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Frontiers in Medicine 2022Weill-Marchesani syndrome 4 (WMS4) is caused by gene variant and clinical abnormalities including lenticular myopia, ectopia lentis, glaucoma, microspherophakia,...
BACKGROUND
Weill-Marchesani syndrome 4 (WMS4) is caused by gene variant and clinical abnormalities including lenticular myopia, ectopia lentis, glaucoma, microspherophakia, brachydactyly, and short stature. Due to free of heart defects and joint stiffness compared with other WMS forms, WMS4 has an insidious onset and is often misdiagnosed as high myopia. We combined multiple imaging biometry and whole-exome sequencing to diagnose a case of WMS4 with a 3-year follow-up.
CASE PRESENTATION
An 8-year-old boy presented to our ophthalmology department with progressive myopia for 1 year. He had high myopia in both eyes with normal funds, intraocular pressure, and axial length. Ocular examination revealed thicker lenses (right 4.38 mm, left 4.31 mm) with a smaller equatorial diameter (right 7.33 mm and left 7.17 mm) compared to normal children of the same age. Finger length measurement indicates brachydactyly. Whole-exome sequencing identified compound heterozygous missense variants c.2984G > A (p.Arg995Gln) and c.2254A > G (p.Ile752Val) in the gene. During the 3 years of follow-up, the thickness of lenses increased significantly (right 4.49 mm, left 4.48 mm), but the equatorial diameter of the lenses had no significant change (right 7.32 mm, left 7.21 mm). As the equivalent lens power increased, the patient's myopia spherical refractive error rose accordingly. Although the anterior chamber angle remained open during follow-up, the intraocular pressure increased to right 20.4 mmHg and left 19.6 mmHg, Iridodonesis and short stature were present.
CONCLUSION
This case report highlights the abnormal thickening of the lens in WMS4 compared to the physiological thinning process during childhood. Comprehensive clinical examinations and genetic testing may improve diagnosis, which allows early therapeutic interventions for complications and better visual outcomes for the patient.
PubMed: 36698805
DOI: 10.3389/fmed.2022.1021489 -
Scientific Reports Jul 2020Weill-Marchesani syndrome (WMS) is a rare disorder displaying short stature, brachydactyly and joint stiffness, and ocular features including microspherophakia and...
Weill-Marchesani syndrome (WMS) is a rare disorder displaying short stature, brachydactyly and joint stiffness, and ocular features including microspherophakia and ectopia lentis. Brachydactyly and joint stiffness appear less commonly in patients with WMS4 caused by pathogenic ADAMTS17 variants. Here, we investigated a large family with WMS from Newfoundland, Canada. These patients displayed core WMS features, but with proportionate hands that were clinically equivocal for brachydactyly. Whole exome sequencing and autozygosity mapping unveiled a novel pathogenic missense ADAMTS17 variant (c.3068 G > A, p.C1023Y). Sanger sequencing demonstrated variant co-segregation with WMS, and absence in 150 population matched controls. Given ADAMTS17 involvement, we performed deep phenotyping of the patients' hands. Anthropometrics applied to hand roentgenograms showed that metacarpophalangeal measurements of affected patients were smaller than expected for their age and sex, and when compared to their unaffected sibling. Furthermore, we found a possible sub-clinical phenotype involving markedly shortened metacarpophalangeal bones with intrafamilial variability. Transfection of the variant ADAMTS17 into HEK293T cells revealed significantly reduced secretion into the extracellular medium compared to wild-type. This work expands understanding of the molecular pathogenesis of ADAMTS17, clarifies the variable hand phenotype, and underscores a role for anthropometrics in characterizing sub-clinical brachydactyly in these patients.
Topics: ADAMTS Proteins; Anthropometry; Bodily Secretions; Brachydactyly; Canada; Female; Fingers; HEK293 Cells; Humans; Male; Mutation, Missense; Phenotype; Weill-Marchesani Syndrome; Exome Sequencing
PubMed: 32616716
DOI: 10.1038/s41598-020-66978-8 -
BMC Medical Genomics Sep 2021Microspherophakia (MSP, OMIM 251,750) is a rare inherited autosomal recessive eye disorder characterized by small spherically shaped lens. Several studies have...
BACKGROUND
Microspherophakia (MSP, OMIM 251,750) is a rare inherited autosomal recessive eye disorder characterized by small spherically shaped lens. Several studies have indicated that the transforming growth factor-beta (TGF-beta) binding proteins(LTBP2) gene mutation is the predominant cause of MSP. In our study, novel compound heterozygous mutations in the LTBP2 gene associated with MSP were reported, which was different from previous reported homozygous mutations.
