Does brittle cornea syndrome have a bone fragility phenotype?
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ABSTRACT:
SUBMITTER: Cundy T
PROVIDER: S-EPMC8426531 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:PurposeThis case series demonstrate diagnostic features, treatment options, and challenges for Brittle Cornea Syndrome. Observations. Three cases presented with bluish sclera and extremely thin cornea. Genetic workup was performed and confirmed the diagnosis of Brittle Cornea Syndrome, a rare autosomal recessive disorder characterized by corneal thinning and blue sclera. Case 1 was a 4-year-old boy who developed cataract and glaucoma after undergoing right tectonic penetrating keratoplasty (PK) secondary to a spontaneous corneal rupture. Glaucoma was controlled medically. Later, the kid underwent right transcorneal lensectomy and vitrectomy with synechiolysis. After 6 weeks, he sustained graft dehiscence that was repaired using onlay patch graft. Case 2 was a 7-year-old boy who underwent PK in the right eye, then a pericardial patch graft in the left eye following spontaneous corneal rupture. Glaucoma in both eyes was controlled medically. Case 3 was the 2-year-old sister of the 2nd case. She had a pachymetry of 238 μm OD and 254 μm OD and 254 .ConclusionsLong-term follow-up of children diagnosed with Brittle Cornea Syndrome is paramount to minimize the morbidity of corneal rupture and late-onset extraocular conditions.
| S-EPMC7109549 | biostudies-literature
Project description:Brittle cornea syndrome (BCS) is an autosomal recessive disorder characterised by extreme corneal thinning and fragility. Corneal rupture can therefore occur either spontaneously or following minimal trauma in affected patients. Two genes, ZNF469 and PRDM5, have now been identified, in which causative pathogenic mutations collectively account for the condition in nearly all patients with BCS ascertained to date. Therefore, effective molecular diagnosis is now available for affected patients, and those at risk of being heterozygous carriers for BCS. We have previously identified mutations in ZNF469 in 14 families (in addition to 6 reported by others in the literature), and in PRDM5 in 8 families (with 1 further family now published by others). Clinical features include extreme corneal thinning with rupture, high myopia, blue sclerae, deafness of mixed aetiology with hypercompliant tympanic membranes, and variable skeletal manifestations. Corneal rupture may be the presenting feature of BCS, and it is possible that this may be incorrectly attributed to non-accidental injury. Mainstays of management include the prevention of ocular rupture by provision of protective polycarbonate spectacles, careful monitoring of visual and auditory function, and assessment for skeletal complications such as developmental dysplasia of the hip. Effective management depends upon appropriate identification of affected individuals, which may be challenging given the phenotypic overlap of BCS with other connective tissue disorders.
| S-EPMC3659006 | biostudies-literature
Project description:Brittle cornea syndrome (BCS) is a rare, generalized connective tissue disorder associated with extreme corneal thinning and a high risk of corneal rupture. Recessive mutations in transcription factors ZNF469 and PRDM5 cause BCS. Both transcription factors are suggested to act on a common pathway regulating extracellular matrix genes, particularly fibrillar collagens. We identified bilateral myopic choroidal neovascularization as the presenting feature of BCS in a 26-year-old-woman carrying a novel PRDM5 mutation (p.Glu134*). We performed immunohistochemistry of anterior and posterior segment ocular tissues, as expression of PRDM5 in the eye has not been described, or the effects of PRDM5-associated disease on the retina, particularly the extracellular matrix composition of Bruch's membrane.Immunohistochemistry using antibodies against PRDM5, collagens type I, III, and IV was performed on the eyes of two unaffected controls and two patients (both with ?9-14 PRDM5). Expression of collagens, integrins, tenascin and fibronectin in skin fibroblasts of a BCS patient with a novel p.Glu134* PRDM5 mutation was assessed using immunofluorescence.PRDM5 is expressed in the corneal epithelium and retina. We observe reduced expression of major components of Bruch's membrane in the eyes of two BCS patients with a PRDM5 ?9-14 mutation. Immunofluorescence performed on skin fibroblasts from a patient with p.Glu134* confirms the generalized nature of extracellular matrix abnormalities in BCS.PDRM5-related disease is known to affect the cornea, skin and joints. Here we demonstrate, to the best of our knowledge for the first time, that PRDM5 localizes not only in the human cornea, but is also widely expressed in the retina. Our findings suggest that ECM abnormalities in PRDM5-associated disease are more widespread than previously reported.
