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Publication
Journal: Ryoikibetsu shokogun shirizu
December/10/2001
Authors
Publication
Journal: American Journal of Medical Genetics, Part A
February/3/2011
Publication
Journal: Ophthalmic Surgery Lasers and Imaging Retina
August/15/2019
Abstract
Knobloch syndrome is a genetic disorder defined by occipital defect, high myopia, and vitreoretinal degeneration. The authors studied retinal changes in patients with Knobloch syndrome using optical coherence tomography (OCT).The authors report patients with Knobloch syndrome who received OCT testing during their care from 2011 to 2016. Diagnosis was based on high myopia, characteristic fundus, and occipital scalp or skull abnormalities with/without featureless irides and/or ectopia lentis. When available, diagnosis was confirmed by the detection of COL18A1 mutations.The authors studied eight eyes from five patients. Two eyes were excluded due to chronic retinal detachment. OCT findings included epiretinal membrane, peripapillary vitreoretinal traction with retinoschisis, absent or rudimentary foveal pits, mean macular thickness of 113.4 μm, poor lamination, retinal pigment epithelium (RPE) atrophy, photoreceptor depletion, and mean choroidal thickness of 168.5 μm with enlarged choroidal vessels.OCT findings in Knobloch syndrome include abnormal vitreoretinal traction, poor foveal differentiation, poor retinal lamination, retinal thinning, RPE attenuation, myopic choroidal thinning, and pachychoroid. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:e203-e210.].
Publication
Journal: Journal of Glaucoma
January/14/2021
Abstract
We report cases of acute angle closure in two young highly myopic siblings with Knobloch syndrome. To our knowledge, this is the first report of acute angle closure in Knobloch syndrome. Both patients were homozygous for a likely pathogenic variant in COL18A1. Both responded to treatment with cyclophotocoagulation and remained stable despite declining or being medically unfit for clear lens extraction. We argue that the recent implication of heterozygous mutations in COL18A1 in familial angle closure supports the argument that acute angle closure in these two patients was likely to be a thus far unreported feature of Knobloch syndrome. In addition, these cases also support the hypothesis that pathogenic variants in COL18A1 may be a risk factor for acute angle closure.
Publication
Journal: American journal of medical genetics
April/29/1992
Abstract
Two sibs affected with Knobloch syndrome comprising severe visual handicap (high myopia and retinal detachment with other defects), atypical occipital cephalocele, and unusual plantar creases are described.
Publication
Journal: Ophthalmic Genetics
July/7/2008
Abstract
Knobloch syndrome (KNO) is a rare autosomal recessive condition caused by pathogenic mutations in the COL18A1 gene. It is characterized by high myopia, vitreoretinal degeneration, retinal detachment and midline encephalocoele or midline occipital bone defect. We report a case of KNO confirmed by direct sequence analysis of the COL18A1 gene with typical ocular features, and previously unreported systemic features: occipital hair tuft with transient CSF leak and bilateral renal abnormalities. This case illustrates a new phenotypic variant of this syndrome.
Publication
Journal: International Journal of Paediatric Dentistry
July/21/2009
Publication
Journal: Ophthalmic Genetics
March/17/2020
Abstract
Background: Knobloch syndrome (OMIM 267750) is a rare autosomal recessive disorder due to genetic defects in the COL18A1 gene. The triad of high myopia, occipital defect, vitreoretinal degeneration has been described as pathognomonic for this condition. Patients with Knobloch syndrome have also extraocular problems as brain and kidney malformations. High genetic and phenotypic variation has been reported in the affected patients.Materials and Methods: Here we provide detailed clinical description of 3 individuals with Knobloch syndrome. Ocular examination and fundus imaging have been performed. Detailed information about systemic conditions has been provided.Results: Mutations in COL18A1 were identified in all three patients. Patient 1 had congenital hip dislocation and patient 2 had renal atrophy, cardiac insufficiency and difficult skin healing.Conclusions: With this report we add to the clinical and genetic knowledge of this rare condition.
Publication
Journal: American Journal of Medical Genetics, Part A
July/23/2020
Abstract
Knobloch Syndrome (KS) is a rare autosomal recessive hereditary disease. Despite its clinical heterogeneity, it is characterized by vitreoretinal degeneration and high myopia, with or without occipital skull defects. It is caused by mutations in the COL18A1 gene, which codifies for collagen XVIII, present in retina and vascular endothelium. Since the first description of the disease by doctors Knobloch and Layer in 1972, over 100 cases and 20 pathogenic or likely pathogenic mutations have been reported. We present the case of a child born from a consanguineous couple in Chile with congenital high myopia and dysmorphisms without an occipital skull defect. Whole exome sequencing analysis revealed an inherited homozygous variant in COL18A1, c.4224_4225delinsC, p.Pro1411Leufs*35.
