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Purpose: This case report delineates the intricacies and challenges encountered in cataract surgery in Ehlers-Danlos syndrome type VI presenting with advanced Keratoglobus (KG), severe cataract and brittle cornea. Observations: Despite meticulous planning and intraoperative precautions, including phacoemulsification with reduced intraocular pressure (low bottle height), the patient experienced corneal ruptures necessitating a shift to Extra Capsular Cataract Extraction (ECCE). Postoperative management involved corneal suturing and vigilant follow-up. Conclusions and Importance: Cataract surgery in patients with brittle cornea poses significant challenges due to extreme corneal fragility. Exhaustive pre-operative assessment, careful intraoperative techniques, and vigilant postoperative care are paramount for successful outcomes in these complex cases.
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Purpose: To report the clinical, tomographic, histopathological and genetic findings of a patient with brittle cornea syndrome and a novel mutation in the ZNF469 gene likely implicated in the development of this disorder. Methods: A 64-year-old man presented with a two-year history of worsening vision in both eyes. The patient and his son were examined by imaging and genetic analysis. Results: The patient exhibited persistent ocular irritation, decreased vision, corneal epithelial defects and corneal stromal opacity. Confocal microscopy revealed that the anterior corneal stroma had a large amount of highly reflective and striated tissue. However, his son had no symptoms. Genetic analysis identified a heterozygous c.1781C > T:p.P594L variation in the ZNF469 gene. Conclusions: We reported a novel mutation in the ZNF469 gene (c.1781C > T:p.P594L) in a patient with brittle cornea syndrome from China, which enriched the spectrum of ZNF469 variants implicated in brittle cornea syndrome.
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Background: Brittle cornea syndrome 1 (BCS1) is a rare autosomal recessive disorder characterized by corneal and sclera thinning and fragility that is caused by zinc finger protein 469 (ZNF469) gene mutation. Keratoconus is another disease related to corneal thinning. Several reports have linked ZNF469 variants and keratoconus. We recruited a four-generation BCS1 family and two keratoconus families to explore pathogenic ZNF469 variants. Methods: This study included 11 members from a family with BCS1, 2 families with keratoconus, 368 sporadic keratoconus patients and 325 unrelated healthy controls. Whole exome sequencing of DNA from peripheral blood and cross species conservation analysis was used to investigate and verify ZNF469 variants. Results: A new homozygous frameshift mutation c. 6727del (p.Asp2243Thr fs*8) in ZNF469 was detected in the BSC1 family. Two ZNF469 heterozygous variants g.88494671G > A (c.793G > A, p.G265S, rs754776767) were detected in keratoconus family 1 and a heterozygous missense variant g.88498262G > A (c.4384G > A, p.D1462 N, rs577890057) was found in keratoconus family 2. Based on the American College of Medical Genetics and Genomics guidelines, rs577890057 and rs754776767 were predicted to be variants of uncertain significance. c. 6727del (p. Asp2243Thr fs*8) in ZNF469 was identified to be pathogenic. Conclusions: We identified a new homozygous frameshift mutation and two heterozygous missense variations in ZNF469 in the three families. Our findings extend the spectrum of ZNF469 variants associated with keratoconus.
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It concerns three siblings (two 28 year old twin boys and a 25 year old woman) who presented a previous history of rupture of eyeball in one eye and very poor vision in the other. At the first ophthalmoscopic and instrumental evaluation, three patients presented with bluish sclera and keratoglobus in the intact eye. A genetic analysis with whole exome sequencing was then performed on the three siblings, identifying a biallelic variant of the PRDM5 gene that led to the diagnosis of Brittle Cornea Syndrome (BCS), a rare autosomal recessive disorder characterized by corneal thinning and blue sclera. To preserve the only intact eye from possible breakage, the three siblings were trained in using protective measures (polycarbonate goggles etc.) to carry out close monitoring of symptoms and were asked to continue with follow-up visits for ocular and systemic diseases associated with BCS. Given the poor best corrected visual acuity achievable with glasses and contact lenses, penetrating keratoplasty was performed, achieving good visual acuity maintained in the 2-year follow-up in two of the three patients. Knowledge of this pathology and its clinical manifestations is essential for early diagnosis and correct management of this rare but very debilitating pathology. To our knowledge, this is the first case series of BCS reported in an Albanian population.