| S-EPMC4642625 | biostudies-literature
Project description:Brittle cornea syndrome (BCS1 OMIM #229200, BCS2 #614170) is a rare autosomal recessive condition characterised by diffuse thinning and fragility of the cornea. Affected individuals are at risk of globe rupture and blindness after relatively minor eye trauma. We describe a 9-year-old girl with BCS1, already blind in one eye following trauma, who had a 14 mm diameter corneoscleral onlay graft to her contralateral eye to reduce gross irregular corneal astigmatism and potentially to reduce further risk from accidental injury. Although there was a significant initial improvement in the unaided visual acuity, there was subsequent visual loss from secondary glaucoma. In addition, despite the onlay graft, an acute corneal hydrops developed approximately 2 years following surgery, suggesting that in BCS1, corneal tissue degeneration or resorption continues despite external support. Finally, because secondary glaucoma is not a feature of BCS1, we speculate that the onlay graft may have reduced aqueous outflow by compression of the thinned sclera.
| S-EPMC6101314 | biostudies-literature
Project description:Brittle cornea syndrome (BCS) is an autosomal-recessive disorder characterized by a thin cornea that tends to perforate, causing progressive visual loss and blindness. Additional systemic symptoms such as joint hypermotility, hyperlaxity of the skin, and kyphoscoliosis place BCS among the connective-tissue disorders. Previously, we assigned the disease gene to a 4.7 Mb interval on chromosome 16q24. In order to clone the BCS gene, we first narrowed the disease locus to a 2.8 Mb interval and systematically sequenced genes expressed in connective tissue in this chromosomal segment. We have identified two frameshift mutations in the Zinc-Finger 469 gene (ZNF469). In five unrelated patients of Tunisian Jewish ancestry, we found a 1 bp deletion at position 5943 (5943 delA), and in an inbred Palestinian family we detected a single-nucleotide deletion at position 9527 (9527 delG). The function of ZNF469 is unknown. However, a 30% homology to a number of collagens suggests that it could act as a transcription factor involved in the synthesis and/or organization of collagen fibers.
| S-EPMC2427192 | biostudies-literature
Project description:Brittle cornea syndrome (BCS) is a rare recessive condition characterised by extreme thinning of the cornea and sclera. BCS results from loss-of-function mutations in the poorly understood genes ZNF469 or PRDM5. In order to determine the function of ZNF469 and to elucidate pathogenic mechanisms, we used genome editing to recapitulate a human ZNF469 BCS mutation in the orthologous mouse gene Zfp469. Ophthalmic phenotyping showed that homozygous Zfp469 mutation causes significant central and peripheral corneal thinning arising from reduced stromal thickness. Expression of key components of the corneal stroma in primary keratocytes from Zfp469BCS/BCS mice is affected, including decreased Col1a1 and Col1a2 expression. This alters the collagen type I/collagen type V ratio and results in collagen fibrils with smaller diameter and increased fibril density in homozygous mutant corneas, correlating with decreased biomechanical strength in the cornea. Cell-derived matrices generated by primary keratocytes show reduced deposition of collagen type I, offering an in vitro model for stromal dysfunction. Work remains to determine whether modulating ZNF469 activity will have therapeutic benefit in BCS or in conditions such as keratoconus in which the cornea thins progressively. This article has an associated First Person interview with the first author of the paper.