Keywords: COL18A1; Knobloch syndrome; high-grade myopia.
Publication
Journal: Clinical Ophthalmology
June/30/2011
Abstract
Knobloch syndrome is an autosomal recessive disorder associated with early-onset ocular abnormalities and central nervous system malformations. Ocular abnormalities are usually severe, and include high myopia, vitreoretinal degeneration, retinal detachment, macular abnormalities, and cataract. The most frequent systemic changes are midline malformations of the brain, ventricular dilation, and occipital encephalocele. Cognitive delay may occur. We report a case of cataract in a child with Knobloch syndrome. Cataract surgery and follow-up are described.
Publication
Journal: Journal of Medical Genetics
February/17/2014
Publication
Journal: British Journal of Ophthalmology
July/18/2012
Abstract
BACKGROUND
Knobloch syndrome is defined as a triad of occipital defect, high myopia and vitreo-retinal degeneration (often with later retinal detachment); however, the ocular phenotype is not well defined. This report characterises eye findings of the syndrome in children with genetically confirmed disease.
METHODS
Case series of Saudi children with previously documented homozygous mutations in COL18A1 or ADAMTS18.
RESULTS
All eight children (4-15 years old; five families) had smooth (cryptless) irides, high myopia (-10 to -20 dioptres) and distinctive vitreo-retinal degeneration consisting of diffuse very severe retinal pigment epithelium atrophic changes with prominent choroidal vessel show, macular atrophic lesions with or without a 'punched out' appearance and white fibrillar vitreous condensations. In two probands and a sibling, this distinctive retinal appearance was the basis for initial clinical diagnosis. Six children had temporal ectopia lentis and four had posterior perinuclear lens opacity. Additional features included developmental delay (two), epilepsy (one) and heterotopic grey matter in the lateral ventricles (one). Four children had no clinically discernible occipital defect.
CONCLUSIONS
Taken together, smooth iridies, ectopia lentis and characteristic vitreo-retinal degeneration seem pathognomonic. Although it is a defining feature of the syndrome, clinically discernible occipital defect is not a sine qua non for the diagnosis. Ophthalmologists are uniquely able to diagnose Knobloch syndrome.
Publication
Journal: JAMA Ophthalmology
May/4/2017
Abstract
Knobloch syndrome is a rare, recessively inherited disorder classically characterized by high myopia, retinal detachment, and occipital encephalocele, but it is now known to have an increasingly variable phenotype. There is a lack of reported electrophysiologic data, and some key clinical features have yet to be described.
To expand on current clinical, electrophysiologic, and molecular genetic findings in Knobloch syndrome.
Twelve patients from 7 families underwent full ophthalmic examination and retinal imaging. Further investigations included electroretinography and neuroradiologic imaging. Bidirectional Sanger sequencing of COL18A1 was performed with segregation on available relatives. The study was conducted from July 4, 2013, to October 5, 2015. Data analysis was performed from May 20, 2014, to November 3, 2015.
Results of ophthalmic and neuroradiologic assessment and sequence analysis of COL18A1.
Of the 12 patients (6 males; mean age at last review, 16 years [range, 2-38 years]), all had high myopia in at least 1 eye and severely reduced vision. A sibling pair had unilateral high myopia in their right eyes and near emmetropia in their left eyes from infancy. Anterior segment abnormalities included absent iris crypts, iris transillumination, lens subluxation, and cataract. Two patients with iris transillumination had glaucoma. Fundus characteristics included abnormal collapsed vitreous, macular atrophy, and a tesselated fundus. Five patients had previous retinal detachment. Electroretinography revealed a cone-rod pattern of dysfunction in 8 patients, was severely reduced or undetectable in 2 patients, and demonstrated cone-rod dysfunction in 1 eye with undetectable responses in the other eye in 2 patients. Radiologic imaging demonstrated occipital encephalocele or meningocele in 3 patients, occipital skull defects in 4 patients, minor occipital changes in 2 patients, and no abnormalities in 2 patients. Cutaneous scalp changes were present in 5 patients. Systemic associations were identified in 8 patients, including learning difficulties, epilepsy, and congenital renal abnormalities. Biallelic mutations including 2 likely novel mutations in COL18A1, were identified in 6 families that were consistent with autosomal recessive inheritance with a single mutation identified in a family with 2 affected children.
This report describes new features in patients with Knobloch syndrome, including pigment dispersion syndrome and glaucoma as well as cone-rod dysfunction on electroretinography. Two patients had normal neuroradiologic findings, emphasizing that some affected individuals have isolated ocular disease. Awareness of the ocular phenotype may aid early diagnosis, appropriate genetic counseling, and monitoring for potential complications.