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Anomalías del Ojo , Inestabilidad de la Articulación , Anomalías Cutáneas , Masculino , Femenino , Humanos , Adulto , Queratoplastia Penetrante , Anomalías Cutáneas/diagnóstico , Anomalías Cutáneas/genética , Anomalías Cutáneas/cirugía , Anomalías del Ojo/diagnóstico , Anomalías del Ojo/genética , Anomalías del Ojo/cirugía , Inestabilidad de la Articulación/diagnóstico , Inestabilidad de la Articulación/genética , Inestabilidad de la Articulación/cirugía , Córnea/patologíaRESUMEN
BACKGROUND: A report of a Brittle cornea syndrome (BCS) case with bluish scleral discoloration, keratoglobus, and myopia based on multimodal imaging modalities including in vivo confocal microscopy (IVCM), high-definition optical coherence tomography (HD-OCT) and scheimpflug corneal densitometry analysis. CASE PRESENTATION: A 36-year-old Chinese female patient presented with significant bluish discoloration of the sclera in both eyes, extreme corneal thinning with increased corneal curvature, increased central corneal densitometry, and nystagmus. She also had scoliosis, severe osteoporosis, and thyroid disease. CONCLUSIONS: Timely diagnosis, early detection, and detailed follow-up are essential for BCS. There has been no report of a BCS evaluation performed by IVCM and corneal densitometry methods thus far in the literature. Furthermore, multimodal imaging can offer a more comprehensive view of BCS and contribute to a deeper understanding of the disease. Interestingly, this is a rare case of BCS in an adult with good vision, an intact cornea, and nystagmus.
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Miopía , Nistagmo Patológico , Adulto , Femenino , Humanos , Córnea/diagnóstico por imagen , Pueblo Asiatico , Imagen MultimodalRESUMEN
Introduction: Brittle cornea syndrome (BCS) is a rare connective tissue disorder with ocular and systemic features. Extreme corneal thinning and fragility are the main hallmarks of BCS. Case Report: A 4-year-old boy presented with recurrent spontaneous corneal perforation. He had blue sclera, corneal leucoma, irregular iris, shallow anterior chamber, corneal astigmatism, and bilateral corneal thinning. He also had several systemic features including hearing loss, skin hyperelasticity, joint hypermobility, scoliosis, and umbilical hernia. A diagnosis of BCS was confirmed with molecular analysis. A homozygous c.17T>G, p.(Val6Gly) variation was identified in the PRDM5 gene. Discussion: p.(Val6Gly) variation in PRDM5 was previously reported in 2 patients with BCS. We also considered PRDM5 c.17T>G, p.(Val6Gly) variation as pathogenic based on the following features: the absence of the variation in population databases, in silico predictions, segregation analysis, and clinical signs of our patient. Extremely thin and brittle corneas lead to corneal perforation spontaneously or after minor trauma. Nearly all patients have lost their vision because of corneal rupture and scars. The key challenge in the management of BCS is the prevention of ocular rupture which relies on early diagnosis. Early diagnosis allows for taking prompt measures to prevent ocular rupture.
