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Knobloch: for professionals


Overview

IncidenceRare, less than 100 cases in literature
InheritanceAutosomal recessive (type 1), autosomal dominant (type 2)
Genes Involved (OMIM No.)COL18A1 (#267750), PAK2 (#618458)
SymptomsReduced vision
Ocular FeaturesMyopia
Vitreoretinal degeneration
Retinal detachment
Macular abnormalities
Lens subluxation
CataractsStrabismus
Systemic FeaturesOccipital skull defects including scaphocephaly and encephalocele
Facial Dysmorphism
Key InvestigationsVisual acuity
Slit lamp examination
Fundoscopy
Ultra-wide field imaging (Optos)
Fundus auto-fluorescence
OCT Ultrasound B-scan
ERG
Genetic TestingRetinal disease gene panel (either through targeted panel, whole exome or whole genome sequencing)
ManagementOcular: Prophylactic retinopexy if indicated
Therapies under ResearchNatural history studies Prevention of retinal detachment studies

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Clinical phenotype

Knobloch syndrome typically presents with a combination of ocular features such as high myopia, vitreoretinal degeneration and craniofacial abnormalities. There are 3 types of Knobloch syndrome which present similarly but can be differentiated by their genetic variation.

Presenting features

Ocular:

    • High myopia (usually more than -10 dioptres)
    • Vitreo-retinal degeneration with severe atrophic changes in the retinal pigment epithelium, prominent choroidal vessels, macular atrophic lesions (with or without a “punched out” appearance), and white fibrillar vitreous condensations.
    • Retinal detachment
    • Lens subluxation
    • Cataracts
    • Strabismus

    Cranial:

    • Craniosynostosis leading scaphocephaly
    • Encephalocele
    • Facial Dysmorphism, including prominent forehead, hypertelorism, and a broad nasal bridge

    Central nervous system:

    • CNS features may be mild or absent.
    • Features can include hydrocephalus, cerebellar hypoplasia, Chiari malformation, developmental delay and cognitive impairment.

    Genetics

    1. Knobloch Syndrome type 1
      • Gene: COL18A1
      • OMIM No.: #267750
      • Inheritance pattern: Autosomal recessive
      • Function: COL18A1 encodes for collagen XVIII, an extracellular matrix protein important for basement membrane structure and angiogenesis regulation. Type XVIII collagen is found in many ocular structures including Bruch’s membrane, the lens capsule, the basement membrane of the iris, the aqueous humor, vitreous, and retina.
    2. Knobloch Syndrome type 2
      • Gene: PAK2
      • OMIM No.: #618458
      • Inheritance pattern: Autosomal dominant
      • Function: PAK2 encodes p21-activated kinase 2, a crucial regulator of cellular processes such as cytoskeletal dynamics, cell motility, and cell proliferation. In the eye PAK2 is involved in cell interactions, the blood-retina barrier and signalling pathways in retinal development.
      • There has been a suggestion that variation in PAK2 are associated with Knobloch, but needs further investigation as this has only been identified 1 family.
    3. Knobloch Syndrome type 3
      • Has been mapped to 17q11.2 but the gene has not yet been identified.

    Further information about each gene can be found on OMIM and Medline Plus.

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    Key investigations

    Ocular

    1. Slit lamp examination and fundoscopy: may identify diffuse severe chorioretinal atrophic changes with prominent choroidal vessel show, retinal colobomas, macular atrophic lesions with or without a punched-out appearance, macular hypoplasia and white fibrillar vitreous condensations. Smooth irides and posterior perinuclear lens opacity are also common features.
    2. Ultra-wide field imaging (Optos): visualisation of the peripheral retina to assess for tears or detachment.
    3. Refraction: usually high myopia greater than -10 dioptres.
    4. Fundus auto-fluorescence: used to assess the health of the retina.
    5. OCT: areas of outer retinal loss corresponding to retinal thinning, and macular pseudocoloboma.
    6. Ultrasound B-scan: measure axial length as patients are typically myopic.
    7. ERG: will show retinal dysfunction, as patients may not present with symptoms other than high myopia.
    8. Genetic testing: Knobloch panel if high suspicion

    Systemic

    1. Assessment by developmental paediatricians: investigate developmental delay
    2. Neurological assessment: investigate cranial or CNS abnormalities
    3. Cranial imaging: identification of cranial abnormalities such as craniosynostosis and encephalocele.

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    Diagnosis

    Diagnosis of Knobloch syndrome is based on the presence of the classical triad of high myopia, vitreoretinal degeneration, and occipital findings (ranging from scalp defect to encephalocele) with infantile onset. This can then be confirmed by the presence of COL18A1 mutations.

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    Differential diagnoses

    The differential diagnosis should include the following syndromes with or without encephalocele: Stickler, Wagner, Marshall, Meckel, and Walker-Warburg syndromes.

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    Management

    The management of Knobloch syndrome focuses on multidisciplinary care to address ocular, cranial, and neurological aspects of the condition

    Ocular

    1. Regular ophthalmology assessment: correct refractive errors and assess for retinal tears.
    2. Vitreoretinal surgery: high risk patients may be offered prophylactic retinopexy, cryopexy or scleral buckle placement. Patients who present with retinal detachment should have surgery to repair this.
    3. Anterior chamber surgery: Lens extraction/replacement may be indicated for ectopia lentis or cataracts, but there is a substantially increased risk of capsular rupture (likely due to modified collagen affecting the integrity of the lens capsule and zonules).
    4. Education: Patients should be educated about the risks and symptoms of retinal detachment to enable early intervention if this occurs. Patients should also be advised to wear eye protection during contact sports.
    5. Low vision rehabilitation: Providing visual aids and adaptive techniques to optimize visual function.

    Systemic

    1. Follow-up with Neurology/Neurosurgery:
      • Comprehensive neurological assessments and interventions to address developmental delays and cognitive impairments.
      • Patients may require surgery to correct cranial abnormalities.

    Family management and counselling

    Patients and families require genetic counselling and can seek advice for family planning including prenatal testing and preimplantation genetic diagnosis.

    Emotional and social support

    Eye Clinic Liaison Officers (ECLOs) act as an initial point of contact for newly diagnosed patients and their parents in clinic. They provide emotional and practical support to help patients and parents deal with the diagnosis and maintain independence. They work closely with the local council’s sensory support team and are able to advise on the broad range of services provided, such as visual rehabilitation, home assessment, work and access to qualified teachers for children with visual impairment (QTVI) among other services.

    Related links

    Referral to a specialist centre

    In the UK, patients should be referred to their local genomic ophthalmology (if available) or clinical genetics services to receive a more comprehensive genetic management of their conditions (genetic testing and genetic counselling) and having the opportunity to participate in clinical research.

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    Current research

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    Further information and support

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    References

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    Updated on June 2, 2024
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