Publication
Journal: Canadian Journal of Ophthalmology
November/14/2020
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Publication
Journal: Ophthalmology. Retina
February/29/2020
Abstract
To describe the findings and the management of macular hole (MH)-related retinal detachment (RD) in children with Knobloch syndrome.Retrospective interventional case series.Patients with Knobloch syndrome who presented with MH-related RD.Retrospective chart review of patients with Knobloch syndrome who presented with MH-related RD from January 2012 to December 2018. Interventions included pars plana vitrectomy and silicone oil tamponade with or without scleral buckle, drainage retinotomy, or relaxing retinectomy.MH characteristics and surgical anatomical outcome.The study included 9 eyes of 5 patients (age range 2 months to 5 years; median age 5.5 months). Presenting symptoms were poor fixation and nystagmus. The fellow eye of 1 patient had RD due to peripheral breaks. The MH was clinically visible in 8 eyes and detected only by OCT in 1 eye. The RD was shallow and extended to the anterior equator in 7 eyes and localized to a punched-out atrophic lesion in 1 eye. Seven eyes underwent surgical repair. At the last follow-up examination (follow-up range 11 to 42 months; mean 24 months, standard deviation 11.8 months), retinal reattachment with MH closure was achieved in 5 eyes along with marked improvement in fixation.Patients with Knobloch syndrome may develop MH-related RD as early as infancy. The condition may be easily overlooked in children but should be suspected in the setting of high myopia, vitreoretinal degeneration, and encephalocele.
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Publication
Journal: Middle East African Journal of Ophthalmology
February/15/2019
Abstract
Knobloch syndrome (KS) is typically characterized by high myopia, vitreoretinal degeneration, retinal detachment, and macular abnormalities. We report a case of glaucoma in KS, which represents the fourth reported case and the first description of the retinal events after the glaucoma procedure. Retinal detachment followed standard cyclophotocoagulation procedure for glaucoma in a 2-month-old boy. Ophthalmologists should be aware of the possibility of retinal detachment from any ocular intervention in patients with KS.
Publication
Journal: American journal of medical genetics
March/14/2000
Abstract
We report on a 4-year-old boy with Knobloch syndrome. He has vitreoretinal degeneration, high myopia, cataract, telecanthus, hypertelorism, and a high-arched palate. He also has a defect of the anterior midline scalp with involvement of the frontal bone as documented by a computed tomography (CT) scan. The brain was normal on CT scan and magnetic resonance imaging. We present a review of the 23 published cases with this syndrome. Our patient illustrates the importance of investigating for underlying ocular and central nervous system pathology whenever midline scalp defects are present.
Publication
Journal: American Journal of Medical Genetics, Part A
February/3/2011
Abstract
Knobloch syndrome (KNO) is caused by mutations in the collagen XVIII gene (COL18A1) and patients develop encephalocele and vitreoretinal degeneration. Here, we report an El Salvadorian family where two sisters showed features of KNO. One of the siblings also developed acute lymphoblastic leukemia. DNA sequencing of COL18A1 revealed a homozygous, 2-bp deletion (c3514-3515delCT) in exon 41, which leads to abnormal collagen XVIII and deficiency of its proteolytic cleavage product endostatin. KNO patients with mutations in COL18A1 may be at risk for endostatin-related conditions including malignancy.
Publication
Journal: Molecular Vision
August/17/2009
Abstract
OBJECTIVE
To facilitate future diagnosis of Knobloch syndrome (KS) and better understand its etiology, we sought to identify not yet described COL18A1 mutations in KS patients. In addition, we tested whether mutations in this gene lead to absence of the COL18A1 gene product and attempted to better characterize the functional effect of a previously reported missense mutation.
METHODS
Direct sequencing of COL18A1 exons was performed in KS patients from four unrelated pedigrees. We used immunofluorescent histochemistry in skin biopsies to evaluate the presence of type XVIII collagen in four KS patients carrying two already described mutations: c.3277C>T, a nonsense mutation, and c.3601G>A, a missense mutation. Furthermore, we determined the binding properties of the mutated endostatin domain p.A1381T (c.3601G>A) to extracellular matrix proteins using ELISA and surface plasmon resonance assays.
RESULTS
We identified four novel mutations in COL18A1, including a large deletion involving exon 41. Skin biopsies from KS patients revealed lack of type XVIII collagen in epithelial basement membranes and blood vessels. We also found a reduced affinity of p.A1381T endostatin to some extracellular matrix components.
CONCLUSIONS
COL18A1 mutations involved in Knobloch syndrome have a distribution bias toward the coding exons of the C-terminal end. Large deletions must also be considered when point mutations are not identified in patients with characteristic KS phenotype. We report, for the first time, lack of type XVIII collagen in KS patients by immunofluorescent histochemistry in skin biopsy samples. As a final point, we suggest the employment of this technique as a preliminary and complementary test for diagnosis of KS in cases when mutation screening either does not detect mutations or reveals mutations of uncertain effect, such as the p.A1381T change.