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AIM: To describe a family segregating a novel truncating ZNF469 homozygous mutation causing brittle cornea syndrome type 1 in a male patient and associated with corneal ectasia in his two heterozygous young children. METHODS: A 49-year-old affected male and his 12- and 8-year-old, apparently healthy, siblings underwent phenotypic and genetic assessment. An Oculus Pentacam Scheimpflug topographer system was employed for keratometries and central corneal thickness measurements. Exome sequencing was performed in DNA from the index case with subsequent Sanger sequencing confirmation of the ZNF469 gene causal variant in his relatives. RESULTS: The index case had a history of bilateral keratoglobus, corneal perforations, bilateral hypoacusia, and skeletal anomalies. His two children exhibited topographic anomalies compatible with keratoconus suspects as well as mild skeletal anomalies. Genetic analysis identified a novel homozygous c.2340delC variant in the ZNF469 gene, which predicts a p.(Arg781Glufs*19) truncated protein. Sanger sequencing identified heterozygosity for the c.2340delC variant in DNA from both siblings. CONCLUSION: Our results expand the mutational spectrum associated with brittle cornea syndrome and provide the first demonstration of early corneal anomalies in subjects carrying monoallelic ZNF469 variants.
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Anomalías del Ojo , Queratocono , Anomalías Cutáneas , Niño , Preescolar , Humanos , Masculino , Persona de Mediana Edad , Córnea , Topografía de la Córnea , Dilatación Patológica , Anomalías del Ojo/diagnóstico , Anomalías del Ojo/genética , Queratocono/genética , Anomalías Cutáneas/diagnóstico , Anomalías Cutáneas/genética , Factores de Transcripción/genética , HeterocigotoRESUMEN
Brittle cornea syndrome is a rare recessively inherited disorder (a sub-type of Ehlers-Danlos syndrome) with a clinical presentation dominated by corneal fragility and deafness. There have been suggestions that it may also have a bone fragility phenotype, but there has been little detailed description. We describe two siblings with brittle cornea syndrome due to compound heterozygous mutations in ZNF469 who had sustained ten or more fractures, the majority before the age of 15. When investigated as adults they had osteopenia, with lower z-scores than their parents who each carried one mutation. A bone biopsy from one sibling showed reduced cortical porosity. Both parents, who were heterozygous mutation carriers, had also suffered fractures but had normal bone density. This data supports the view that brittle cornea syndrome may have a bone fragility phenotype.
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Brittle cornea syndrome is among the few special scenarios in ophthalmology that are a nightmare not only for the operating surgeon but also for the patient. Here, the thin and fragile corneas are unable to maintain the shape and structural integrity of the globe and are more prone to minor traumatic or spontaneous corneal perforations. Suturing a brittle cornea and closure of the corneal perforation in a brittle cornea are very challenging requiring the utmost care and special precautions. If proper measures are not taken during the surgery, it may be difficult to salvage the eye. Hence, it is imperative to diagnose appropriately, suture effectively, taking necessary preventive measures in salvaging these corneas. This manuscript aims at providing tips for handling brittle corneal perforations. It will also discuss the problems encountered during surgery, highlight the suturing techniques that can be customized, and finally give an insight into postoperative care.
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Perforación Corneal , Anomalías del Ojo , Anomalías Cutáneas , Córnea/cirugía , Perforación Corneal/diagnóstico , Perforación Corneal/etiología , Perforación Corneal/cirugía , Humanos , Técnicas de SuturaRESUMEN
Brittle cornea syndrome (BCS) is a rare autosomal recessive disorder characterized by corneal thinning and fragility, leading to corneal rupture, the main hallmark of this disorder. Non-ocular symptoms include not only hearing loss but also signs of connective tissue fragility, placing it in the Ehlers-Danlos syndrome (EDS) spectrum. It is caused by biallelic pathogenic variants in ZNF469 or PRDM5, which presumably encode transcription factors for extracellular matrix components. We report the clinical and molecular features of nine novel BCS families, four of which harbor variants in ZNF469 and five in PRDM5. We also performed a genotype- and phenotype-oriented literature overview of all (n = 85) reported patients with ZNF469 (n = 53) and PRDM5 (n = 32) variants. Musculoskeletal findings may be the main reason for referral and often raise suspicion of another heritable connective tissue disorder, such as kyphoscoliotic EDS, osteogenesis imperfecta, or Marfan syndrome, especially when a corneal rupture has not yet occurred. Our findings highlight the multisystemic nature of BCS and validate its inclusion in the EDS classification. Importantly, gene panels for heritable connective tissue disorders should include ZNF469 and PRDM5 to allow for timely diagnosis and appropriate preventive measures for this rare condition.
