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.

[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 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.

Optical Coherence Tomography in Knobloch Syndrome.

BACKGROUND AND OBJECTIVE: 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). PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSION: 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.].

Retinal Detachment After Cyclophotocoagulation in a Child with Knobloch Syndrome.

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.

Optical coherence tomography findings and successful repair of retina detachment in Knobloch syndrome.

A 7-year-old Afghani girl was referred to the retina clinic of Massachusetts Eye and Ear for a chronic-appearing, macula-off retinal detachment in the left eye. On examination, best-corrected visual acuity was 20/400 in the right eye and 20/800 in the left eye. She had bilateral horizontal nystagmus. Ophthalmoscopy revealed prominent choroidal vessels, chorioretinal atrophy in the macular area, attenuated retinal vasculature, and pale optic discs bilaterally. Spectral domain optical coherence tomography demonstrated atrophy of the choriocapillaris and the retinal pigment epithelium, retinal thinning, and abnormal foveal contour. In the right eye, findings were reminiscent of dome shape maculopathy with an adjacent lesion suspicious for inactive choroidal neovascularization. A suspected diagnosis of Knobloch syndrome was confirmed by genetic testing, which showed a homozygous variant in exon 33 of the COL18A1 gene defined as c.3213dupC. She underwent cryotherapy and scleral buckling surgery in the left eye and remained attached bilaterally at 3 years' follow-up, with progressive myopia and best-corrected visual acuity of 20/100 in the right eye and 20/125 in the left eye.

Avascular Retinal Findings in a Child With Achondroplasia.

The authors present clinical and angiographic findings in a 12-year-old girl with achondroplasia who presented with bilateral retinal peripheral nonperfusion and unilateral rhegmatogenous retinal detachment, which has not been previously described in achondroplasia. This report contributes incremental knowledge regarding aberrant retinal vascular phenomena observed in pediatric disease states and implicates the possible role of mutations in the FGFR3 gene in peripheral vascular abnormalities. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:272-274.].

Collagen XVIII in tissue homeostasis and dysregulation - Lessons learned from model organisms and human patients.

Collagen XVIII is a ubiquitous basement membrane (BM) proteoglycan produced in three tissue-specific isoforms that differ in their N-terminal non-collagenous sequences, but share collagenous and C-terminal non-collagenous domains. The collagenous domain provides flexibility to the large collagen XVIII molecules on account of multiple interruptions in collagenous sequences. Each isoform has a complex multi-domain structure that endows it with an ability to perform various biological functions. The long isoform contains a frizzled-like (Fz) domain with Wnt-inhibiting activity and a unique domain of unknown function (DUF959), which is also present in the medium isoform. All three isoforms share an N-terminal laminin-G-like/thrombospondin-1 sequence whose specific functions still remain unconfirmed. The proteoglycan nature of the isoforms further increases the functional diversity of collagen XVIII. An anti-angiogenic domain termed endostatin resides in the C-terminus of collagen XVIII and is proteolytically cleaved from the parental molecule during the BM breakdown for example in the process of tumour progression. Recombinant endostatin can efficiently reduce tumour angiogenesis and growth in experimental models by inhibiting endothelial cell migration and proliferation or by inducing their death, but its efficacy against human cancers is still a subject of debate. Mutations in the COL18A1 gene result in Knobloch syndrome, a genetic disorder characterised mainly by severe eye defects and encephalocele and, occasionally, other symptoms. Studies with gene-modified mice have elucidated some aspects of this rare disease, highlighting in particular the importance of collagen XVIII in the development of the eye. Research with model organisms have also helped in determining other structural and biological functions of collagen XVIII, such as its requirement in the maintenance of BM integrity and its emerging roles in regulating cell survival, stem or progenitor cell maintenance and differentiation and inflammation. In this review, we summarise current knowledge on the properties and endogenous functions of collagen XVIII in normal situations and tissue dysregulation. When data is available, we discuss the functions of the distinct isoforms and their specific domains.

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.

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.

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.