| S-EPMC8476817 | biostudies-literature
Project description:Extreme corneal fragility and thinning, which have a high risk of catastrophic spontaneous rupture, are the cardinal features of brittle cornea syndrome (BCS), an autosomal-recessive generalized connective tissue disorder. Enucleation is frequently the only management option for this condition, resulting in blindness and psychosocial distress. Even when the cornea remains grossly intact, visual function could also be impaired by a high degree of myopia and keratoconus. Deafness is another common feature and results in combined sensory deprivation. Using autozygosity mapping, we identified mutations in PRDM5 in families with BCS. We demonstrate that regulation of expression of extracellular matrix components, particularly fibrillar collagens, by PRDM5 is a key molecular mechanism that underlies corneal fragility in BCS and controls normal corneal development and maintenance. ZNF469, encoding a zinc finger protein of hitherto undefined function, has been identified as a quantitative trait locus for central corneal thickness, and mutations in this gene have been demonstrated in Tunisian Jewish and Palestinian kindreds with BCS. We show that ZNF469 and PRDM5, two genes that when mutated cause BCS, participate in the same regulatory pathway.
| S-EPMC3113239 | biostudies-literature
Project description:Connective tissue diseases, including osteogenesis imperfecta (OI) and Ehlers-Danlos syndrome (EDS), exhibit a high degree of clinical and genetic heterogeneity. We report two sisters with blue sclerae, joint hypermobility and hearing loss. Whole-exome sequencing identified two compound heterozygous ZNF469 loss-of-function mutations due to a frameshift. Since these findings indicate the presence of brittle cornea syndrome (BCS), we performed ocular optical coherence tomography (OCT) and pachymetry, which revealed a moderate decrease in corneal thickness. While only one traumatic fracture was observed in each of the patients, a detailed skeletal assessment indicated no specific patterns of bone mass and microstructure reduction as well as normal bone turnover markers. Taken together, our findings point to a mild form of brittle cornea syndrome with a phenotype compatible with the extraskeletal features of OI but also with EDS.
| S-EPMC7415034 | biostudies-literature
Project description:A 3-year-old boy presented with acute corneal hydrops on the left eye and spontaneous corneal rupture on the right eye. A diagnosis of brittle cornea syndrome was confirmed by molecular analysis. A novel mutation, the homozygous variant c.17T>G, p.V6G, was found in the gene for PR-domain-containing protein 5 (PRDM5) in exon 1. Brittle cornea syndrome is a rare connective tissue disease with typical ocular, auditory, musculoskeletal, and cutaneous disorders. Almost all patients suffer from declined vision due to corneal scarring, thinning, and rupture. The most common ophthalmologic findings include keratoconus, progressive central corneal thinning, high myopia, irregular astigmatism, retinal detachment, and high risk for spontaneous corneal or scleral rupture. In addition to describing the case with a novel mutation here we review the current literature on brittle cornea syndrome pathogenesis, clinical findings, and therapy.
| S-EPMC4499622 | biostudies-other
Project description:Central corneal thickness (CCT), one of the most highly heritable human traits (h(2) typically>0.9), is important for the diagnosis of glaucoma and a potential risk factor for glaucoma susceptibility. We conducted genome-wide association studies in five cohorts from Australia and the United Kingdom (total N = 5058). Three cohorts were based on individually genotyped twin collections, with the remaining two cohorts genotyped on pooled samples from singletons with extreme trait values. The pooled sample findings were validated by individual genotyping the pooled samples together with additional samples also within extreme quantiles. We describe methods for efficient combined analysis of the results from these different study designs. We have identified and replicated quantitative trait loci on chromosomes 13 and 16 for association with CCT. The locus on chromosome 13 (nearest gene FOXO1) had an overall meta-analysis p-value for all the individually genotyped samples of 4.6x10(-10). The locus on chromosome 16 was associated with CCT with p = 8.95x10(-11). The nearest gene to the associated chromosome 16 SNPs was ZNF469, a locus recently implicated in Brittle Cornea Syndrome (BCS), a very rare disorder characterized by abnormal thin corneas. Our findings suggest that in addition to rare variants in ZNF469 underlying CCT variation in BCS patients, more common variants near this gene may contribute to CCT variation in the general population.
| S-EPMC2869325 | biostudies-literature