Two patients with Knobloch syndrome due to mutation in COL8A1 gene: case report and review of the literature.

BACKGROUND: Knobloch syndrome (KNO, OMIM # 267,750) is a rare ciliopathy group sydrome characterized by a collagen synthesis disorder. It represents an uncommon cause of pediatric retinal detachment. This report presents two cases with different COL18A1 gene mutations, complicated by retinal detachment. CASE PRESENTATION: Both cases exhibited high myopia and various degrees of occipital skull defect. The first case, a female, had bilateral congenital retinal detachment, posterior embryotoxon, and strabismus. The second case, a male, had unilateral congenital retinal detachment and neuromotor developmental delay. The first case, diagnosed in the early months of life, underwent successful retinal reattachment surgery. However, surgery was not performed on the second case, who presented with late-stage unilateral retinal detachment and pre-phthisis. CONCLUSIONS: The report describes two patients with Knobloch syndrome, one of whom responded favorably to surgery for retinal detachment in both eyes. Successful anatomical results were achieved with early surgical interventions. It is essential to recognize the phenotypic and genetic heterogeneity within KNO.

Dominant monoallelic variant in the PAK2 gene causes Knobloch syndrome type 2.

Knobloch syndrome is an autosomal recessive phenotype mainly characterized by retinal detachment and encephalocele caused by biallelic pathogenic variants in the COL18A1 gene. However, there are patients clinically diagnosed as Knobloch syndrome with unknown molecular etiology not linked to COL18A1. We studied an historical pedigree (published in 1998) designated as KNO2 (Knobloch type 2 syndrome with intellectual disability, autistic behavior, retinal degeneration, encephalocele). Whole exome sequencing of the two affected siblings and the normal parents resulted in the identification of a PAK2 non-synonymous substitution p.(Glu435Lys) as a causative variant. The variant was monoallelic and apparently de novo in both siblings indicating a likely germ-line mosaicism in one of the parents; the mosaicism, however, could not be observed after deep sequencing of blood parental DNA. PAK2 encodes a member of a small group of serine/threonine kinases; these P21-activating kinases (PAKs) are essential in signal transduction and cellular regulation (cytoskeletal dynamics, cell motility, death and survival signaling and cell cycle progression). Structural analysis of the PAK2 p.(Glu435Lys) variant that is located in the kinase domain of the protein predicts a possible compromise in the kinase activity. Functional analysis of the p.(Glu435Lys) PAK2 variant in transfected HEK293T cells results in a partial loss of the kinase activity. PAK2 has been previously suggested as an autism-related gene. Our results show that PAK2-induced phenotypic spectrum is broad and not fully understood. We conclude that the KNO2 syndrome in the studied family is dominant and caused by a deleterious variant in the PAK2 gene.

Mutations in the COL18A1 gen associated with knobloch syndrome and structural brain anomalies: a novel case report and literature review of neuroimaging findings.

. COL18A1 gene mutations have been associated with Knobloch syndrome, which is characterized by ocular and brain abnormalities. Here we report a 4.5 years-old male child with autism and two novel COL18A1 mutations (NM_030582.4: c.1883_1891dup and c.1787C>T). Hypermetropic astigmatism, but not brain migration disorders, was observed. However, an asymmetric pattern of cerebellar perfusion and a smaller arcuate fascicle were found.  Low levels of collagen XVIII were also observed in the patient´s serum. Thus, biallelic loss-of-function mutations in COL18A1 may be a new cause of autism  without the brain malformations typically reported in patients with Knobloch syndrome.

[Knobloch syndrome: a case report].

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, a Rare Cause of Occipital Encephalocele and Seizures: A Case Report.

