Knobloch syndrome is a rare genetic disorder classically defined by a triad of occipital defect, high myopia, and vitreoretinal degeneration with a high risk for retinal detachment. Additional ocular features include ectopia lentis, smooth iris, nystagmus, high myopia, and a tessellated fundus with geographic macular atrophy, whereas persistent fetal vasculature, glaucoma, and iris transillumination have been reported in isolated reports that may have occurred by chance.1–3 The largest series describing the clinical features of Knobloch syndrome reported that five of the 12 patients had previous retinal detachment.3 Associated occipital abnormalities may range from an encephalocele to small areas of occipital alopecia or cutis aplasia.4 However, patients may also have a normal occiput.1 Less common systemic features include developmental delay, epilepsy, structural brain abnormalities, lung hypoplasia, cardiac dextroversion, generalized hyperextensibility of the joints, duplication of the renal collecting system, abnormal palmar crease, flat nasal bridge, high arched palate, micrognathnia, and midfacial hypoplasia.4 Knobloch syndrome is an autosomal recessive disorder resulting from mutations in the COL18A1 gene on chromosome 21q22.3, which encodes for the alpha-1 subunit of collagen 18.4–6
There are reports examining optical coherence tomography (OCT) findings in patients with Knobloch syndrome.3,9–11 The aim of the present study is to further characterize the morphological changes of the retina and choroid to facilitate diagnosis of Knobloch syndrome.
Patients and Methods
This study was approved by the Wills Eye Hospital institutional review board as an observational, retrospective case series of patients diagnosed with Knobloch syndrome. This study followed the tenets of the Declaration of Helsinki and the Health Insurance Portability and Accountability Act. All patients underwent OCT testing as part of their routine clinical care from March 2011 through February 2016 at the Ocular Genetics Program at Wills Eye Hospital. The diagnosis of Knobloch syndrome was made on the basis of high myopia, characteristic fundus appearance (macular hypoplasia, macular geographic atrophy, fundus tessellation out of proportion to myopia, and pattern of choroidal vessels radiating outward from the geographic area), and the presence of occipital scalp or skull abnormalities with or without featureless iridies and/or ectopia lentis. When possible, the diagnosis was confirmed by the detection of COL18A1 mutations. The patient's medical record was reviewed to identify the ages, ophthalmic findings, systemic findings, and results of other testing.
Spectral-domain OCT was done on all patients either awake (Spectralis; Heidelberg Engineering, Heidelberg, Germany) or under general anesthesia (Bioptigen, Morrisville, NC). No patient underwent testing or general anesthesia solely for the purpose of this study. For patients who had OCT testing while awake, subfoveal retinal and choroidal thickness was measured using the standard software provided by the manufacturer. For patients who had OCT testing under anesthesia, retinal and choroidal thicknesses were manually measured using the caliper of the Bioptigen instrument. As patients characteristically had geographic atrophy of the macula, this thinning allowed for full choroidal visualization without enhanced depth technology. OCT images that demonstrated macular retinal detachment or insufficient quality were excluded. Axial length (AL) was measured in awake patients by partial coherence interferometry (Zeiss IOLMaster; Carl Zeiss, Jena, Germany) or under anesthesia by immersion A-scan ultrasonography (Ellex I3; Ellex, Eden Prairie, MN). Indocyanine green angiography and fluorescein angiography were not performed. Historical normative age-matched values from the medical literature were used for comparison. Descriptive statistics of mean, range, median, and standard deviation were calculated.
During a 5-year period, five patients with Knobloch syndrome had OCT testing. Demographic and clinical features are presented in Table 1. Two eyes (right eye of K3 and right eye of K5) were excluded due to chronic retinal detachment, resulting in eight total eyes included in analysis. The mean patient age was 8.7 years (median: 10 months; range: 3 months to 39 years). All patients had the onset of ocular signs of reduced vision (nystagmus, poor acuity) or high myopia detected prior to 4 months of age. Four patients demonstrated occipital defects (Figure 1). Two patients had confirmed biallelic mutations in the COL18A1 gene, one patient had a heterozygous COL18A1 mutation, and the remaining two patients did not have DNA testing. Additional clinical features observed include one patient with otitis media and constipation; one patient with dry skin; and one patient with high arched palate, mild arachnodactyly, and pectus carinatum. No patient had a history of premature birth.
