Stickler syndrome

From EyeWiki
Original article contributed by: Alan Hromas, MD
All contributors: Alan Hromas, MD, Donny W. Suh, MD,FAAP and K. David Epley, M.D.
Assigned editor: Donny W. Suh, M.D.,FAAP
Review: Assigned status Update Pending by Donny W. Suh, MD,FAAP on December 14, 2014.



Stickler syndrome
Classification and external resources
ICD-9 759.89
DiseasesDB 29327


Stickler syndrome was originally described by pediatrician Gunnar B. Stickler in 1965, as hereditary progressive arthro-ophthalmopathy.[1]

Stickler syndrome is a systemic connective tissue disorder characterized by defective collagen production.[2] The condition is commonly associated with ophthalmologic manifestations including vitreous abnormalities, congential megalophthalmos, radial perivascular retinal degeneration and retinal detachment, in addition to systemic findings which may include orofacial, auditory and musculoskeletal abnormalities.

Disease Entity

Stickler syndrome ICD-9 759.89

Disease

Stickler syndrome a genetically inherited abnormality in collagen production that produces a number of pathologic maxillofacial, ocular, auditory and joint manifestations.

Etiology

Types 1-4 Stickler syndrome are classically inherited in an autosomal dominant fashion[3], though a significant number of cases may be sporadic.[4] 

Risk Factors

The only known risk factor for Stickler syndrome is a family history of the condition. The child of an affected parent has at least a 50% chance of manifesting the condition.

Pathophysiology

Stickler syndrome is believed to be a direct result of abnormalities in the production of collagen types II, IX and XI, all of which are recognized as components of the human vitreous.[5] Normal collagen fibrils are composed of three identical (homotrimer) or differing (heterotrimer) polypeptide chains; genetic mutations affecting the ability of consitiuent polypeptide chains to successfully form stable trimers therefore prevent the production of mature collagen and subsequently produce the clinical manifestations of Stickler syndrome. The condition has been divided into subgroups based on ocular and systemic clincal findings, with each subgroup also corresponding to a specific genetic defect.[6]

Table: Subgroups of Stickler syndrome
Type Clinical features Gene
Type 1 (STL1) Membranous vitreous, congenital megophthalmos, arthropathy, deafness, PRS COL2A1
Type 2 (STL2) Beaded vitreous, otherwise similar to type 1 COL11A1
Type 3 (STL3) No ocular involvement, otherwise similar to type 1 COL11A2
Type 4 (STL4) Membranous vitreous, congenital megophthalmos; no systemic findings COL9A1, COL9A2

Primary prevention

As Stickler syndrome is related to a genetic abnormality, there is no known primary prevention. Genetic counseling may be beneficial for affected patients of childbearing age.
Recent studies have suggested that prophylactic peripheral retinal cryotherapy may be effective in preventing development of rhegmatogenous Retinal Detachment, the most common cause of acute visual loss in affected patients.

Diagnosis

History

Stickler syndrome classically presents in the pediatric population due to the characteristic facies associated with Pierre-Robin sequence.  Ophthalmic manifestions, if not detected early, may not present until a retinal detachment develops; classically, this occurs in young adulthood, but may occur at any age.  Pertinent history may be elicited by inquiring specifically about associated symptoms of hearing loss and joint pain.

Signs

Radial perivascular retinal degeneration in Stickler syndrome
The most common ocular findings in Stickler syndrome are vitreous syneresis in a membranous or beaded configuration and radial perivascular retinal Lattice degeneration, both of which are present in up to 100% of affected patients[7]. These vitreoretinal abnormalities may lead to a giant retinal tear and rhegmatogenous retinal detachment in up to 50% of patients. Less common findings include axial myopia (present in 80%) resulting from megaophthalmos, open-angle glaucoma resulting from anterior segment dysgenesis, and cataract. The cataract is typically a congenital quadrantic lamellar opacity which may not involve the visual axis.

Systemic findings may include micrognathia and macroglossia resulting in cleft palate (Pierre-Robin sequence: an unusually small mandible (micrognathia), posterior displacement or retraction of the tongue (glossoptosis), upper airway obstruction, and cleft palate), evidence of osteoarthritis on hip, spine and knee radiography, and hearing loss, which may be conductive, sensorineural, or both. The presence of a cleft palate or a typical Pierre-Robin sequence facies may be readily apparent and provide helpful diagnostic information.