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Proteínas de Unión al ADN/genética , Anomalías del Ojo/genética , Inestabilidad de la Articulación/congénito , Anomalías Cutáneas/genética , Factores de Transcripción/genética , Adolescente , Adulto , Niño , Preescolar , Análisis Mutacional de ADN , Anomalías del Ojo/epidemiología , Anomalías del Ojo/patología , Familia , Femenino , Estudios de Asociación Genética , Humanos , Lactante , Inestabilidad de la Articulación/epidemiología , Inestabilidad de la Articulación/genética , Inestabilidad de la Articulación/patología , Masculino , Mutación , Linaje , Anomalías Cutáneas/epidemiología , Anomalías Cutáneas/patología , Secuenciación del Exoma , Adulto JovenRESUMEN
A 3-year-old girl presenting with blue sclera, hyperlaxity and developmental dysplasia of hip was found to have bilateral corneal thinning with astigmatism and keratoconus. By clinical exome sequencing, a frameshift mutation c.713_716 del TTTG p.(Val238Alafs*35) in PRDM5 gene causing brittle cornea syndrome 2 and a novel frameshift mutation c.401dup p.(Ser135Glufs*53) in SLC6A5 gene causing Hyperekplexia 3 were identified. No features of hyperekplexia were identified in proband. The novel homozygous mutation of SLC6A5 gene in the proband was presently asymptomatic but they were apprised of the possibility of developing neurological symptoms in the later years.
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Anomalías del Ojo , Queratocono , Preescolar , Córnea , Proteínas de Unión al ADN/genética , Anomalías del Ojo/diagnóstico , Anomalías del Ojo/genética , Femenino , Proteínas de Transporte de Glicina en la Membrana Plasmática , Humanos , Inestabilidad de la Articulación/congénito , Mutación , Anomalías Cutáneas , Factores de Transcripción/genéticaRESUMEN
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.
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Anomalías del Ojo/genética , Inestabilidad de la Articulación/congénito , Anomalías Cutáneas/genética , Factores de Transcripción/genética , Adulto , Femenino , Humanos , Inestabilidad de la Articulación/genética , Persona de Mediana Edad , Mutación , Hermanos , Secuenciación del ExomaRESUMEN
AIMS: Brittle cornea syndrome (BCS) is a rare autosomal recessive disorder. The aim of this study was to review ZNF469 mutations associated with BCS type 1 to date and to describe an additional case of Czech/Polish background. METHODS: Whole genome sequencing was undertaken to identify the molecular genetic cause of disease in the proband. Sequence variants in ZNF469 previously reported as BCS type 1-causing were searched in the literature, manually curated and aligned to the reference sequence NM_001127464.2. RESULTS: The proband has been reviewed since childhood with progressive myopia and hearing loss. Aged 13 years had been diagnosed with Stickler syndrome. Aged 16.5 years, he developed acute hydrops in the left eye managed by corneal transplantation. At the age of 26, he experienced right corneal rupture after blunt trauma, also managed by grafting. He had a number of secondary complications and despite regular follow-up and timely management, the right eye became totally blind and the left eye had light perception at the last follow-up visit, aged 42. He was found to be a compound heterozygote for two novel mutations c.1705C>T; p.(Gln569*) and c.1402_1411del; p.(Pro468Alafs*31) in ZNF469. In total 22 disease-causing variants in ZNF469 have been identified, mainly in consanguineous families or endogamous populations. Only four probands, including the case described in the current study, harboured compound heterozygous mutations. CONCLUSION: BCS occurs very rarely in outbred populations which may cause diagnostic errors due to poor awareness of the disease. Investigation into the underlying molecular genetic cause in patients with connective tissue disorders may lead to a re-evaluation of their clinical diagnosis.