Demographic Data and Clinical Features
Occiput abnormalities and smooth irides in patients with Knobloch syndrome. (Top, left) Patient K1 with cutaneous cysts of the occipital scalp. (Top, right) Patient K3 with occipital focal linear alopecia which was overlying a dermal sinus. (Bottom) Anterior segment photos show smooth irides in Patient K4 (left) and Patient K5 (right).
Best-corrected visual acuity, cycloplegic refraction, AL, anterior segment examination, funduscopic examination, and OCT findings of the studied eyes are presented in Tables 2 and 3. The mean spherical equivalent in six eyes (excluding two aphakic eyes) was −15.75 diopters (D) (standard deviation [SD] = 5.20; range: −11.00 D to −22.0 D). The mean AL in all eight eyes was 26.38 mm (SD = 1.69; range: 22.7 mm to 28.31 mm). In patient K2, both eyes were aphakic due to lens removal at 10 years old for ectopia lentis. No iris transillumination, cataract, or glaucoma were noted in any eyes.
Optical Coherence Tomography Findings
Representative macular OCT images, one from each patient, are shown in Figure 2. Common findings included abnormally thin maculas, poor retinal lamination with the outer segment and photoreceptors being the most affected, retinal pigment epithelium (RPE) atrophy or attenuation, and epiretinal membrane (ERM) with vitreoretinal traction and peripapillary retinoschisis (Figure 3). Although excluded from the study due to chronic retinal detachment, the right eye of patient K3 also had abnormal vitreoretinal traction and retinoschisis. The retinal foveal thickness could be measured in a total of five eyes from four patients, with a mean of 113.4 μm (SD = 53.2 μm; range: 66 μm to 203 μm).
Fundus photographs and macular optical coherence tomography (OCT) images. (First row, left) Right eye (OD) of Patient K1. (First row, right) OD of Patient K2. (Second row, left) Left eye (OS) of Patient K3. (Third row, left) OD of Patient K4. (Third row, right) OS of Patient K5. Fundus photographs show macular hypoplasia, macular geographic atrophy, a tessellated fundus and optic nerve atrophy. OCT images show thin retinas with loss of retinal lamination, questionable rudimentary foveal pits (arrows), myopic choroidal thinning, and pachychoroid with dilated choroidal vessels (arrowheads).
Optical coherence tomography images of retinoschisis. (Left) Right eye (OD) of Patient K3 with retinal detachment and retinoschisis overlying dilated choroidal vessels and pachychoroid. (Right) OD of Patient K4 with abnormal epiretinal membranes, and retinoschisis. (The vitreoretinal traction is not clearly visible in these images).
Qualitative evaluation of the choroid showed three eyes with an atrophied choroid and choroidal vessels, two eyes with normal appearing choroidal vessels and choroidal thinning, and three eyes with dilated choroidal vessels and pachychoroid. The choroidal thickness below the putative area of the foveal pit was measured in four eyes from three patients, with a mean of 168.5 μm (SD = 43.1 μm; range: 119 μm to 207 μm).
In the current report, we aimed to further characterize the OCT findings in this syndrome to potentially facilitate diagnosis and management in this syndrome, which is particularly important in view of the high risk for retinal detachment that requires periodic screening.
