Variable phenotype of Knobloch syndrome due to biallelic COL18A1 mutations in children.

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.

Knobloch syndrome is a rare collagenopathy characterized by severe early onset myopia, retinal detachment, and occipital encephalocele with various additional manifestations due to biallelic changes in the COL18A1 gene. Here we reported a Chinese family with two affected siblings presented with antenatal occipital encephalocele, infantile onset retinal detachment, and pronounced high myopia at early childhood. Quartet whole exome sequencing was performed in this family and identified that both siblings carried novel compound heterozygous variants in the COL18A1 gene (NM_001379500.1): the maternally inherited variant c.1222-1G>A at the consensus acceptor splice site of intron 8, and the paternally inherited frameshift variant c.3931_3932delinsT p.(Gly1311Serfs*25) in the last exon. Both patients had successful surgical treatment for the occipital encephalocele soon after birth. They had normal neurocognitive outcome and good general conditions examined at the age of 7 years old for the elder sister and 4 years old for the younger brother. The younger brother developed infantile onset retinal detachment at 7 months of age while the sister had high myopia without signs of retinal detachment until 7 years old. This report expands the phenotype and genotype spectrum of Knobloch syndrome with antenatal and postnatal findings.

Knobloch syndrome 1 (KS) is an autosomal recessive inherited ocular syndrome characterized by a combination of high myopia, vitreoretinal degeneration, and occipital encephalocele. KS is caused by biallelic pathogenic variants in the COL18A1 gene. Diagnosing KS can be challenging due to its clinical heterogeneity and the rarity of the syndrome. We conducted comprehensive clinical and instrumental ophthalmological examinations, whole-exome sequencing, Sanger sequencing, and segregation analysis to evaluate affected families. Two patients presenting with high myopia, low visual acuity, chorioretinal atrophy, and occipital skin/skull defects were diagnosed with Knobloch syndrome 1 (KS). In Case 1, a 14-year-old boy, the COL18A1 variants identified were c.2673dup and c.3523_3524del in a compound heterozygous state. Case 2 involved a 3-year-old girl, the c.1637_1638dup and c.3523_3524del variants were identified in a compound heterozygous state. In Case 3, a retrospectively observed boy of 3 y.o. with KS, the variants c.929-2A>G and c.3523_3524del were defined earlier. We confirmed KS molecularly in two novel families. Additionally, in Case 3 of a retrospectively analyzed third family and in both novel cases, one of the biallelic causative variants was the same known 2bp deletion in exon 40 of the collagen XVIII gene. Cases 1 and 3 were characterized by connective tissue dysplasia features and a pathognomonic Knobloch triad. No neurological manifestations and no trends in the genotype-phenotype relationship were found. The heterogeneity of phenotype in the case series is likely to be the result of further factors and/or genetic background.

A 5-year-old girl came to the Tianjin Medical University Eye Hospital in May 2021 because of her poor eyesight after birth. The physical examination showed that she had high myopia, esotropia, horizontal tremor, and high myopia retinopathy of both eyes. After inquiring about her medical history, we found that the baby's occipital cystic mass swelled after birth, and CT examination showed that the occipital skull plate defect with meningocele, but without treatment, at present, the occipital mass had subsided by itself. Considering the eye manifestations and skull changes of the child, it may be conformed to Knobloch syndrome, after the detection of V4 by full exon gene, it was found that the child had the compound heterozygous variation of pathogenic gene COL18A1, and Knobloch syndrome was definite, Knobloch syndrome is a rare autosomal recessive hereditary disease with typical features of high myopia, retinal detachment and occipital encephalocele. At present, there is no clear treatment plan, and gene therapy may be an effective treatment for Knobloch syndrome in the future.

Knobloch syndrome is a rare genetic disorder characterized by high myopia, vitreoretinal degeneration with retinal detachment and occipital cephalocele. The inheritance has been described as autosomal recessive (AR) but in addition to the original report with 5 affected patients [Knobloch and Layer, 1971] only one other family with 2 affected sibs has been described [Czeizel et al., 1992]. We have studied a large consanguineous kindred in which there are 12 patients with severe ocular alterations associated with a congenital occipital encephalocele, compatible with the diagnosis of Knobloch syndrome. CT scan and MRI performed in one of the patients, allowed a better understanding of the cranial and ocular alterations in this syndrome. The pattern of occurrence in this highly inbred family clearly confirms autosomal recessive inheritance of Knobloch syndrome.

To the Editor We recently reported in JMG one case of Knobloch syndrome (KS), offspring of first cousin parents with no detectable mutation in COL18A1. By autozygosity mapping and exome...

Knobloch syndrome (KS), characterized by high myopia, vitreoretinal degeneration with retinal detachment, macular abnormalities and occipital encephalocele, was recently confirmed as autosomal recessive. Here we report the assignment of the gene for this syndrome to 21q22.3 with the marker D21S171 through homozygosity mapping in a highly inbred Brazilian family with 11 affected individuals. A total of nine markers spanning a region of 15.2 cM of the chromosome 21q22.3 were tested and the candidate region was restricted to an interval of 4.3 cM.

