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Stickler syndrome

Authors:
Pukhraj Rishi at University of Nebraska Medical Center
Pukhraj Rishi
Abhilasha Maheshwari at Kapil Eye Hospital
Abhilasha Maheshwari
  • Kapil Eye Hospital
Ekta Rishi at Tamil Nadu Dr. M.G.R. Medical University
Ekta Rishi
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© 2015 Indian Journal of Ophthalmology | Published by Wolters Kluwer - Medknow
Shri Bhagwan Mahavir Vitreoretinal Services, Sankara Nethralya,
Chennai, India
Correspondence to: Dr. Pukhraj Rishi, Shri Bhagwan Mahavir
Vitreoretinal Services, Sankara Nethralaya, 18 College Road,
Chennai ‑ 600 006, Tamil Nadu, India. E‑mail: docrishi@yahoo.co.in
Manuscript received: 11.01.15; Revision accepted: 15.05.15
Stickler syndrome is a well‑described but uncommon clinical
entity. It is a hereditary connective tissue disorder of brillar
collagen with autosomal dominant inheritance. Phenotype
manifests as four dierent features that is, ocular, orofacial,
auditory, and musculoskeletal.
Case Description
A 17‑year‑old male reported with gradual, progressive, painless
diminution of vision in both eyes since 3 months. Family
history was unremarkable. The best corrected visual acuity
was the perception of light+ in right eye and 20/400 in the left
eye. The anterior segment showed dense cataract in the right
Photo Essay
Stickler syndrome
Pukhraj Rishi, Abhilasha Maheshwari, Ekta Rishi
Key words: Cleft palate, radial laices, retinal detachment, Stickler syndrome
Cite this article as: Rishi P, Maheshwari A, Rishi E. Stickler syndrome. Indian
J Ophthalmol 2015;63:614-5.
This is an open access article distributed under the terms of the Creative
Commons Attribution‑NonCommercial‑ShareAlike 3.0 License, which allows
others to remix, tweak, and build upon the work non‑commercially, as long as the
author is credited and the new creations are licensed under the identical terms.
For reprints contact: reprints@medknow.com
Figure 1: External (slit‑lamp) photo reveals cataract in the right eye
(right arrow) and posterior chamber intraocular lens implant in the left
eye (left arrow)
Figure 2: Left eye color fundus montage showing multiple radial,
perivascular lattices (arrows), tessellated fundus, and posterior
staphyloma
and posterior chamber intraocular lens in the left eye [Fig. 1].
Intraocular pressure was 4 mmHg in the right and 16 mmHg
in the left eye. Left eye fundus revealed multiple radial
perivascular laices, vitreous condensation, tessellations, and
posterior staphyloma [Fig. 2], and an axial length of 26.3 mm.
The left eye was amblyopic. Ultrasound B‑scan of the right eye
revealed closed funnel retinal detachment (RD) and reduced
axial length (21.2 mm) [Fig. 3]. Electroretinogram showed
normal responses in the left and expected nonrecordable
responses in the right eye [Fig. 4]. Systemic examination
revealed speech abnormality (nasal twang), large cleft
palate [Fig. 5], and mild hearing defect.
Discussion
Stickler syndrome was first reported in 1965 by
Stickler et al.[1] as hereditary arthro‑ophthalmopathy. It
is now divided into subgroups depending on the clinical
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DOI:
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July 2015 615
Rishi, et al.: Stickler syndrome
manifestations. Vitreous assessment is the diagnostic
criteria[2] and guides to molecular genetic analysis.[3]
Complications such as RD (70%), cataract (49%), and ocular
hypertension (10%)[4] are progressive and can lead to
blindness. A multidisciplinary approach is required. Ocular
rehabilitation includes spectacles/contact lenses, frequent
retinal examinations, cataract surgery, and prophylactic
retinal laser photocoagulation. Meticulous systemic
examination and genetic counseling help in identifying
the disorder in newborns and preventing complications.
Mutations in the COL2A1, COL11A1, COL11A2, COL9A1,
and COL9A2 genes can cause Stickler syndrome, Types I to V.
