Knobloch syndrome is a rare autosomal recessive syndrome that was first described by Knobloch and Layer in 1971.1 The syndrome shows clinical heterogeneity and mainly presents with an occipital encephalocele, high myopia, and vitreoretinal degeneration with retinal detachment. Additional variable features include lung hypoplasia, mid-face hypoplasia, and possible cataract. Patients may also present with progressive unexplained loss of vision.
A 24-month-old boy was referred to the retina service at our institution for a retinal detachment in the left eye. He was born at 36 weeks’ gestational age via an uncomplicated pregnancy and did not receive supplemental oxygen therapy. He had no significant medical problems, no hospitalizations, and normal growth and development. He was previously diagnosed as having high myopia, foveal hypoplasia, and possible albinism. An electroretinogram was within normal limits for the degree of myopia.
Our examination revealed high myopia (−17.75 in both eyes), “follows light” visual acuity in both eyes, and bilateral foveal hypoplasia. Intraocular pressures were 16 mm Hg in the right eye and 9 mm Hg in the left eye. On anterior examination, the right eye was within normal limits and there was a dense cataract in the left eye with extensive posterior synechiae that limited fundus examination. Right eye examination revealed a blond fundus with extensive visibility of the choroidal vasculature and lacquer-cracking in the mid-periphery (Figure 1). Echography revealed an axial length of 27.8 mm in the right eye and 25.6 mm in the left eye, completely attached retina in the right eye, and total retinal detachment in the left eye. Lensectomy, scleral buckle implantation, pars plana vitrectomy with membrane peeling for proliferative vitreoretinopathy, perfluoro-n-octane injection, endolaser, and fluid–air exchange followed by silicone oil infusion were performed on the left eye.
Color fundus photograph of the right eye at 24 months of age, with evidence of vitreoretinal degeneration, choroidal show, and lacquer-cracking in the mid-periphery.
During the postoperative follow-up period, the diagnosis of Knobloch syndrome was made after an observation of a midline occipital scalp defect, completing the classic clinical triad of this syndrome of high myopia, vitreoretinal degeneration, and occipital scalp defects (Figure 2). Genetic testing was offered, but the family opted not to pursue it. After thorough discussion with the family, prophylactic scleral buckle of the right eye was performed when the patient was 29 months old to decrease the risk of retinal detachment.
Photograph of the midline occipital scalp defect, a common finding in Knobloch syndrome.
At 5 years old, the patient’s uncorrected visual acuity was 20/200 in the right eye and 20/400 in the left eye. Intraocular pressure was 14 and 15 mm Hg in the right and left eyes, respectively. Examination of the left eye revealed a clear cornea and aphakia, with emulsified oil in the anterior segment. Examination of the posterior segment of both eyes revealed attached retina with circumferential scleral buckles (Figure 3).
Fundus photographs, spectral-domain optical coherence tomography, and echography at 5 years of age. Color fundus photographs of the (A) right and (B) left eyes conveying sharp discs, slightly tortuous retinal vessels, diffuse atrophy of the retinal pigment epithelium, normal choroidal vasculature appearance, and attached retina with circumferential scleral buckles. Spectral-domain optical coherence tomography (Heidelberg Engineering, Heidelberg Germany) images of the (C) right and (D) left eye showing significant retinal thinning precluding clear identification of the retinal layers; there is loss of foveal contour and choroidal thinning. Echography of the left eye (E) superiorly and (F) inferiorly, demonstrating attached retina and residual silicone oil.
Knobloch syndrome, first described in 1971, is a rare autosomal recessive disorder characterized by a triad of high myopia, vitreoretinal degeneration, and congenital occipital scalp defects.1,2 Patients with this disorder most commonly inherit a genetic variant in COL18A1 (21q22.3), which is critical for collagen formation, resulting in a disruption in the ability to produce collagen XVIII, a protein found in the basement membranes of many ocular tissues, including Bowman’s membrane, the lens capsule, trabecular meshwork, ciliary body, iris, retinal pigment epithelium (RPE), internal limiting membrane, Bruch’s membrane, and vessels of the retina and choroid.3,4 Cleavage of collagen XVIII produces endostatin, a protein with anti-angiogenic effects; collagen XVIII and endostatin play a role in ocular development and maintaining visual function, and deficiency of these proteins in mice predisposes to delayed regression of vitreoretinal blood vessels after birth, abnormal outgrowth of retinal vessels, and age-dependent pathological accumulation of sub-RPE deposits.4,5 A novel homozygous mutation was recently described in the ADAMTS18 gene (16q23.1), which encodes a zinc-dependent protease with strong expression of the gene in the lens and retina.6 Reports have focused largely on the clinical presentation and genetic findings of patients suffering from this disorder, with less discussion regarding the ocular management.