High incidence of autosomal recessive nonsyndromal congenital retinal nonattachment (NCRNA) in an Iranian founding population.

In an isolated and founding Iranian population the prevalence of congenital total blindness is 1.1%. Clinical findings such as lack of perception of light, massive retrolental mass, shallow anterior chamber and nystagmus, in otherwise normal individuals, correspond to nonsyndromal congenital retinal nonattachment. To determine the inheritance of this disease we constructed an extensive nine-generation pedigree of the affected kindred living in the Iranian founding population. The pedigree, which includes 42 patients from 25 sibships, clearly suggests autosomal recessive inheritance. To verify the inheritance, we compared the average coefficient of inbreeding (F) of the affected sibships with that of the control sibships, calculated the patients' sex ratio, and also compared the observed relative frequency of the disease with its expected relative frequencies for different modes of inheritance. The patients' average F value is significantly greater than that of the controls (P < 0.001). The sex ratio of the patients is close to unity and the observed relative frequency of the disease is close to that of an autosomal recessive trait. All these findings strongly support autosomal recessive transmission of this disease.

Unilateral benign medulloepithelioma associated with bilateral retinal detachment.

A two-month-old girl presented with a unilateral benign cystic medulloepithelioma from the ciliary body associated with bilateral retinal non-attachment. The authors discuss the histopathologic findings and the pathogenesis of the congenital retinal non-attachment: are these incidental occurrences or do they arise from a common pathogenetic mechanism?

Vitreo-retinopatia familial exsudativa: relato de uma família / Familial exudative vitreoretinopathy: report of a family

Os aa. apresentam 6 casos de vítreo-retinopatia familial exsudativa enfatizando os principais aspectos clínicos, oftalmoscópicos, angiográficos e ecográficos que permitiram o diagnóstico desta rara patologia. Fazem uma revisäo do assunto e concluem ser esta patologia de diagnótico fácil se analisada em conjunto, porém, em casos isolados o diagnóstico diferencial deve ser feito com a fibroplasia retrocristaliana e Doença de Coats, devendo sempre ser lembrada frente a um caso de leucocoria na infância

Cutis marmorata telangiectatica congenita associated with bilateral congenital retinal detachment.

Cutis marmorata telangiectatica congenita is a rare congenital vascular disorder of the skin, characterized by persistent telangiectasia of the cutaneous blood vessels often associated with cutaneous ulcers. The only previously recognized ophthalmic association with this condition has been rare instances of unilateral congenital open angle glaucoma. The authors report their observations in a child in whom this cutaneous disorder was associated with congenital bilateral total retinal detachments and secondary neovascular glaucoma. The retinal detachments produced bilateral leukocoria simulating retinoblastoma. The cutaneous disorder and the ocular findings were confirmed histopathologically.

The pathogenesis of retinal detachment with morning glory disc and optic pit.

A child with nonrhegmatogenous retinal detachment associated with morning glory disc underwent first a vitrectomy and then, some months later, an optic nerve sheath fenestration. The latter procedure led to retinal reattachment. It also produced a biopsy specimen that confirmed the perineural herniation of poorly differentiated retinal tissue in this condition, similar to that in congenital pit of the optic nerve. It demonstrated continuity of the vitreous cavity with the perineural space, both histologically and by the fact that gas injected through the pars plana into the vitreous cavity bubbled out the window in the optic nerve sheath. The authors suggest that morning glory disc and optic pit share similar anatomic features, differing more in degree than in kind, and that the porous nature of the poorly differentiated tissue herniated around the optic nerve into the subarachnoid space in these conditions makes several sources of subretinal fluid possible.

Congenital blindness with ocular developmental anomalies, including retinal dysplasia, in Doberman Pinscher dogs.

Hereditary, congenital blindness was studied in 15 Doberman Pinscher pups. The eyes were smaller than normal, and there was complete absence of the anterior chamber, aphakia, retinal detachment, and dysplasia as well as an irregular swelling and partial depigmentation of the retinal pigment epithelial cells. It was concluded that the condition was inherited as a recessive, autosomal trait.