Our patient had characteristic features of Type I Stickler
syndrome, such as cleft palate and hearing decit, except
a positive family history. Genetic testing was oered but
declined by the patient. Differentials include multiple
epiphyseal dysgenesis, Kniest dysplasia (musculoskeletal
involvement), Knobloch (encephalocele), and Wagner
syndrome (ocular involvement only).
Financial support and sponsorship
Nil.
Conicts of interest
There are no conicts of interest.
References
1. Stickler GB, Belau PG, Farrell FJ, Jones JD, Pugh DG,
Steinberg AG, et al. Hereditary progressive arthro‑ophthalmopathy.
Mayo Clin Proc 1965;40:433‑55.
2. Snead MP, McNinch AM, Poulson AV, Bearcroft P, Silverman B,
Gomersall P, et al. Stickler syndrome, ocular only variants and a
key diagnostic role for ophthalmologist. Eye 2011;25:1389‑400.
3. Snead MP, Yates JR. Clinical and molecular genetics of Stickler
syndrome. J Med Genet 1999;36:353‑9.
4. Spallone A. Stickler’s syndrome: A study of 12 families. Br J
Ophthalmol 1987;1:504‑9.
Figure 4: Electroretinogram showing nonrecordable photopic and
scotopic responses in oculus dexter and normal responses in left eye
Figure 5: Oral examination reveals large cleft palate
Figure 3: Ultrasonography B‑scan showing closed funnel retinal
detachment with axial length of 21.2 mm (a) in right eye and axial
length of 26.3 mm in left eye (b)
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... Stickler syndrome [Online Mendelian Inheritance in Man (OMIM) nos. 108300, 609508, 604841,184840, 614134 and 614284], first reported in 1965 by Stickler et al (1), is a group of inherited connective tissue disorders, with an incidence of 1 in 10,000 (2,3). Stickler syndrome is frequently misdiagnosed due to its widely varied clinical manifestations, which may resemble other diseases (4,5). ...
... Stickler syndrome is frequently misdiagnosed due to its widely varied clinical manifestations, which may resemble other diseases (4,5). It commonly involves distinctive ocular and facial abnormalities, hearing loss and joint problems (3,(6)(7)(8). Patients with Stickler syndrome typically present with shallow supraorbital ridges, hypoplastic short nose with anteverted nares, buphthalmic eyes, a flat hypoplastic midface with a depressed nasal bridge, long philtrum and micrognathia (9). ...
... Type (17). The development of Stickler syndrome is progressive and can ultimately lead to blindness (3). The molecular mechanism of Stickler syndrome is not fully characterized. ...
Targeted next‑generation sequencing identifies two novel COL2A1 gene mutations in Stickler syndrome with bilateral retinal detachment
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Stickler syndrome is a group of inherited connective tissue disorders characterized by distinctive facial and ocular abnormalities, hearing loss and early‑onset arthritis. The aim of the present study was to investigate the genetic changes in two Chinese patients with Stickler syndrome, manifested as bilateral retinal detachment and peripheral retinal degeneration. Complete ophthalmic examinations, including best‑corrected visual acuity, slit‑lamp examination and fundus examination, were performed. Genomic DNA was extracted from leukocytes of the peripheral blood collected from the patients, their unaffected family members and 200 unrelated control subjects from the same population. Next‑generation sequencing of established genes associated with ocular disease was performed. A heterozygous collagen type II α1 chain (COL2A1) mutation c.1310G>C (p.R437P) in exon 21 was identified in Family 1 and a heterozygous COL2A1 mutation c.2302‑1G>A in intron 34 was identified in Family 2. The functional effects of the mutations were assessed by polymorphism phenotyping (PolyPhen) and sorting intolerant from tolerant (SIFT) analysis. The c.1310G>C mutation was predicted to damage protein structure and function, and the c.2302‑1G>A mutation was predicted to result in a splicing defect. The findings of the current study expand the established mutation spectrum of COL2A1, and may facilitate genetic counseling and development of therapeutic strategies for patients with Stickler syndrome.