Knobloch syndrome (KS) is an autosomal recessive disorder caused by biallelic pathogenic variants in COL18A1 . KS clinically manifests with the typical eye findings (high myopia, vitreoretinal degeneration, retinal detachment, and lens subluxation), variable neurological findings (occipital encephalocele, polymicrogyria, cerebellar malformations, epilepsy, and intellectual disability), and the other uncommon clinical manifestations. Literature review of all KS patients (source PubMed) was done with special reference to cerebellar abnormalities. Here, we report two siblings with typical KS with posterior fossa malformations and novel cerebellar midline cleft abnormality analyzed by whole exome sequencing. Known pathogenic homozygous variant c.2908C > T; (p.Arg970Ter) in exon 26 of COL18A1 was found as a cause for KS. These two siblings presented with early-onset severe ocular manifestations, facial dysmorphism, and variable central nervous system manifestations along with novel cerebellar midline cleft abnormality. The presence or absence of structural brain malformations and genotypes does not absolutely predict cognitive functions in KS patients. However, the presence of posterior fossa abnormality may be predictive for the development of ataxia in later life and needs further studies.

Introduction Pediatric rhegmatogenous retinal detachments, especially those presenting at birth or soon afterward, have a high likelihood of syndromic associations that can be confirmed by genetic testing. Materials and Methods A 5-month-old child was found to have high myopia in the right eye (RE) with highly tessellated fundus, opalescent vitreous, and peripheral thinning. Left eye had a shallow retinal detachment for which he underwent belt buckling. The baby had an occipital skin tag. A provisional diagnosis of Stickler syndrome was made. Results On 1-month follow-up, left eye retina was attached and 360° laser barrage was done. Fluorescein angiography was done which revealed peripheral avascular retina in both eyes. MRI and genetic testing were suggestive of syndromic association. Genetic testing revealed pathogenic mutation in COL 18A1 suggestive of Knobloch syndrome in the baby, and both parents were found to be carriers of the same mutation. However, brain MRI showed features not pathognomonic of Knobloch syndrome. Conclusion Although Knobloch syndrome is associated with vitreoretinal degeneration and high risk of retinal detachment, there seems to be no recommendation for prophylaxis in the other eye and therefore we preferred to observe the RE closely. A unique feature noted in our case was the peripheral avascular zone (PAZ). The PAZ could be contributed by multiple factors such as high myopia, or due to endostatin deficiency (which is a derivative of collagen XVIII) or an underlying WNT signalling abnormality.

Knobloch syndrome (KNO) is an autosomal recessive disorder characterized by ocular abnormalities (myopia and retinal detachment) and occipital encephalocele. The syndrome is clinically and genetically heterogeneous (KNO1, KNO2). Previously germline mutations in COL18A1 (21q22.3) were detected in some families, but in other kindreds linkage to COL18A1 was excluded. We ascertained a large consanguineous family with high myopia, vitreoretinal degeneration and occipital scalp defect with autosomal recessive mode of inheritance. Due to the overlapping clinical presentation of this family with Knobloch syndrome we propose this phenotype as a type III variant of KS (KNO3). A genome wide linkage study using microsatellite markers at 10-20 cM interval revealed linkage to 17q11.2 with a maximum LOD scores 3.40 (theta = 0.00) for markers D17S1307 and D17S1166. Fine mapping defined a 2.67 cM disease region between D17S1307 and D17S798. Mutation analysis of three candidate genes (UNC119, MYO1D, and RAB11FIP4) within the disease region did not identify any disease-associated mutation in affected individuals.

Knobloch syndrome is a rare autosomal recessive disorder characterized by a triad of high myopia, vitreoretinal degeneration, and congenital occipital scalp defects. On literature review of all reported cases, 25 of 85 eyes (29%) of patients diagnosed as having Knobloch syndrome have suffered retinal detachment. Due to high myopia, surgical repair of the retinal detachment is challenging and patients frequently require several reoperations. Even after vitrectomy or scleral buckle for retinal detachment, the final visual acuity outcomes are poor, with 11 of 12 (92%) patients having 20/200 visual acuity or worse and 6 of 12 (50%) having counting fingers visual acuity or worse. The role of retinal detachment prophylaxis has been discussed for other vitreoretinal degeneration disorders, but not for this disease. The authors report the case of a child affected with Knobloch syndrome who presented with total retinal detachment in the left eye at 24 months of age. He underwent successful repair and was then treated with prophylactic scleral buckle implantation in the right eye 5 months later. The retina in both of his eyes remains attached 4 years later. [J Pediatr Ophthalmol Strabismus 2014;51:e40–e43.]

This case series describes the clinical features and genetic testing results of four patients from two families affected by Knobloch syndrome (KS). KS is an autosomal recessive collagenopathy characterized by vitreoretinal degeneration, high myopia, retinal detachment, and occipital encephalocele. In addition, a myriad of other ophthalmic and systemic features may be present in the affected individuals. Mutations in the COL18A1 gene are primarily implicated in the pathogenesis of the disease. The phenotypical differences seen in our genetically-proven patients show the clinical heterogeneity of this condition. Diagnosis of KS type-1 was confirmed by genetic analysis in all affected patients. Surgical intervention was done to salvage vision in three patients. This case series highlights the importance of meticulous clinical examination and diagnosis of this rare condition. Genetic counseling and testing are important for suspected patients and for guiding patients on the visual prognosis of the disease.

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.

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.

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.