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A rare systemic disorder characterized by vitreoretinal and macular degeneration, as well as occipital encephalocele.
ORPHA:1571Classification level: Disorder
The exact prevalence of Knobloch syndrome (KS) is unknown but less than 100 cases have been reported in the literature so far.
KS is characterized by early-onset severe myopia (usually becoming apparent in the first year of life), vitreoretinal degeneration with retinal detachment, macular abnormalities, and midline encephalocele (mainly in the occipital region). Predisposition to hydrocephalus is frequent. Ocular abnormalities vary and may include congenital cataract, iris abnormalities, and lens subluxation. Numerous extraocular abnormalities have been described: a single umbilical artery, pyloric stenosis, a flat nasal bridge, midface hypoplasia, bilateral epicanthic folds, abnormal lymphatic vessels in the lung, patent ductus arteriosus, cardiac dextroversion, generalized hyperextensibility of the joints, unusual palmar creases, and unilateral duplication of the renal collecting system. Structural brain defects, epilepsy and cognitive abnormalities have also been frequently reported. However, the full phenotypic spectrum is yet to be defined.
The syndrome is caused by inactivating mutations in the collagen XVIII/endostatin gene (COL18A1; 21q22.3) which is highly expressed throughout the human eye. As a mutational hot-spot the c.4063_4064delCT is the most common mutation detected in Knobloch syndrome to date. İn one reported family the locus remains unmapped.
Diagnosis is based on ocular abnormalities and occipital encephalocele (detected by computed tomography and magnetic resonance imaging). Magnetic resonance imaging of the brain would also help to detect associated developmental brain abnormalities. Sequencing of (COL18A1) gene.
The differential diagnosis should include the following syndromes with or without encephalocele: Stickler, Wagner, Marshall, Meckel, and Walker-Warburg syndromes.
KS is inherited as an autosomal recessive trait. Genetic counseling should be offered to individuals with a causative mutation, informing them of a 25% risk to transmit it to their offspring.
Management and treatment
Management of the ocular manifestations requires referral to an ophthalmologist specialist in retinopathies. Treatment modalities include retinal reattachment surgery, prophylactic treatment of the vitreoretinal pathology and photodynamic therapy. Encephalocele should be treated by surgical methods, aiming to restore normal anatomy with repair of the defective dura, bone and skin.
The eye findings in KS are severe and progressive, and regularly lead to bilateral blindness at a young age.