Symptoms

Ocular symptoms may include visual field loss related to rhegmatogenous retinal detachment, as well as decreased acuity secondary to myopia or cataract. Systemic symptoms may include hearing loss and joint pain.

Clinical diagnosis

Beaded vitreous in Type 2 Stickler syndrome
The diagnosis of Stickler syndrome has historically been based on the presence of characteristic clinical features; in Types 1-3, the systemic findings may prompt ophthalmic referral prior to development of any visual complaints. Type 4, the ocular-only variant, may remain asymptomatic prior to routine eye examination or development of retinal detachment; the ophthalmologist therefore plays a key diagnostic role in these cases[8]. Reflecting its large collagen content, the vitreous is the primary ocular site affected in Stickler syndrome. Classically, the Stickler vitreous is described as “optically empty”[9], though differing phenotypes have been described based on slit lamp findings: The so-called membranous vitreous appears as a collection of gel in the immediate retrolental space, posteriorly bounded by a membranous condensation. The beaded vitreous contains diffuse, sparse lamellae with a beaded appearance. A third variant has been described as a generally hypoplastic vitreous with the “optically empty” appearance but lacking the membranous or beaded features. As noted above, the membranous and beaded phenotypes are associated with the COL2A1 and COL11A1 genes, respectively; this relationship has proven useful in performing targeted molecular genetic analysis.

Due to the difficulty in slit-lamp examination of infants and young children, the earliest ophthalmic findings noted may be the characteristic radial perivascular retinal degeneration visible on indirect ophthalmoscopy. This finding is not present at birth, but may be seen within the first 4 years of life, and typically manifests as patches of retinal pigment epithelium atrophy around the major vessels which subsequently become darkly hyperpigmented. In ocular-only variants, this may be the only obvious clue to early pediatric diagnosis[10]. Retinal tears, when present, typically occur at the edge of an atrophied area.

Diagnostic procedures

Diagnosis of Stickler syndrome is clinical. Targeted molecular genetic analysis based on the vitreous phenotype has been successful, though the benefit of genetic screening is unclear at this time. Detection of the typical ophthalmic findings generally warrants evaluation for associated systemic abnormalities; this would include audiometric and radiographic evaluation.

Differential diagnosis

The differential diagnosis includes other type II/XI collagenopathies:

Management

General treatment

Treatment of Stickler syndrome is primarily supportive, although there may be a role for prophylactic treatment to prevent complicated retinal detachment.

Medical therapy

With the possible exception of topical ocular antihypertensives for associated glaucoma, there is no effective medical treatment for prophylaxis or amelioration of the ocular signs and symptoms of Stickler syndrome. Medical treatment by the pediatrician or primary care physician may be beneficial for the associated precocious osteoarthritis.

Surgery

Retinal detachment is a common cause of visual loss in patients with Stickler syndrome; it is estimated to occur in up to 65% of affected patients, and indeed, Stickler syndrome is the most common inherited cause of rhegmatogenous retinal detachment.[11] Detachment causing visual loss most typically occurs in young adulthood, but may occur within the first five years of life. Patients are particularly at risk of developing a Giant retinal tear (GRT), which typically occurs during Posterior vitreous detachment. Associated retinal detachments are notoriously difficult to manage and patients are prone to development of Proliferative vitreoretinopathy (PVR).[12][13] Treatment with primary vitrectomy is generally more successful than scleral buckling procedures and has been suggested to the procedure of choice in Stickler syndrome-related retinal detachment.

Prophylactic treatment of peripheral retina using 360-degree cryotherapy or circumferential laser appears may be effective in reducing rates of retinal detachment. Both treatment modalities have been retrospectively compared to observation and both are apparently effective in significantly decreasing risk of retinal detachment; however, neither modality has been shown to be superior to the other.[14] It has been recommended that the option for prophylactic treatment be discussed with patients in early life.[15][16]

Patients with associated open-angle glaucoma may require surgical intervention. The availability of published data to guide management in such cases is limited; however, glaucoma in Stickler syndrome is presumed to be related to anterior segment dysgenesis and therefore angle surgery (Goniotomy or Trabeculotomy) may be beneficial. Filtering procedures remain viable options for refractory cases.

