STICKLER SYNDROME: AN UNDERDIAGNOSED DISEASE. REPORT OF A FAMILY. DE KEYZER THW*, DE VEUSTER I*, SMETS R-M E*

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1 STICKLER SYNDROME: AN UNDERDIAGNOSED DISEASE. REPORT OF A FAMILY. DE KEYZER THW*, DE VEUSTER I*, SMETS R-M E* ABSTRACT Purpose: To report a family diagnosed with Stickler syndrome. To emphasize that early recognition of patients with Stickler syndrome could improve the visual outcome. Methods: Case report. Results: A 14 year old girl of Mahgrebian origin presented with a longstanding subtotal RRD in the right eye. Subsequently 6 family members in 3 generations have been identified with the same COL2A1 mutation. 4 e lost perception of light and 1 eye was enucleated. Stickler syndrome is the commonest inherited cause of rhegmatogenous retinal detachment (RRD). These tend to be complex and to occur at young age, frequently affecting both e. Other ocular features consist of high myopia, optically empty vitreous cavity, posterior radial paravascular lattice-type degeneration, cataract and glaucoma. Non-ocular findings include midface hypoplasia, musculoskeletal changes and hearing loss. In severe cases the disorder will readily be suspected. In mildly affected patients, clinical diagnosis can be quite difficult. Therefore, all family members of a Stickler patient should be offered molecular genetic testing. Stickler patients benefit from a multidisciplinary approach, including audiologic examination. They should be informed about the symptoms associated with retinal tears and retinal detachment and have priviliged access to the ophthalmic care unit. In case of RRD, vitrectomy is the preferred surgery. Prophylaxis of RRD in Stickler syndrome patients consisting of a 360 peripheral cryotherapy or photocoagulation has been proposed. Practical guidelines for follow up or thresholds for initiating treatment have not been formulated. Conclusions: Stickler syndrome remains under-diagnosed. Hightened awareness of Stickler syndrome could improve visual outcome in affected individuals and makes genetic counseling possible KEYWORDS Stickler syndrome - Retinal detachment - Genetic counselling zzzzzz * M.D., Department of Ophthalmology, Antwerp University Hospital Submitted: May 12, 2011 Accepted: Jul 25, 2011 Bull. Soc. belge Ophtalmol., 318, 45-49,

2 INTRODUCTION Stickler syndrome is the commonest inherited cause of rhegmatogenous retinal detachment (RRD) (2,15). These tend to be complex and to occur at young age, frequently affecting both e. (1) As children rarely report visual symptoms, this often results in late detection of the RRD and poor visual function, even after successful surgical repair. Early recognition of the RRD could improve the visual outcome in patients with Stickler syndrome, but the condition remains under-diagnosed. MATERIALS AND METHODS Case report and short review of literature. RESULTS The proband, a 14 year old girl of Mahgrebian origin (II.8 in Figure 1), presented with a longstanding subtotal RRD in the right eye. Myopia, perivascular pigmentary changes and severe vitreous liquefaction were observed bilaterally. A high arched palatum was noted. Stickler syndrome was suspected. Audiometry disclosed bilateral sensorineural hearing loss. Genetical testing confirmed an autosomal dominant variant of Stickler syndrome c insc (p.pro938fsx943) mutation in the COL2A1 gene. Six family members in 3 generations (Pedigree Figure 1) have since been identified with the same COL2A1 mutation. They all had a myopic astigmatism (mean myopia: -5,3D, range [-2,25D to -19,0D]; mean astigmatism: -1,5D, range [-1,0D to -3,0D]). Their clinical details and year of presentation are summarized in Table I. In the family we report, the diagnosis of Stickler syndrome was finally made after a period of 20 years, during which 5 RRD occurred. Meanwhile, 4 e lost perception of light and 1 eye was enucleated. Since the genetic mutation was confirmed, 1 RRD was treated in an early stage with preservation of preoperative visual acuity. In another eye multiple asymptomatic retinal tears were photocoagulated. One affected child is in regular follow up. A newborn with cleft palate did not have ophthtalmologic screening untill now. DISCUSSION Stickler syndrome (hereditary arthro-ophthalmopathy) was first reported in (17) It is an inherited collagen disorder, caused by spe- Table 1: Summary of clinical findings Sibling Year of presentation I Age (years) at presentation Opthalmologic history Bilateral pseudophakia Open angle glaucoma Multiple perivascular retinal breaks Best corrected Visual Acuity RE : 0,5 LE: 0,32 II RE: RRD, aphakia RE: no LP LE: 0,16 II Bilateral RRD RE : no LP LE: no LP II Bilateral RRD RE: enucleated II RE: aphakia, disseminated pigment migration, LE: RRD, aphakia RE: no LP LE: 0,16 RE : no LP LE: 0,25 II RE: RRD, aphakia RE: CF LE: 0,3 III Axial anisometropia with left amblyopia RE: 0,63 LE: 0,5 Hearing loss No No Additional finding High arched palatum III Newborn unknown unknown Cleft palate LP: Light perception; CF: counting fingers; RRD: rhegmatogenous retinal detachment 46