Publication
Journal: Journal of Medical Genetics
March/12/2012
Abstract
BACKGROUND
Knobloch syndrome (KS) is a developmental disorder characterised by occipital skull defect, high myopia, and vitreo-retinal degeneration. Although genetic heterogeneity has been suspected, COL18A1 is the only known KS disease gene to date.
OBJECTIVE
To identify a novel genetic cause of KS in a cohort of Saudi KS patients enrolled in this study.
METHODS
When COL18A1 mutation was excluded, autozygosity mapping was combined with exome sequencing.
RESULTS
In one patient with first cousin parents, COL18A1 was excluded by both linkage and direct sequencing. By filtering variants generated on exome sequencing using runs of autozygosity in this simplex case, the study identified ADAMTS18 as the only gene carrying a homozygous protein altering mutation. It was also shown that Adamts18 is expressed in the lens and retina in the developing murine eye.
CONCLUSIONS
The power of combining exome and autozygome analysis in the study of genetics of autosomal recessive disorders, even in simplex cases, has been demonstrated.
Publication
Journal: American journal of medical genetics
May/31/1993
Abstract
An apparently autosomal recessive syndrome of hereditary vitreoretinal degeneration (VRD) with retinal detachment, high myopia, and congenital encephalocele was described in 1971 by Knobloch and Layer [J Pediatr Ophthalmol 8:181-184]. Clinical confirmation of the presence of encephaloceles was lacking, and no neuropathologic studies were reported. We have evaluated a similarly affected family with 2 sibs with high myopia, VRD, and occipital scalp defects. Histologic examination of the scalp defects showed heterotopic neuronal tissue in both instances. The older girl has had a unilateral retinal detachment. Her other eye and both eyes of the younger sib have so far been treated successfully with prophylactic retinal cryotherapy. Both children have normal to above normal intelligence. The family reported by Knobloch and Layer [1971] and the sibship herein described appear to represent a distinct autosomal recessive trait. Analysis of the associated defects suggests an underlying defect in early cephalic neuroectodermal morphogenesis. Data from these families imply that congenital occipital scalp defects rather than true encephaloceles may, as is true in some cases of Meckel syndrome, accompany Knobloch syndrome. The presence of a congenital midline scalp defect should alert the clinician to possible underlying central nervous system and/or ocular pathology and should lead to consideration of further diagnostic evaluations and prophylactic measures.
Publication
Journal: Ophthalmic Genetics
November/12/2017
Abstract
Knobloch syndrome is a pathognomonic vitreo-retinopathy that includes zonular weakness, high myopia, and a distinct fundus appearance with tessellation out of proportion to the degree of myopia. Whether myopia in Knobloch syndrome is axial or lenticular is unclear. Also not known are the optical coherence tomography (OCT) correlates to the distinct fundus appearance. In this study we assess cycloplegic refraction, biometry, and macular spectral domain (SD) OCT in children with Knobloch syndrome.
A retrospective case series of seven children (12 eyes) with Knobloch syndrome.
Twelve eyes with attached retinas (seven patients, aged 6-17 years old, mean 11 years) were identified, seven of which had OCT. Best-corrected vision was typically 20/300 or worse. Axial length divided by corneal radius was >3 for all eyes (3.23-3.77, mean 3.52), consistent with axial myopia, and axial lengths (26.58-30.27 mm, mean 28.16) were consistent with spherical equivalent degree of myopia (-10.00 to -18.50, mean -12) when compared to historical controls. OCT revealed lack of choriocapillaries, outer retinal disorganization, and lack of or only rudimentary foveal pit.
Refractions and biometry in Knobloch syndrome are consistent with the myopia being axial. In addition to vitreo-retinopathy, choroidopathy is part of the phenotype and is an anatomical correlate to the distinctive fundus appearance.
Publication
Journal: American Journal of Medical Genetics, Part A
September/27/2007
Publication
Journal: Genes
October/22/2021
Abstract
Knobloch syndrome is an inherited disorder characterized by high myopia, retinal detachment, and occipital defects. Disease-causing mutations have been identified in the COL18A1 gene. This study aimed to investigate novel variants of COL18A1 in Knobloch syndrome and describe the associated phenotypes in Chinese patients. We reported six patients with Knobloch syndrome from four unrelated families in whom we identified five novel COL18A1 mutations. Clinical examination showed that all probands presented with high myopia, chorioretinal atrophy, and macular defects; one exhibited rhegmatogenous retinal detachment in one eye. Occipital defects were detected in one patient.
Keywords: COL18A1; Knobloch syndrome; macular dysplasia; whole exon sequencing.
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