Our patients demonstrated several typical features of Knobloch syndrome including the characteristic fundus appearance, smooth irides, occipital defects, and vitreoretinal degeneration with retinal detachment. We also observed the previously unreported finding of posterior embryotoxon in two patients. Posterior embryotoxon can be found in the general population12 and it is difficult to discern if this is coincidence or a feature of Knobloch syndrome. Likewise, three patients had previously unreported systemic features including hearing loss, dry skin, otitis media, and constipation, which may or may not be related to the Knobloch syndrome diagnosis but have a high likelihood of being coincidental. DNA confirmation of the diagnosis was only available for three patients. It has been suggested, however, that clinical diagnosis is sufficient.4 The absence of a second mutated allele in one patient is consistent with prior reports where a lack of protein expression was detected despite the inability to find the second allele.2 In addition, it has been suggested that the ophthalmic features alone may be diagnostic of Knobloch syndrome.1 The presence of an occipital soft mass in patient K2 strengthens this diagnosis. Other barriers to genetic testing included insurance coverage and cost.
The retinal and choroidal thicknesses in our series (mean: 114.25 μm and 168.5 μm, respectively) are both thin compared to normal eyes of children (218 μm ± 15 μm and 330 μm ± 65 μm, respectively).13 These data are difficult to interpret as we are unaware of choroidal thickness reference values for myopic eyes of otherwise healthy children this young. Read et al. also report a mean choroidal thickness of myopic children as 303 μm ± 79 μm. However, the children in their report were aged 10 to 15 years old with a lesser degree of myopia (2.4 D ± 1.5 D) than in our series.14 Although the AL of pediatric eyes rapidly change within the first 18 months of life, the two patients in our series with myopic choroidal thinning (K1 and K5) had eyes with axial lengths estimated to be about 30% to 40% longer than what would be expected at their respective ages.15 The two oldest patients (K2 and K3) had the most severe choroidal atrophy.
Three eyes demonstrated dilated choroidal vessels suggestive of pachychoroid disease. Pachychoroid has been described as four disease groups that each may develop into the next: in order of advancing severity, pachychoroid pigment epitheliopathy, central serous chorioretinopathy, pachychoroid neovasculopathy, and polypoidal choroidal vasculopathy.16 The common characteristics shared in this spectrum include a thick choroid with prominent vessels in the Haller layer and attenuated Sattler and choriocapillaris layers.16 The pathophysiology of the pachychoroid spectrum is not well characterized. It has been suggested that hyper permeability and congestion in the choroidal vessels may play a role.17 An additional factor may be RPE ischemia and subsequent increase in angiogenic signaling. Pachychoroid disease is typically bilateral even if only one eye is symptomatic, suggesting a possible systemic etiology.16 There may also be genetic influences.16,17 The choroidal thickness in pachychoroid disease has been described as greater than 390 µm.16 The three eyes in our series suggestive of pachychoroid are well below this (119 μm, 202 μm, and 207 μm). However, given that most patients in our series are younger than 1 year of age and their degree of myopia with dilated vessels in Haller layer with attenuated Sattler and choriocapillaris, we propose that these findings may represent an attenuated form of pachychoroid. Current research suggests that the underlying pathophysiology of pachychoroid may involve abnormal angiogenic signaling and structural changes of the choriocapillaris with increased vascular permeability. This has shifted the definition of pachychoroid away from a reliance on choroidal thickness, but rather toward a morphologic description of the choroidal vessels.18
Collagen 18 is found in the basement membranes of various tissues throughout the body including the iris, vitreous, retina, and vascular endothelium.19 Collagen 18 also plays an important role in the production of endostatin, an inhibitor of angiogenesis.20 In the eye, the loss of endostatin has been shown to cause delayed fetal blood vessel regression and failure of the normal vascular development in the retina.20 The proposed pathophysiology of the pachychoroid diseases and the choroidal changes in Knobloch syndrome share similarities with increased angiogenic signaling and abnormal vessel integrity.17,20 The mechanism by which abnormal endostatin may result in pachychoroid requires further research.
