Knobloch syndrome (OMIM 267750) is a rare genetic disorder first described by Knobloch and Layer in 1971. It is characterized by the triad of high myopia, vitreoretinal degeneration, and occipital skull defects, with high phenotypic variability.
The causative gene is COL18A1 located on the long arm of chromosome 21 (21q22.3). Autosomal recessive mutations lead to abnormal production of type XVIII collagen 1). Genetic mutations cause widespread impairment in the development of ocular and neural tissues.
Epidemiologically, at least 48 families and 90 cases have been reported since the initial description, with no specific ethnic predilection; cases have been identified sporadically across many ethnic groups.
It follows an autosomal recessive inheritance pattern. Parents who carry a single mutation (carriers) are usually asymptomatic, but their child has a 25% (1 in 4) risk of developing the syndrome.
Ocular abnormalities are present in all patients, and most develop before 1 year of age.
High myopia (usually ≥10 diopters) and vitreoretinal degeneration are the main findings.
Fundus Findings
Chorioretinal atrophy: Extensive and severe chorioretinal atrophic changes with prominent visibility of choroidal vessels.
Macular abnormalities: Punched-out macular atrophic lesions, macular hypoplasia, and macular pseudocoloboma.
Others: Retinal vascular narrowing, optic disc pallor, and white fibrous vitreous condensation.
Anterior Segment Findings
Iris abnormalities: Smooth iris, absence of iris crypts, iris transillumination defects, and poor pupillary dilation.
Lens abnormalities: Lens subluxation, posterior nuclear cataract, and persistent pupillary membrane.
Others: Band keratopathy, glaucoma, and pigment dispersion syndrome.
Electrophysiology and Imaging
Electroretinogram: Dysfunction of both cones and rods is observed.
OCT: Loss of foveal depression, disruption of outer retinal layers, severe retinal thinning, and macular pseudocoloboma.
FAF: Highlights areas of RPE damage more clearly.
Occipital bone defects are the most characteristic neurological finding. In a few cases, neuroimaging reveals polymicrogyria, subependymal nodules, and cerebellar vermis atrophy. CNS involvement may be associated with cognitive developmental delay.
It can be diagnosed in some cases. Occipital bone defects are characteristic but may be absent. Clinical diagnosis is possible based on a combination of characteristic ocular findings (smooth iris, ectopia lentis, characteristic vitreoretinal degeneration), and confirmed by COL18A1 genetic testing.
Knobloch syndrome is caused by autosomal recessive mutations in the COL18A1 gene (21q22.3)1). This gene contains 43 exons and produces three different isoforms in humans. At least 20 polymorphic changes have been identified in this syndrome.
Additional studies have suggested the ADAMTS18 gene as a novel causative locus in Knobloch syndrome.
The diagnosis of Knobloch syndrome is based on the presence of the following three signs:
The combination of smooth iris, ectopia lentis, and characteristic vitreoretinal degeneration is suggested to be pathognomonic for Knobloch syndrome. Diagnosis may be possible by ophthalmic examination alone even without occipital bone defects.
| Test | Main findings |
|---|---|
| OCT | Loss of foveal depression, outer retinal loss, retinal thinning |
| FAF | Visualization of RPE damage areas |
| Electroretinogram | Cone and rod dysfunction |
| Genetic testing | Confirmation of COL18A1 mutation |
Confirmation of a COL18A1 gene mutation is most useful for a definitive diagnosis. Immunohistochemical evaluation of type XVIII collagen and measurement of endostatin by ELISA are also used for diagnosis.
Differentiation from other congenital vitreoretinopathies is important.
| Disease | Distinguishing features |
|---|---|
| Stickler syndrome | Radial perivascular degeneration, no macular atrophy, good visual acuity, midface hypoplasia |
| ADVIRC | Well-demarcated peripheral degeneration, anterior segment dysgenesis, autosomal dominant |
Treatment of Knobloch syndrome is symptomatic, aiming to address individual symptoms of both ocular and occipital bone defects. No curative treatment has been established.
As an autosomal recessive disorder, both parents are often carriers. The risk for each offspring to develop the syndrome is 25%. Genetic counseling for affected patients and families is important.
Ocular abnormalities are severe, progressive, and irreversible, usually leading to bilateral blindness. Retinal detachment occurs in nearly all cases despite surgical intervention or prophylactic cryotherapy. Retinal detachment tends to occur in the late teens or later.
Ocular abnormalities are severe, progressive, and irreversible, usually leading to bilateral blindness. Retinal detachment occurs in nearly all cases and is often difficult to prevent even with surgical intervention. Early diagnosis and regular ophthalmic follow-up are important for maintaining visual function.
Mutations in the COL18A1 gene lead to abnormal production or absence of type XVIII collagen1). Type XVIII collagen is widely distributed in many ocular tissues, including Bruch’s membrane, the lens capsule, the basement membrane of the iris, aqueous humor, vitreous body, and retina.
Basement Membrane Maintenance
Structural role: Maintains the structural integrity of the epithelial basement membrane (BM) in ocular tissues.
Affected tissues: Involved in the stability of many ocular structures such as Bruch’s membrane, lens capsule, and iris basement membrane.
Angiogenesis Regulation
Anti-angiogenesis: The C-terminal fragment endostatin acts as a potent inhibitor of angiogenesis.
Clinical significance: Lack of type XVIII collagen impairs normal ocular and neurovascular development.
Signal Transduction
Wnt/β-catenin signaling: Involved in the Wnt/β-catenin signaling pathway, regulating neural and ocular development.
Impact on development: Disruption of signaling is thought to lead to occipital bone defects and abnormal formation of ocular tissues.
COL18A1 mutations result in loss of structural and functional integrity of ocular tissues, leading to ocular pathologies such as high myopia, vitreoretinal degeneration, and macular pseudocoloboma. Concurrently, structural support of basement membranes in neural tissue development is compromised, manifesting as neurosurgical findings such as occipital bone defects and encephalocele. Mutations affecting extracellular matrix proteins, vitreous structure, and scleral remodeling are thought to impair the biomechanical stability of the posterior pole, leading to axial elongation and progressive high myopia1).