BACKGROUND: Knobloch syndrome (KS) is a rare autosomal recessive disorder associated with multiple ocular and cranial abnormalities. Occult occipital skull defect or encephalocele should raise suspicion of this disease. It is never reported in neurosurgical literature, possibly due to a lack of clinician familiarity, leading to underdiagnosis and inadequate management. Our patient also had seizures, which is a sporadic presentation of this syndrome. CASE DESCRIPTION: Here, we report a clinico-radiologic finding of a 7-year-old boy who presented with seizures, cataracts, and an occipital bone defect along with bilateral subependymal heterotopias and polymicrogyria. CONCLUSIONS: This case highlights the importance of consideration of this syndrome in children with a midline occipital bone defect with or without encephalocele and seizures. Early recognition of this presentation is critical for obtaining access to appropriate genetic counseling and subsequent monitoring and prevention of complications by surgical intervention.

Knobloch syndrome in a patient from Chile.

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.

Progressive retinal degeneration in a girl with Knobloch syndrome who presented with signs of ocular albinism.

PURPOSE: We report for the first time electroretinographic (ERG) evidence of progressive retinal abnormalities in a girl who presented in infancy with ocular features of albinism and gradually developed choroidal sclerosis and patchy retinal atrophy leading to a diagnosis of Knobloch syndrome (KS, OMIM 267750, COL18A1). METHODS: At age 2 months, nystagmus and esotropia prompted ophthalmic evaluation. The appearance of choroidal sclerosis and atrophic retinal patches led to further evaluation at age 8 years. Genetics consultation was obtained in infancy and again at age 8 years as retinal findings evolved. Full field ERG responses in both scotopic and photopic conditions were recorded at both ages and compared to those in healthy control subjects. RESULTS: At age 2 months ERG response parameters were within normal limits for age and tyrosinase (TYR) gene sequencing revealed one novel mutation, p.S466F, and the temperature-sensitive polymorphism, p.R402Q, suggesting the diagnosis of oculocutaneous albinism type 1 (OCA1). At age 8 years, there was significant attenuation of both scotopic and photopic ERG responses. Genetic re-analysis led to the identification of a homozygous mutation, c.3213dupC, in the COL18A1 gene, thus confirming the diagnosis of Knobloch syndrome. CONCLUSIONS: Our patient with Knobloch syndrome developed abnormal ERG responses similar to those found in col18a1 knockout mice. Thus, we have documented progressive attenuation of the scotopic and photopic responses in KS.

Knobloch syndrome associated with Polymicrogyria and early onset of retinal detachment: two case reports.

BACKGROUND: Knobloch Syndrome (KS) is a rare congenital syndrome characterized by occipital skull defects and vitreoretinal degeneration. Retinal detachment (RD) often occurs at the end of the first decade of life or later. Aside from occipital skull defects, central nervous system abnormalities are uncommon. CASE PRESENTATIONS: We report on two siblings with KS. The first, a seven month old male, presented with nystagmus and was found to have a serous RD and a tessellated retinal appearance. His sister had a history of multiple visual abnormalities and had a similar retinal appearance although no signs of RD, but retina staphylomas. Genetic testing performed on both siblings showed a mutation in COL18A1, diagnostic of KS. MRI of both siblings demonstrated polymicrogyria but did not show occipital defects. CONCLUSIONS: Although several families with KS have been described previously, our case is noteworthy for several reasons. The RD observed in our first patient occurred at an early age, and we find evidence of only one patient with KS who had an RD identified at an earlier age. The findings of polymicrogyria are not characteristic of KS, and we found only a few previous reports of this association. Additionally, we review potential treatment options for this condition.

Prenatal Diagnosis of a Case of Norrie Disease with Late Development of Bilateral Ocular Malformation.

We report a case of Norrie disease, diagnosed by prenatal ultrasound, confirmed by Sanger sequencing of the DNP gene from the aborted fetal cord blood and histologically. Prenatal ultrasound revealed no abnormality in either eye at 22+1 and 31+4 gestational weeks, but at 36+5 gestational weeks both eyes had massive vitreous cavity opacities with complete retinal detachment. Norrie disease was initially suspected because of an older male sibling with the disease. To our knowledge, prenatal ultrasound diagnosis of Norrie disease has been previously described only one case in 1993 in a 34-week-old fetus. The normal eye development until after 31 + 4 gestational weeks provides insight into the first manifestation and then the rapid progression of the eye disease.