Rather than a progressive spectrum, in our series we observed choroidal thicknesses to fall within two groups, either thick (pachychoroid) or thin (myopic choroidal thinning or atrophy). These findings suggest that different regions in the affected in COL18A1 gene may produce the distinction in these phenotypes. Perhaps abnormal collagen 18 increases AL, which may or may not have superimposed choroidal thickening (pachychoroid) dependent on whether the mutation also alters the expression of endostatin. There have been few studies reporting the OCT findings in patients with Knobloch syndrome.9–11 AlBakri et al.9 reported findings in 12 eyes of seven patients (mean age: 11 years; range: 6 to 17 years). They found mean spherical equivalents and ALs (−13.43 D, −28.16 mm) similar to those in our series. OCT findings showed some similarities with our series including poor foveal identification, loss of retinal lamination especially in the outer retina and photoreceptors, RPE attenuation, choroidal atrophy, and retinal excavation. Our series gives further evidence to support these findings and expands on their findings in particular by refining the characterization of the choroid. The OCT findings in our series of ERM and vitreoretinal traction have also not been previously reported. Retinoschisis has once before been reported in a single patient by Ebrahimiadib et al.10 In patient K4, the retinoschisis and traction were located in the peripapillary area while the macula remained attached. The right eye of patient K3, who was excluded from this study due to chronic retinal detachment, also had these findings. An explanation of these findings may be offered by murine knockout models of COL18A1 that have shown abnormal hyaloid vessel regression and abnormal separation of the vitreous from the inner limiting membrane.7,21
We demonstrate numerous OCT findings in Knobloch syndrome including abnormal vitreoretinal traction, ERM, poor foveal identification, poor retinal lamination, retinal thinning, RPE attenuation, myopic choroidal thinning, and paradoxically in some eyes, an atypical form of pachychoroid with dilated choroidal vessels. These findings may be useful in recognizing this condition with a high retinal detachment risk.
- Khan AO, Aldahmesh MA, Mohamed JY, Al-Mesfer S, Alkuraya FS. The distinct ophthalmic phenotype of Knobloch syndrome in children. Br J Ophthalmol. 2012;96(6):890–895. doi:10.1136/bjophthalmol-2011-301396 [CrossRef]
- Aldahmesh MA, Khan AO, Mohamed JY, et al. No evidence for locus heterogeneity in Knobloch syndrome. J Med Genet. 2013;50(8):565–566. doi:10.1136/jmedgenet-2013-101755 [CrossRef]
- Hull S, Arno G, Ku CA, et al. Molecular and clinical findings in patients with Knobloch syndrome. JAMA Ophthalmol. 2016;134(7):753–762. doi:10.1001/jamaophthalmol.2016.1073 [CrossRef]
- Caglayan AO, Baranoski JF, Aktar F, et al. Brain malformations associated with Knobloch syndrome — review of literature, expanding clinical spectrum, and identification of novel mutations. Pediatr Neurol. 2014;51(6):806–813. doi:10.1016/j.pediatrneurol.2014.08.025 [CrossRef]