The ocular disease in Knobloch syndrome is progressive and eventually bilateral. Patients may present with minimal retinal pathology early in life and rapidly progress with vitreoretinal degeneration and retinal detachment, or may have a more insidious course.1–3,7 Ten-year follow-up of the patients in the initial report of Knobloch syndrome revealed that surgery to repair retinal detachment failed in 6 of 10 cases and those that succeeded required multiple operations.1,7 Furthermore, literature review reveals 25 of 85 eyes (29%) of patients with Knobloch syndrome had retinal detachment. The prevalence of retinal detachment in these patients is likely to be higher because many of the cases do not include long-term follow-up and the vitreoretinal pathology in this disease is usually progressive. Surgical repair of the retinal detachment is challenging due to high myopia and patients frequently require several re-operations. Even with aggressive treatment, the mean visual acuity after surgical intervention for retinal detachment in these patients is poor. Review of all literature reports reveals that 11 of 12 (92%) patients with Knobloch syndrome treated with vitrectomy or scleral buckle for retinal detachment had a final visual acuity of 20/200 or worse, 1 with counting fingers, 2 with hand motions, and 3 with no light perception.1,2,8,9 The role of retinal detachment prophylaxis has been discussed in other vitreoretinal degeneration disorders, but not in Knobloch syndrome.10
Given the progressive nature of the vitreoretinal pathology in this disease, it is important to consider prophylactic treatment to reduce the likelihood of retinal detachment. In a retrospective study of 204 patients with type 1 Stickler syndrome, prophylactic cryotherapy significantly reduced the prevalence of retinal detachment compared to untreated patients (P < .001).10 To date, four attempts to prevent retinal detachment in patients with Knobloch syndrome have been reported in the literature, all by way of prophylactic cryotherapy (Table 1).2,7 Long-term follow-up was not available in 2 cases and retinal detachment occurred 28 months after the prophylactic cryotherapy in 1 case.2,7 In the fourth case of a 2.5-year-old girl with a small hole in the retina inferotemporally, cryotherapy was used as prophylaxis and two subsequent rounds of cryotherapy were performed; her retina remained attached through 8 years of follow-up.2 The vitreoretinal degeneration observed in these patients often involves multiple quadrants of the peripheral retina, thus decreasing the value of prophylactic cryotherapy.
Outcomes of Prophylactic Treatment Against Retinal Detachment in Patients With Knobloch Syndrome
The diagnosis of Knobloch syndrome should be considered in children with high myopia and vitreoretinal degeneration because they require close follow-up due to the progressive nature of the disease. In our patient, the diagnosis was made after observation of a midline occipital scalp defect during postoperative follow-up for retinal detachment repair. Retinal detachment repair in the left eye and prophylactic scleral buckle in the right eye have maintained the anatomic integrity of the retina to 4 years of follow-up. Ideally, clinical trials would compare the efficacy of prophylactic cryotherapy versus scleral buckle in patients diagnosed as having Knobloch syndrome and similar degenerative diseases. Because these diseases are rare, such trials are unlikely. Although we recommend prophylactic therapy for patients with Knobloch syndrome, the management should vary based on the individual patient.
- Knobloch WH, Layer JM. Retinal detachment and encephalocele. J Pediatr Ophthalmol. 1971;8:181–184.
- Seaver LH, Joffe L, Spark RP, Smith BL, Hoyme HE. Congenital scalp defects and vitreoretinal degeneration: redefining the Knobloch syndrome. Am J Med Genet. 1993;46:203–208. doi:10.1002/ajmg.1320460221 [CrossRef]
- Passos-Bueno MR, Marie SK, Monteiro M, et al. Knobloch syndrome in a large Brazilian consanguineous family: confirmation of autosomal recessive inheritance. Am J Med Genet. 1994;52:170–173. doi:10.1002/ajmg.1320520209 [CrossRef]
- Fukai N, Eklund L, Marneros AG, et al. Lack of collagen XVIII/endostatin results in eye abnormalities. EMBO J. 2002;21:1535–1544. doi:10.1093/emboj/21.7.1535 [CrossRef]
- Marneros AG, Olsen BR. Physiological role of collagen XVIII and endostatin. FASEB J. 2005;19:716–728. doi:10.1096/fj.04-2134rev [CrossRef]
- Aldahmesh MA, Khan AO, Mohamed JY, et al. Identification of ADAMTS18 as a gene mutated in Knobloch syndrome. J Med Genet. 2011;48:597–601. doi:10.1136/jmedgenet-2011-100306 [CrossRef]
- Cook GR, Knobloch WH. Autosomal recessive vitreoretinopathy and encephaloceles. Am J Ophthalmol. 1982;94:18–25.
- Kliemann SE, Waetge RT, Suzuki OT, Passos-Bueno MR, Rosemberg S. Evidence of neuronal migration disorders in Knobloch syndrome: clinical and molecular analysis of two novel families. Am J Med Genet A. 2003;119A:15–19. doi:10.1002/ajmg.a.20070 [CrossRef]
- Williams TA, Kirkby GR, Williams D, Ainsworth JR. A phenotypic variant of Knobloch syndrome. Ophthalmic Genet. 2008;29:85–86. doi:10.1080/13816810701850041 [CrossRef]
- Ang A, Poulson AV, Goodburn SF, Richards AJ, Scott JD, Snead MP. Retinal detachment and prophylaxis in type 1 Stickler syndrome. Ophthalmology. 2008;115:164–168. doi:10.1016/j.ophtha.2007.03.059 [CrossRef]
Outcomes of Prophylactic Treatment Against Retinal Detachment in Patients With Knobloch Syndrome
|Case||Sex||Age (y) at Prophylactic Treatment||Eye||Preop VA||Prophylactic Treatment||Age (y) at Last Follow-up||Postop VA||Outcome|
|12||F||7||Left||20/400||Cryotherapy||9||20/400||Single large, posterior horseshoe tear and many equatorially located flap tears superotemporally|
|27||F||2.5||Right||–||Cryotherapy, 3 times||11||20/200||No retinal breaks|
|3, 42||M||2.5||Both||–||Cryotherapy, 2 times||3||–||No long-term follow-up|