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Osteodysplasia with Isolated or Contemporary Interest of Epiphysis, Metaphysis, and Vertebral Bodies
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Osteodysplasias affecting the epiphyses, metaphyses, and partly the vertebral bodies cannot be studied with prenatal ultrasound because these bone segments are still in the cartilaginous phase of development. However, knowledge of them can help the sonographer to suspect this group of dysplasias, which will then be confirmed by genetic diagnosis. It is also possible to inform the pregnant about the risk of recurrence and about many of these syndromes that are not associated with mental retardation.
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Stickler and Wagner Syndrome in African Americans
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Background: Stickler (STL) and Wagner (WGN) syndromes are rare inherited vitreoretinopathies associated with retinal detachments (RD). There is a paucity of case reports describing these diseases in African American patients. Methods: An IRB-approved, retrospective chart review of African American patients with genetically proven ocular-only STL or WGN was performed, and 6 patients were identified. Results: Three patients had a COL2A1 mutation, two had a COL11A1 mutation, and one had a VCAN mutation. None had Pierre Robin facies. All were myopes with lattice degeneration and five had RD. Three underwent RD repair with vitrectomy (PPV), scleral buckle (SB), endolaser (EL), and silicone oil (SO). Two received laser retinopexy for localized RD and one received a prophylactic SB with 360° peripheral laser retinopexy. Conclusion: STL and WGN should be considered in myopic African American patients with lattice degeneration, giant retinal tears, abnormal vitreous, or spontaneous RD. Prophylactic laser treatment and aggressive surgical treatment of RD should be considered. [Ophthalmic Surg Lasers Imaging Retina 2023;54:97-101.].
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Autosomal recessive Stickler syndrome associated with homozygous mutations in the COL9A2 gene
Article
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Background: Stickler syndrome is a hereditary disorder of collagen tissues causing ocular, auditory, orofacial, and joint manifestations. Ocular findings typically include vitreous degeneration, high myopia, retinal detachment, and cataract. Many subjects demonstrate sensorineural or conductive hearing loss. The inheritance is autosomal dominant with mutations in COL2A1, COL11A1, or COL11A2 or autosomal recessive due to mutations in COL9A1, COL9A2, or COL9A3. We describe a family with Stickler syndrome caused by homozygous loss-of-function mutations in COL9A2. Methods: Two brothers from a consanguineous family were examined with genetic testing, visual acuity, Goldmann perimetry, full-field and multifocal electroretinography (ffERG, mERG), optical coherence tomography (OCT), fundus autofluorescence (FAF), fundus photography, and pure-tone audiograms. Results: Both subjects were homozygous for the mutation c.1332del in COL9A2. Their parents were heterozygous for the same mutation. The boys demonstrated reduced visual acuity, vitreous changes and myopia. The proband was operated for retinal detachment and cataract in one eye. FfERG revealed reduced function of both rods and cones and mERG showed reduced macular function. No morphological macular changes were found by OCT or FAF. Both brothers have severe sensorineural hearing loss with down-sloping audiograms but only subtle midface hypoplasia and no, or mild joint problems. Conclusion: Only a few families with Stickler syndrome caused by COL9A2 mutations have been reported. We confirm previous descriptions with a severe ocular and auditory phenotype but mild orofacial and joint manifestations. Moreover, we demonstrate reduced macular and overall retinal function explaining the reduced visual acuity in patients with Stickler syndrome also without retinal complications.
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Digenic inheritance of mutations in EPHA2 and SLC26A4 in Pendred syndrome
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Enlarged vestibular aqueduct (EVA) is one of the most commonly identified inner ear malformations in hearing loss patients including Pendred syndrome. While biallelic mutations of the SLC26A4 gene, encoding pendrin, causes non-syndromic hearing loss with EVA or Pendred syndrome, a considerable number of patients appear to carry mono-allelic mutation. This suggests faulty pendrin regulatory machinery results in hearing loss. Here we identify EPHA2 as another causative gene of Pendred syndrome with SLC26A4. EphA2 forms a protein complex with pendrin controlling pendrin localization, which is disrupted in some pathogenic forms of pendrin. Moreover, point mutations leading to amino acid substitution in the EPHA2 gene are identified from patients bearing mono-allelic mutation of SLC26A4. Ephrin-B2 binds to EphA2 triggering internalization with pendrin inducing EphA2 autophosphorylation weakly. The identified EphA2 mutants attenuate ephrin-B2- but not ephrin-A1-induced EphA2 internalization with pendrin. Our results uncover an unexpected role of the Eph/ephrin system in epithelial function. While biallelic mutations of the SLC26A4 gene cause non-syndromic hearing loss with enlarged vestibular aqueducts or Pendred syndrome, a considerable number of patients carry mono-allelic mutations. Here the authors identify EPHA2 as another causative gene of Pendred syndrome with SLC26A4.