- Mahajan VB, Olney AH, Garrett P, et al. Collagen XVIII Mutation in Knobloch syndrome with acute lymphoblastic leukemia. Am J Med Genet A. 2010;152A(11):2875–2879. doi:10.1002/ajmg.a.33621 [CrossRef]
- Suzuki OT, Sertié AL, Der Kaloustian VM, et al. Molecular analysis of collagen XVIII reveals novel mutations, presence of a third isoform, and possible genetic heterogeneity in Knobloch syndrome. Am J Hum Genet. 2002;71(6):1320–1329. doi:10.1086/344695 [CrossRef]
- Fukai N, Eklund L, Marner AG, et al. Lack of collagen XVIII/endostatin abnormalities. EMBO J. 2002;21(7):1535–1544. doi:10.1093/emboj/21.7.1535 [CrossRef]
- Passos-Bueno MR, Suzuki OT, Armelin-Correa LM, et al. Mutation in Collagen 18A1 (COL18A1) and their relevance to the human phenotype. An Acad Bras Cienc. 2006;78(1):123–131. doi:10.1590/S0001-37652006000100012 [CrossRef]
- AlBakri A, Ghazi NG, Khan AO. Biometry, optical coherence tomography, and further clinical observation in Knobloch syndrome. Ophthalmic Genet. 2017;38(2):138–142. doi:10.3109/13816810.2016.1164197 [CrossRef]
- Ebrahimiadib N, Modjtahedi BS, Ferenchak K, et al. Optical coherence tomography findings and successful repair of retinal detachment in Knobloch syndrome. Digit J Ophthalmol. 2017;23(1):29–32. doi:10.5693/djo.02.2017.01.002 [CrossRef]
- White RJ, Wang Y, Tang P, Montezuma SR. Knobloch syndrome associated with Polymicrogyria and early onset of retinal detachment: Two case reports. BMC Ophthalmol. 2017;17(1):214. doi:10.1186/s12886-017-0615-z [CrossRef]
- Rennie CA, Chowdhury S, Khan J, et al. The prevalence and associated features of posterior embryotoxon in the general ophthalmic clinic. Eye (Lond). 2005;19(4):396–399. doi:10.1038/sj.eye.6701508 [CrossRef]
- Read SA, Alonso-Caneiro D, Vincent SJ, Collins MH. Longitudinal changes in choroidal thickness and eye growth in childhood. Invest Ophthalmol Vis Sci. 2015;56(5):3103–3112. doi:10.1167/iovs.15-16446 [CrossRef]
- Read SA, Collins MJ, Vincent SJ, Alonso-Caneiro D. Choroidal thickness in myopic and nonmyopic children assessed with enhanced depth imaging optical coherence tomography. Invest Ophthalmol Vis Sci. 2013;54(12):7578–7586. doi:10.1167/iovs.13-12772 [CrossRef]
- Hussain RN, Shahid F, Woodruff G. Axial length in apparently normal pediatric eyes. Eur J Ophthalmol. 2014;24(1):120–123. doi:10.5301/ejo.5000328 [CrossRef]
- Akkaya S. Spectrum of pachychoroid diseases. Int Ophthalmol. 2018;38(5):2239–2246. doi:10.1007/s10792-017-0666-4 [CrossRef]
- Manayath GJ, Shah VS, Saravanan VR, Narendran V. Polypoidal choroidal vasculopathy associated with central serous chorioretinopathy: Pachychoroid spectrum of diseases. Retina. 2018;38(6):1195–1120. doi:10.1097/IAE.0000000000001665 [CrossRef]
- Cheung CMG, Lee WK, Koizumi H, Dansingani K, Lai TYY, Freund KB. Pachychoroid disease. Eye (Lond). 2019;33(1):14–33. doi:10.1038/s41433-018-0158-4 [CrossRef]
- Maatta M, Heljasvaara R, Pihlajaniemi T, Uusitalo M. Collagen XVIII/endostatin shows a ubiquitous distribution in human ocular tissues and endostatin-containing fragments accumulate in ocular fluid samples. Arch Clin Exp Ophthalmol. 2007;245(1):74–81. doi:10.1007/s00417-006-0281-y [CrossRef]