As noted above, the typical cataract found in Stickler syndrome is of a congenital quadratic lamellar type[17]. Such cataracts may or may not negatively impact vision; if decreased vision is present, removal may be performed with standard Lensectomy or Phacoemulsification. Patients are at an increased risk of both vitreous loss and post-operative retinal detachment; retinal breaks should be addressed prior to cataract surgery.[18]

Follow up

Untreated patients and patients who have undergone prophylactic cryotherapy or laser remain at increased lifetime risk of retinal detachment. Patients who have undergone operative repair of retinal detachment similarly remain at risk for re-detachment and all patients should be monitored regularly on a long-term basis.

Patients undergoing glaucoma angle or filtering procedures and patients undergoing cataract extraction require routine follow up.

Prognosis

There is currently no available data on long-term visual prognosis of Stickler syndrome; however, prophylactic treatment to prevent retinal detachment is expected to improve long term visual prognosis. Ocular and systemic abnormalities are progressive and the rate of significant disability from blindness, hearing loss and crippling arthritis would be expected to increase with increasing age.

Additional Resources

References

  1. STICKLER G. HEREDITARY PROGRESSIVE ARTHRO-OPHTHALMOPATHY. Mayo Clinic proceedings. 1965-06;40:433-55.
  2. Snead M. Stickler syndrome, ocular-only variants and a key diagnostic role for the ophthalmologist. Eye (London). 2011-11;25:1389-400.
  3. Pediatric Ophthalmology and Strabismus, Section 6. Basic and Clinical Science Course, AAO, 2011-2012.
  4. Snead M. Stickler syndrome, ocular-only variants and a key diagnostic role for the ophthalmologist. Eye (London). 2011-11;25:1389-400.
  5. Snead M. Stickler syndrome, ocular-only variants and a key diagnostic role for the ophthalmologist. Eye (London). 2011-11;25:1389-400.
  6. Snead M. Stickler syndrome, ocular-only variants and a key diagnostic role for the ophthalmologist. Eye (London). 2011-11;25:1389-400.
  7. E.S. Parma, J. Korkko, W.S. Hagler, L. Ala-Kokko. Radial perivascular retinal degeneration: a key to the clinical diagnosis of an ocular variant of Stickler syndrome with minimal or no systemic manifestations. Am J Ophthalmol, 134 (2002), pp. 728–734
  8. Snead M. Stickler syndrome, ocular-only variants and a key diagnostic role for the ophthalmologist. Eye (London). 2011-11;25:1389-400.
  9. Pediatric Ophthalmology and Strabismus, Section 6. Basic and Clinical Science Course, AAO, 2011-2012.
  10. E.S. Parma, J. Korkko, W.S. Hagler, L. Ala-Kokko. Radial perivascular retinal degeneration: a key to the clinical diagnosis of an ocular variant of Stickler syndrome with minimal or no systemic manifestations. Am J Ophthalmol, 134 (2002), pp. 728–734
  11. Ang A. Retinal detachment and prophylaxis in type 1 Stickler syndrome. Ophthalmology (Rochester, Minn.). 2008-01;115:164-8.
  12. Ang A. Retinal detachment and prophylaxis in type 1 Stickler syndrome. Ophthalmology (Rochester, Minn.). 2008-01;115:164-8.
  13. Retina and Vitreous, Section 12. Basic and Clinical Science Course, AAO, 2011-2012.
  14. Carroll C. The clinical effectiveness and safety of prophylactic retinal interventions to reduce the risk of retinal detachment and subsequent vision loss in adults and children with Stickler syndrome: a systematic review. Health technology assessment (Winchester, England). 2011-04;15:iii-xiv, 1-62.
  15. Snead M. Stickler syndrome, ocular-only variants and a key diagnostic role for the ophthalmologist. Eye (London). 2011-11;25:1389-400.
  16. Retina and Vitreous, Section 12. Basic and Clinical Science Course, AAO, 2011-2012.
  17. Snead M. Stickler syndrome, ocular-only variants and a key diagnostic role for the ophthalmologist. Eye (London). 2011-11;25:1389-400.
  18. Pediatric Ophthalmology and Strabismus, Section 6. Basic and Clinical Science Course, AAO, 2011-2012.