proteins accelerate microfibril biogenesis, constitutes a consilience suggesting that some ADAMTS proteins evolved to provide a novel mechanism regulating microfibril formation and consequently cell behavior.