Optic disc pit with maculopathy ­ a case report. / [Dolek rozwojowy tarczy nerwu wzrokowego z makulopatia ­ opis przypadku].

The article presents a case of an 18-year old man with bilateral optic disc pit associated with serous macular detachment in the left eye. Optic disc pit is a rare congenital abnormality of the optic nerve head, which affects 1:11 000 people, with no gender predilection. Optic disc pits are usually incidental findings on fundus examination. In ophthalmic examination, optic disc pit presents as an oval, gray, white or yellowish depression in the optic disc, commonly involving temporal quadrants, but may be situated in any sector. Approximately 25­75% of eyes with optic disc pits have a poor visual prognosis, as a result of serous macular detachment and macular holes. There are no guidelines on the management of patients with optic disc pit maculopathy. Numerous techniques have been described, including laser photocoagulation, intravitreal gas injection and pars plana vitrectomy with many different modifications.

Identification of ADAMTS18 as a gene mutated in Knobloch syndrome.

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. CONCLUSION: The power of combining exome and autozygome analysis in the study of genetics of autosomal recessive disorders, even in simplex cases, has been demonstrated.

Walker-Warburg syndrome diagnosed by findings of typical ocular abnormalities on prenatal ultrasound.

Walker-Warburg syndrome (WWS) is a rare, lethal autosomal recessive disorder characterized by congenital muscular dystrophy and brain and eye anomalies. A prenatal finding of hydrocephalus associated with posterior fossa anomalies and/or encephalocele is nonspecific, whereas additional ocular anomalies are typical for WWS. We report a fetus of consanguineous parents found to have encephalocele at US in week 15 of gestation. The parents did not wish to terminate the pregnancy. Follow-up US revealed bilateral abnormal ocular echoic structures suggesting a major form of persistent primary vitreous. WWS was suspected. The POMT2 mutation confirmed this diagnosis. In hydrocephalus associated with posterior fossa anomalies and/or encephalocele, we recommend detailed US examination of the fetal eyes. Ocular anomalies in this context strongly suggest WWS.

A distinct autosomal recessive ocular anomaly in Chaharborj, Islamic Republic of Iran.

In Chaharborj, a village in north-eastern ofthe Islamic Republic of Iran, a high prevalence of congenital blindness (1.1%) has been reported. The clinical findings have not been fully described. We therefore assessed the clinical aspects of this condition in a case series of 20 congenitally blind patients and 24 of their parents. All patients had been blind since birth. There was anterior segment dysgenesis and retinal non-attachment in all patients. There were no systemic anomalies. Histopathologically, there was iridocorneal adhesion, normal angle structure and retinal dysplasia. No significant difference was found in the frequency of different HLA class I alleles compared with the general population. The anomaly causing congenital blindness in these patients has components of both anterior and posterior segment dysgenesis. It appears to be a distinct entity with an autosomal recessive pattern of inheritance.

Whole genome sequencing in a Knobloch syndrome family confirms the molecular diagnosis.

BACKGROUND: To establish the molecular diagnosis in two brothers presenting with the ocular features of Knobloch Syndrome using whole genome sequencing (WGS). METHODS: Clinical examination and ophthalmological phenotyping were completed under general anaesthesia. DNA samples were tested on a targeted retinal dystrophy next-generation sequencing panel. Subsequently, WGS was performed to identify additional variants. RESULTS: Clinical examination confirmed the diagnosis of Knobloch Syndrome. Targeted sequencing identified a novel heterozygous frameshift pathogenic variant in COL18A1, c.2864dupC; p.(Gly956ArgfsX20), inherited from their mother. A second paternally inherited heterozygous missense variant was identified in both brothers, c.5014 G > A; p.(Asp1672Asn), which was initially considered to have too high frequency to be pathogenic (MAF 8.8%). This led to an in-depth analysis of the COL18A1 locus using WGS data, which confirmed that Asp1672Asn is a likely pathogenic hypomorphic allele. CONCLUSION: To date, all confirmed genetic diagnoses of Knobloch syndrome are attributable to variants in COL18A1. The family described here has a heterozygous novel loss of function variant. Detailed analysis of WGS data combined with family segregation studies concluded that although Asp1672Asn has a high population frequency, it is the most likely second pathogenic variant in our family. This supports the hypothesis that this is a hypomorphic allele, which, in combination with a loss of function pathogenic variant, leads to Knobloch syndrome.To our knowledge, this is the first time that WGS has been used to confirm a molecular diagnosis of Knobloch syndrome in this way and has provided further insight into the molecular mechanisms in this rare disorder.