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Anomalías del Ojo/diagnóstico , Inestabilidad de la Articulación/congénito , Anomalías Cutáneas/diagnóstico , Factores de Transcripción/genética , Adulto , Artritis/diagnóstico , Enfermedades del Tejido Conjuntivo/diagnóstico , Edema Corneal/fisiopatología , Edema Corneal/cirugía , Perforación Corneal/fisiopatología , Perforación Corneal/cirugía , Errores Diagnósticos , Anomalías del Ojo/genética , Anomalías del Ojo/fisiopatología , Glaucoma/fisiopatología , Glaucoma/cirugía , Pérdida Auditiva Sensorineural/diagnóstico , Heterocigoto , Humanos , Inestabilidad de la Articulación/diagnóstico , Inestabilidad de la Articulación/genética , Inestabilidad de la Articulación/fisiopatología , Queratoplastia Penetrante , Masculino , Miopía/fisiopatología , Reoperación , Desprendimiento de Retina/diagnóstico , Desprendimiento de Retina/fisiopatología , Desprendimiento de Retina/cirugía , Anomalías Cutáneas/genética , Anomalías Cutáneas/fisiopatología , Trabeculectomía , VitrectomíaRESUMEN
BACKGROUND: To report a patient who presented with bluish scleral discoloration, keratoconus, and progressive high myopia. CASE PRESENTATION: A 6-year-old Chinese female patient presented with a significant bluish discoloration of the sclera in both eyes and extreme corneal thinning with anterior corneal protrusion. General pediatric physical examination was normal for all systems and no genetic disorders known were observed. CONCLUSIONS: We aim to highlight the importance of diagnosis and treatment of patients suffering from Brittle cornea syndrome. Timely diagnosis and early provision of protective glasses seem to be the most important step in treating BCS. To our knowledge, this is the first case of BCS being reported in the Asia area.
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Anomalías del Ojo/patología , Inestabilidad de la Articulación/congénito , Anomalías Cutáneas/patología , Niño , Diagnóstico Diferencial , Anomalías del Ojo/terapia , Dispositivos de Protección de los Ojos , Anteojos , Femenino , Humanos , Inestabilidad de la Articulación/patología , Inestabilidad de la Articulación/terapia , Queratocono/patología , Miopía Degenerativa/patología , Esclerótica/patología , Anomalías Cutáneas/terapiaRESUMEN
PURPOSE: Brittle cornea syndrome 1 (BCS1) is a rare recessive condition characterized by extreme thinning of the cornea and sclera, caused by mutations in ZNF469. Keratoconus is a relatively common disease characterized by progressive thinning and ectasia of the cornea. The etiology of keratoconus is complex and not yet understood, but rare ZNF469 variants have recently been associated with disease. We investigated the phenotype of BCS1 carriers with known pathogenic ZNF469 mutations, and recruited families in which aggregation of keratoconus was observed to establish if rare variants in ZNF469 segregated with disease. METHODS: Patients and family members were recruited and underwent comprehensive anterior segment examination, including corneal topography. Blood samples were donated and genomic DNA was extracted. The coding sequence and splice sites of ZNF469 were PCR amplified and Sanger sequenced. RESULTS: Four carriers of three BCS1-associated ZNF469 loss-of-function mutations (p.[Glu1392Ter], p.[Gln1930Argfs*6], p.[Gln1930fs*133]) were examined and none had keratoconus. One carrier had partially penetrant features of BCS1, including joint hypermobility. ZNF469 sequencing in 11 keratoconus families identified 9 rare (minor allele frequency [MAF] ≤ 0.025) variants predicted to be potentially damaging. However, in each instance the rare variant(s) identified, including two previously reported as potentially keratoconus-associated, did not segregate with the disease. CONCLUSIONS: The presence of heterozygous loss-of-function alleles in the ZNF469 gene did not cause keratoconus in the individuals examined. None of the rare nonsynonymous ZNF469 variants identified in the familial cohort conferred a high risk of keratoconus; therefore, genetic variants contributing to disease pathogenesis in these 11 families remain to be identified.