Molecular and Clinical Findings in Patients With Knobloch Syndrome

Abstract

IMPORTANCE Knobloch syndrome is a rare, recessively inherited disorder classically characterized by high myopia, retinal detachment, and occipital encephalocele, but it is now known to have an increasingly variable phenotype. There is a lack of reported electrophysiologic data, and some key clinical features have yet to be described.OBJECTIVE To expand on current clinical, electrophysiologic, and molecular genetic findings in Knobloch syndrome. DESIGN, SETTING, AND PARTICIPANTSTwelve patients from 7 families underwent full ophthalmic examination and retinal imaging. Further investigations included electroretinography and neuroradiologic imaging. Bidirectional Sanger sequencing of COL18A1 was performed with segregation on available relatives. The study was conducted from July 4, 2013, to October 5, 2015. Data analysis was performed from May 20, 2014, to November 3, 2015. MAIN OUTCOMES AND MEASURESResults of ophthalmic and neuroradiologic assessment and sequence analysis of COL18A1. RESULTSOf the 12 patients (6 males; mean age at last review, 16 years [range, 2-38 years]), all had high myopia in at least 1 eye and severely reduced vision. A sibling pair had unilateral high myopia in their right eyes and near emmetropia in their left eyes from infancy. Anterior segment abnormalities included absent iris crypts, iris transillumination, lens subluxation, and cataract. Two patients with iris transillumination had glaucoma. Fundus characteristics included abnormal collapsed vitreous, macular atrophy, and a tesselated fundus. Five patients had previous retinal detachment. Electroretinography revealed a cone-rod pattern of dysfunction in 8 patients, was severely reduced or undetectable in 2 patients, and demonstrated cone-rod dysfunction in 1 eye with undetectable responses in the other eye in 2 patients. Radiologic imaging demonstrated occipital encephalocele or meningocele in 3 patients, occipital skull defects in 4 patients, minor occipital changes in 2 patients, and no abnormalities in 2 patients. Cutaneous scalp changes were present in 5 patients. Systemic associations were identified in 8 patients, including learning difficulties, epilepsy, and congenital renal abnormalities. Biallelic mutations including 2 likely novel mutations in COL18A1, were identified in 6 families that were consistent with autosomal recessive inheritance with a single mutation identified in a family with 2 affected children. CONCLUSIONS AND RELEVANCEThis report describes new features in patients with Knobloch syndrome, including pigment dispersion syndrome and glaucoma as well as cone-rod dysfunction on electroretinography. Two patients had normal neuroradiologic findings, emphasizing that some affected individuals have isolated ocular disease. Awareness of the ocular phenotype may aid early diagnosis, appropriate genetic counseling, and monitoring for potential complications.

Knobloch syndrome in a patient from Chile

“…Our patient presents with early onset high myopia and other characteristic eye findings of KS, along with a focal occipital alopecic lesion (OAL). Diffuse chorioretinal atrophy and abnormal vitreous condensations like hers have been described as key features of vitreoretinal degeneration (Hull et al, 2016). Variable presentations include abnormalities of the anterior segment and an asymmetric involvement of eye globes (Corbett et al, 2017;Hull et al, 2016), both of which are also observed in our patient.…”

“…Diffuse chorioretinal atrophy and abnormal vitreous condensations like hers have been described as key features of vitreoretinal degeneration (Hull et al, 2016). Variable presentations include abnormalities of the anterior segment and an asymmetric involvement of eye globes (Corbett et al, 2017;Hull et al, 2016), both of which are also observed in our patient. High myopia usually presents in infancy as nystagmus and/or strabismus and can eventually lead to a collapsed abnormal vitreous, glaucoma, ectopia and retinal detachment during childhood.…”

“…High myopia usually presents in infancy as nystagmus and/or strabismus and can eventually lead to a collapsed abnormal vitreous, glaucoma, ectopia and retinal detachment during childhood. Pigmentary changes such as retinal epithelium and cone-rod dysfunction have also been reported (Hull et al, 2016). Usually all eye abnormalities progress to bilateral blindness (Suzuki et al, 2002), and our patient is considered "legally disabled" in Chile due to her progressive myopia, with no history of retinal detachment.…”

“…Skull involvement might manifest as just focal scalp alopecia without underlying skull defect. There might be additional brain malformations (polymicrogiria, cerebral atrophy, pachygiria and heterotopia), intellectual disability (seen in approximately 20% of patients) and epilepsy (in 16.7% of patients) (Corbett et al, 2017;Hull et al, 2016). Involvement of other organs such as kidney and lungs has been inconsistently reported in some cases (Hull et al, 2016;Seaver, Joffe, Spark, Smith, & Hoyme, 1993).…”

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

“…Additional ocular manifestations include white fibrillar vitreous condensation, diffuse severe vitreoretinal atrophy, persistent fetal vasculature, distinct macular atrophy, cone-rod dysfunction, electroretinogram diminution, retinal pigment epithelial atrophy, prominent choroidal vessels, smooth (cryptless) irides, zonular weakness with temporal lens subluxation, pigment dispersion syndrome and associated glaucoma, and some degree of cataract. 2 Neurologic deficits include epilepsy, developmental delay, and midline cranial defects. Occipital defects may range from bony defects to an encephalocele.…”