Acute Angle Closure in Knobloch Syndrome.

We report cases of acute angle closure in 2 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 2 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.

Knobloch Syndrome Associated with Novel COL18A1 Variants in Chinese Population.

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.

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

PURPOSE: Knobloch syndrome is a rare, recessively inherited disorder classically characterized by high myopia, retinal detachment, and occipital encephalocele. Our aim is to report the clinical and genetic findings of four Israeli children affected by Knobloch syndrome. METHODS: Retrospective study of four patients diagnosed with Knobloch syndrome, who underwent full ophthalmic examination, electroretinography, and neuroradiologic imaging. Genetic analysis included whole exome sequencing (WES) and Sanger sequencing. RESULTS: The four patients included in this study had high myopia and nystagmus at presentation. Ocular findings included vitreous syneresis, macular atrophy, macular coloboma, and retinal detachment. One child had iris transillumination defects and an albinotic fundus, initially leading to an erroneous clinical diagnosis of albinism. Electroretinography revealed a marked cone-rod pattern of dysfunction in all four children. Brain imaging demonstrated none to severe occipital pathology. Cutaneous scalp changes were present in three patients. WES analysis, confirmed by Sanger sequencing revealed COL18A1 biallelic null mutations in all affected individuals, consistent with autosomal recessive inheritance. CONCLUSIONS: This report describes variable features in patients with Knobloch syndrome, including marked lack of eye pigment similar to albinism in one child, macular coloboma in two children as well as advanced cone-rod dysfunction in all children. One patient had normal neuroradiologic findings, emphasizing that some affected individuals have isolated ocular disease. Awareness of this syndrome, with its variable phenotype may aid early diagnosis, monitoring for potential complications, and providing appropriate genetic counseling.

Collagen XVIII mutation in Knobloch syndrome with acute lymphoblastic leukemia.

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.

Stickler syndrome in Pierre-Robin sequence prenatal ultrasonographic diagnosis and postnatal therapy: two cases report.

The Pierre-Robin Syndrome (PRS) is a rare congenital abnormality, with an approximately 1/30,000 estimated rate, characterized by the presence of the combination of mandibular hypoplasia (micrognathia or small jaw), glossoptosis (retrusion of the tongue into the pharyngeal airway) and, often, a posterior cleft of the secondary palate. It may be an isolated occurrence or part of a more complex syndrome and it is associated with long-term respiratory, nutritional, and developmental difficulties. Stickler syndrome (SS) is a rare autosomal dominant connective tissue disorder estimated to affect approximately 1/7500 newborns. It is diagnosed clinically and, at present, there is no consensus on a minimal clinical diagnostic criterion. The most frequent diagnosis in patients with syndromic Pierre Robin sequence is Stickler syndrome, which may be complicated by congenital high myopia and substantial risk of retinal detachment. However, cases of Stickler syndrome with probable visual complications are rarely identified among this group of patients by members of the cleft team. The patient had an acute unilateral hydrops, with a monolateral keratoconus. The ocular abnormalities included: severe myopia, abnormalities of the vitreous, and high risk of retinal detachment (with subsequent blindness). We report two extremely rare cases of prenatal diagnosis of PRS and SS, prematurely identified by prenatal ultrasonography and successively managed by oculists ophthalmogists.