- Haghighi A, Tiwari A, Piri N, Nürnberg G, et al. Homozygosity mapping and whole exome sequencing reveal a novel homozygous COL18A1 mutation causing Knobloch syndrome. PLoS One. 2014;9(11):e112747. doi:10.1371/journal.pone.0112747 [CrossRef]
- Ylikärppä R, Eklund L, Sormunen R, et al. Lack of type XVIII collagen results in anterior ocular defects. FASEB J. 2003;17(15):2257–2259. doi:10.1096/fj.02-1001fje [CrossRef]
Demographic Data and Clinical Features
|Patient No.||Age||Gender||Age at Diagnosis||Presenting Symptoms||Occipital Abnormalities||Systemic Features||Family History||COL18A1 Mutations|
|K1||10 months||Male||2 months||Nystagmus||Cysts||None||Negative||c.2797C>T (p.Arg933Stop), c.3213dupC (p.Gly1072Argfs*9)|
|K2||39 years||Male||Perinatal||Poor vision||Soft mass||High palate, mild arachnodactyly, pectus carinatum||Brother w/reported clinical Knobloch syndrome||Not done|
|K3||3 years||Male||3 months||Nystagmus||Dermal sinus||Dry skin||Negative||c.3514_3515delCT, (p.L1172VFs*72)|
|K4||5 months||Male||4 month||Strabismus||Focal alopecia||Otitis media and constipation||Negative||c.2969_2978del10 (p.Pro990Leufs*35), c.1187_1200dup14 (p.Pro401Glyfs*36)|
|K5||3 months||Female||perinatal||Abnormal red reflex||Normal||None||Negative||Not done|
|Patient No./Eye||Visual Acuity||Anterior Segment||Retina||Retinal Vessels||Optic Nerve||Vitreous||Cycloplegic Refraction (Diopters)||A-Scan (mm)|
|K1/OD||CNSM||WNL||Tes FD, Mac hypo||Attenuated||Mild atrophy||N/D||−21.50+3.00 ×90||26.33|
|K1/OS||CNSM||WNL||Tes FD, Mac hypo||Attenuated||Mild atrophy||N/D||−23.00+2.00 ×75||26.06|
|K2/OD||20/300||Smooth iris, aphakia||Tes FD, Mac hypo||Mildly attenuated||Tilted, PPA||Optically empty anterior vitreous||+7.00+0.50 ×90||27.94|
|K2/OS||20/400||Smooth iris, aphakia||Tes FD, Mac hypo||Mildly attenuated||Tilted, PPA||Optically empty anterior vitreous||+6.50+0.50 ×25||28.31|
|K3/OS||20/800||WNL||Tes FD, Mac GA||Attenuated||Normal||Vitreous veils in temporal periphery||−13.00 Sph||26.59|
|*K4/OD||20/400||Smooth iris||Tes FD, Mac GA||Peripapillary schisis||Normal||Peripheral abnormal vitreoretinal interface, consistency of vitreous OS > OD||−11.00+3.00 ×95||26.78|
|*K4/OS||20/400||Smooth iris||Tes FD, Mac GA||Normal||Normal||−11.50+2.50 ×90||26.35|
|K5/OS||CSM||Smooth iris, post em||Tes FD, Mac GA||Normal||Mildly anomalous||Vitreoretinal interface condensations extending onto pars plana||−14.50 Sph||22.7|
Optical Coherence Tomography Findings
|OCT Findings in Macular Area|
|Patient No./Eye||Fovea (Thickness)||Epiretinal Membrane and Vitreoretinal Traction||Lamination||Photoreceptors||RPE||Choroid|
|K1/OD||Not identifiable||No||Poor (I,O) and thin||Diminished PRs||WNL||Myopic thinning|
|K1/OS||Not identifiable||No||Poor (I,O) and thin||Diminished PRs||WNL||Myopic thinning|
|K2/OD||Rudimentary (110 µm)||No||Poor (I,O) and thin||No PRs||Atrophic||Atrophic|
|K2/OS||Not identifiable||No||Poor (I,O) and thin||No PRs||Atrophic||Atrophic|
|K4/OD||Yes (82 µm)||Yes||Poor (O) and retinoschisis (PP)||No PRs||Atrophic||Pachychoroid (202 microns) with enlarged vessels|
|K4/OS||Yes (66 µm)||Yes||Poor (O) and retinoschisis (PP)||No PRs||Atrophic||Pachychoroid (207 microns) with enlarged vessels|
|K5/OS||Rudimentary (203 µm)||No||Poor (O)||Diminished PRs||WNL||Mild myopic thinning (146 microns)|