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Article
Full-text available
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  • DOC OPHTHALMOL
Purpose To determine the characteristics of the full-field electroretinograms (ERGs) of eyes with Stickler syndrome. Methods Twenty-two eyes of 14 Japanese patients from nine families with Stickler syndrome were studied. All of the patients were found to have mutations in the COL2A1 gene and had undergone ERG recordings. The ERGs from one of the two eyes were compared to 11 eyes of 11 normal control subjects who were matched by age, sex, and refractive error. Results One patient had non-recordable ERGs under both scotopic and photopic conditions. For the remaining 13 patients, the amplitudes of the b-waves of the scotopic combined, rod, and cone responses were significantly smaller than those of the control subjects (P = 0.0001, P = 0.015, P = 0.0006, respectively). The implicit times of the b-wave of the scotopic combined and photopic responses were significantly prolonged (P = 0.0037 and P = 0.0126). The age was inversely and significantly correlated with the amplitudes of the scotopic combined a-wave (P = 0.0184) and b-wave (P = 0.0076) in 13 eyes. The amplitudes of the scotopic combined b-wave amplitudes were not significantly correlated with the refractive error. Conclusions The reduced or absent full-field ERGs in eyes with Stickler syndrome indicate that the physiology of the entire retina was negatively altered. The greater reduction in the ERGs with increasing age suggests that the physiological alterations of the retina are progressive.
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Stickler syndrome, ocular-only variants and a key diagnostic role for the ophthalmologist
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The entity described by Gunnar Stickler, which included hereditary arthro-ophthalmopathy associated with retinal detachment, has recently been recognised to consist of a number of subgroups, which might now more correctly be referred to as the Stickler syndromes. They are the most common clinical manifestation of the type II/XI collagenopathies and are the most common cause of inherited rhegmatogenous retinal detachment. This review article is intended to provide the ophthalmologist with an update on current research, subgroups, and their diagnosis together with a brief overview of allied conditions to be considered in the clinical differential diagnosis. We highlight the recently identified subgroups with a high risk of retinal detachment but with minimal or absent systemic involvement--a particularly important group for the ophthalmologist to identify.
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Stickler's syndrome: A study of 12 families
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Clinical and Molecular genetics of Stickler syndrome
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Stickler syndrome is an autosomal dominant disorder with characteristic ophthalmological and orofacial features, deafness, and arthritis. Abnormalities of vitreous gel architecture are a pathognomonic feature, usually associated with high myopia which is congenital and non-progressive. There is a substantial risk of retinal detachment. Less common ophthalmological features include paravascular pigmented lattice degeneration and cataracts. Non-ocular features show great variation in expression. Children with Stickler syndrome typically have a flat midface with depressed nasal bridge, short nose, anteverted nares, and micrognathia. These features can become less pronounced with age. Midline clefting, if present, ranges in severity from a cleft of the soft palate to Pierre-Robin sequence. There is joint hypermobility which declines with age. Osteoarthritis develops typically in the third or fourth decade. Mild spondyloepiphyseal dysplasia is often apparent radiologically. Sensorineural deafness with high tone loss may be asymptomatic or mild. Occasional findings include slender extremities and long fingers. Stature and intellect are usually normal. Mitral valve prolapse was reported to be a common finding in one series but not in our experience. The majority of families with Stickler syndrome have mutations in the COL2A1 gene and show the characteristic type 1 vitreous phenotype. The remainder with the type 2 vitreous phenotype have mutations in COL11A1 or other loci yet to be identified. Mutations in COL111A2 can give rise to a syndrome with the systemic features of Stickler syndrome but no ophthalmological abnormality.
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