CASE PRESENTATION
The proband was an 18-year-old male in Western China with bilateral MSP, accompanied by ectopia lentis, secondary glaucoma and blindness in both eyes. In our hospital, he received bilateral lens resection and trabeculectomy combined with peripheral iridotomy. Using next-generation sequencing (NGS)-based gene panel tests, we identified pathogenic mutations in the peripheral blood DNA sample from the proband: c.3614_3618dupCTGGC (exon24, NM_000428) and c.2819G > A (exon18, NM_000428). The presence of the novel compound heterozygous mutations in the LTBP2 gene was linked with the development of MSP. Sanger sequencing confirmed the existence of one of the two variants in each parent respectively.
CONCLUSION
Our results demonstrated a rare case of MSP phenotype associated with novel compound heterozygous mutations in the LTBP2 gene using NGS technology.
Topics: Corneal Diseases; Ectopia Lentis; Glaucoma; Iris
PubMed: 34535142
DOI: 10.1186/s12920-021-01080-0 -
Matrix Biology : Journal of the... Jan 2021Latent-transforming growth factor beta-binding protein 2 (LTBP-2) is a major component of arterial and lung tissue and of the ciliary zonule, the system of extracellular...
Latent-transforming growth factor beta-binding protein 2 (LTBP-2) is a major component of arterial and lung tissue and of the ciliary zonule, the system of extracellular fibers that centers and suspends the lens in the eye. LTBP-2 has been implicated previously in the development of extracellular microfibrils, although its exact role remains unclear. Here, we analyzed the three-dimensional structure of the ciliary zonule in wild type mice and used a knockout model to test the contribution of LTBP-2 to zonule structure and mechanical properties. In wild types, zonular fibers had diameters of 0.5-1.0 micrometers, with an outer layer of fibrillin-1-rich microfibrils and a core of fibrillin-2-rich microfibrils. LTBP-2 was present in both layers. The absence of LTBP-2 did not affect the number of fibers, their diameters, nor their coaxial organization. However, by two months of age, LTBP-2-depleted fibers began to rupture, and by six months, a fully penetrant ectopia lentis phenotype was present, as confirmed by in vivo imaging. To determine whether the seemingly normal fibers of young mice were compromised mechanically, we compared zonule stress/strain relationships of wild type and LTBP-2-deficient mice and developed a quasi-linear viscoelastic engineering model to analyze the resulting data. In the absence of LTBP-2, the ultimate tensile strength of the zonule was reduced by about 50%, and the viscoelastic behavior of the fibers was altered significantly. We developed a harmonic oscillator model to calculate the forces generated during saccadic eye movement. Model simulations suggested that mutant fibers are prone to failure during rapid rotation of the eyeball. Together, these data indicate that LTBP-2 is necessary for the strength and longevity of zonular fibers, but not necessarily for their formation.
Topics: Animals; Cilia; Ectopia Lentis; Eye; Fibroblasts; Humans; Latent TGF-beta Binding Proteins; Longevity; Mice; Mice, Knockout; Microfibrils; Ocular Physiological Phenomena; Saccades; Tensile Strength; Viscoelastic Substances
PubMed: 33039488
DOI: 10.1016/j.matbio.2020.10.002 -
Beyoglu Eye Journal 2023We present the long-term results of the implantation of a capsular tension ring (CTR) and Ahmed capsular tension segments (CTS) together for the management of...
We present the long-term results of the implantation of a capsular tension ring (CTR) and Ahmed capsular tension segments (CTS) together for the management of mikrospherophakia in a 35-year-old female patient. The patient had uncontrolled secondary angle-closure glaucoma, despite previous laser peripheral iridotomy, and visual impairment due to lenticular myopia. Clear lens extraction was performed under general anesthesia. The capsular bag was stabilized with a classical CTR and two Ahmed CTSs sutured to the sclera. A single-piece hydrophobic acrylic intraocular lens (32.0 D for the right and 30.0 D for the left eye) was implanted in the capsular bag. The anterior chamber depth was stable, and intraocular pressure (IOP) was 10-12 mmHg in both eyes in the early post-operative period. The bag complex gradually moved forward, IOP gradually increased, and the left eye underwent trabeculectomy surgery in the 4 year of follow-up.
PubMed: 37521882
DOI: 10.14744/bej.2023.57625 -
The British Journal of Ophthalmology Dec 2022To identify the mutation spectrum and genotype-phenotype correlations of () mutations in a Chinese cohort with congenital ectopia lentis (EL).
AIMS
To identify the mutation spectrum and genotype-phenotype correlations of () 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 mutations from unrelated families were recruited. Around 65% of the probands were children younger than 9 years old. Overall, 110 distinct 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 mutation spectrum and provided novel insights into its clinical correlation regarding EL and MSP in the Chinese population.
Topics: Humans; Ectopia Lentis; Fibrillin-1; Fibrillins; Marfan Syndrome; Microfilament Proteins; Phenotype; Mutation; Genotype; China; DNA Mutational Analysis
PubMed: 34281902
DOI: 10.1136/bjophthalmol-2021-319084 -
American Journal of Ophthalmology Case... Dec 2022To report a case of congenital ciliary body cysts causing microspherophakia, ectopia lentis, and secondary angle closure glaucoma in an infant.
PURPOSE
To report a case of congenital ciliary body cysts causing microspherophakia, ectopia lentis, and secondary angle closure glaucoma in an infant.
OBSERVATIONS
A 16-month-old male was found to have bilateral ciliary body cysts associated with zonular laxity or absence causing microspherophakia and ectopia lentis as demonstrated on multimodal imaging. Additionally, the patient had secondary angle closure glaucoma which was likely multi-factorial related to both lens abnormalities and anterior displacement of the iris from the cysts themselves. The patient underwent lensectomy and cyst removal which resulted in intraocular pressure stabilization and visual rehabilitation.
CONCLUSIONS AND IMPORTANCE
Congenital ciliary body cysts are a rare cause of lens abnormalities and secondary angle closure glaucoma in children. Information regarding genetic underpinnings or systemic associations is limited.
PubMed: 36275188
DOI: 10.1016/j.ajoc.2022.101723 -
Frontiers in Genetics 2022Geleophysic dysplasia and Weill-Marchesani syndrome from the acromelic dysplasias group of genetic skeletal disorders share remarkable clinical and genetic overlap....
Geleophysic dysplasia and Weill-Marchesani syndrome from the acromelic dysplasias group of genetic skeletal disorders share remarkable clinical and genetic overlap. Ophthalmological, physical, radiological examinations were conducted with a female patient in her early 30 s. Whole exome sequencing followed by Sanger sequencing validation was performed to identify the genetic cause. The patient, born to consanguineous Chinese parents, presented with microspherophakia, lens subluxation, high myopia, short statue, small hands and feet, stiff joints, and thickened skin. A diagnosis of Weill-Marchesani syndrome was initially made for her. However, genetic testing reveals that the patient is homozygous for the c.1966G>A (p.Gly656Ser) variant in , and that the patient's healthy mother and daughter are heterozygous for the variant. As mutations in are known to cause autosomal recessive geleophysic dysplasia, the patient is re-diagnosed with geleophysic dysplasia in terms of her genotype and phenotype. The present study describes the clinical phenotype of the homozygous p. Gly656Ser variant, which increases our understanding of the genotype-phenotype correlation in acromelic dysplasias.
PubMed: 36246610
DOI: 10.3389/fgene.2022.1014188 -
Trauma Case Reports Dec 2023We report a case of traumatic bleb leak following trabeculectomy and dislocated intraocular lens treated with combined minimally invasive conjunctival surgery (MICS) and...
PURPOSE
We report a case of traumatic bleb leak following trabeculectomy and dislocated intraocular lens treated with combined minimally invasive conjunctival surgery (MICS) and lens repositioning.
OBSERVATIONS
A 36-year-old woman with a history of phacomorphic glaucoma secondary to microspherophakia and status post trabeculectomy underwent combined MICS and lens repositioning for a late-onset bleb leak and dislocated intraocular lens following minor trauma. The patient's vision rapidly improved postoperatively with prompt resolution of hypotony.
CONCLUSION/IMPORTANCE
MICS is an effective treatment for traumatic bleb leak following trabeculectomy that can be a particularly useful approach for patients undergoing concurrent ophthalmic surgery.
PubMed: 37810536
DOI: 10.1016/j.tcr.2023.100936 -
The National Medical Journal of India 2019
Topics: Child; Corneal Diseases; Ectopia Lentis; Female; Glaucoma; Humans; Iris; Lens, Crystalline
PubMed: 32769256
DOI: 10.4103/0970-258X.291302