3 Fig. 1: Pedigree cific mutations in certain genes coding for collagen II, IX, XI. (4,11,13,18) Collagens maintain structural strength in tissues throughout the body. At least 22 different collagen types have been detected in the eye. Several types of collagen are recognized: fibril-forming (fibrillar) collagens, fibril-associated collagens and collagens that form structures unrelated to fibrils. The fibrillar collagen providing structural strength of the vitreous and cartilage, consists in major part of type II.. Type XI has a role in collagen fibril assembly, which is of great importance in transparent tissues, such as vitreous and cornea (mutations in type XI collagen can result in thicker than normal fibrils). Type IX collagen fibrils are regularly aligned along the surface of the fibrils composed of collagen types II and XI. (15,18) Stickler syndrome due to mutations in type II and type XI collagen has an autosomal dominant pattern of inheritance, while mutations in collagen type IX causes an autosomal recessive disorder. (12,16,18) Observed differences in vitreal appearance have led to subtyping of Stickler syndrome. (11,12,15) (Table II). However, recently less correlation between gene mutation and vitreous phenotypes has been suggested. (14) Besides Stickler syndrome, a variety of other inherited disorders can be caused by mutations in fibrillar collagen genes, like osteogenesis imperfecta, otospondylomegaepiphyseal dysplasia and some types of Ehlers-Danlos syndrome. (15) Clinical features Stickler syndrome s estimated incidence is about 1 in newborns. This number is much higher (15%-30%) in neonates with Robin sequence: the triad of micro- and/or retrognatia, glossoptosis and cleft palate. (7,19) In Stickler syndrome usually a congenital non progressive high myopia is reported. (16) In some of our Stickler patients we noticed a subnormal visual acuity. Because timely and appropriate refractive correction was provided in infancy, the possibility of an organic based amblyopia could be considered. Abnormalities of vitreous formation and gel architecture are characteristic of Stickler syndrome. (5,16) The vitreous is typically empty. A vestigial retrolental vitreous gel, bordered by a distinct folded membrane is typical of Type I Stickler. Sparse, irregularly thickened collagen bundles are observed in type II. (11,12,15) More recently another vitreous type was found in a Stickler family and was described as less dense, hypoplastic architecture of the vitreous. (14) Paravascular lattice-type degeneration, although one of the most consistent findings in Stickler syndrome, is not pathognomonic for the disorder, as it has also been associated with syphilis, tuberculosis and variants of retinitis pigmentosa. (4) In Stickler syndrome nearly half of the patients suffer from RRD, often from a giant retinal tear (GRT). This can occur early in childhood. This contrasts strongly with the 1: incidence in the general population. (5,7) Congenital and non-progressive cataract may occur. Also glaucoma due to developmental abnormalities in anterior chamber structures was reported. (16) Non-ocular findings include midface hypoplasia, broad nasal bridge, micrognathia. These features become less apparent with increasing age. (16,18) 47

4 Table II: Stickler vitreous types Stickler syndrome vitreous type Inheritance Collagen type Mutation I: membranous or afibrillar AD Type II COL2A1 II: beaded AD Type XI COL11A1 III: non-ocular AD Type XI COL11A2 Some evidence of midline clefting, ranging from the extreme Pierre Robin sequence, through clefting of the hard/soft palate, to the mildest manifestation of bivid uvula is present in 25% of the cases. (7,16,19) Hearing loss (sensorineural, mixed and conductive), typically high tone and subtle occurs in 40% of Stickler syndrome patients. (16,18) Typical musculoskeletal changes (spondyloepiphyseal dysplasia, hip subluxation, hyperextensive joints and severe premature arthropathy) become clinically apparent afther the 4 th decade. (16) Diagnosis Early recognition of the Stickler syndrome phenotype is important for accurate counseling and optimal treatment. (7,11,12) In severe cases the disorder will readily be suspected. In mildly affected patients, clinical diagnosis can be quite difficult. Therefore, all family members of a Stickler patient should be offered molecular genetic testing. Prenatal ultrasound exam can detect micrognathia or cleft palate at weeks of gestation. However, the absence of Pierre Robin sequence does not exclude the diagnosis of Stickler syndrome. (10,11,16) When the disease causing mutation is known, prenatal diagnosis of Stickler syndrome can be considered. Prenatal diagnosis or exclusion of COL2A1 mutation was reported by DNA analysis from a chorionic villus sample. (8,19) General management Stickler patients benefit from a multidisciplinary approach. (16) Audiologic examination is designated to detect sensorineural hearing loss. In case of learning difficulties due to combined visual and auditory impairment educational advice should be offered. Ocular management Stickler patients should be informed about the symptoms associated with retinal tears and retinal detachment: floaters, photopsia and visual field loss. Furthermore, they must be instructed to seek urgent ophthalmic care in the event of such symptoms. Priviliged access to the ophthalmic care unit is undisputed. In case of Stickler RRD, vitrectomy is the preferred surgery. Abeysiry et al found in a retrospective observational study that anatomical results and functional visual outcome were better after primary vitrectomy than after primary bucling. (1) Prophylaxis of RRD in Stickler syndrome patients consisting of a 360 peripheral cryotherapy or photocoagulation has been proposed. (2,8) Ang et al stated that transconjunctival contiguous post-oral retinal cryotherapy, in Stickler e unaffected from RRD, could reduce the risk of GRT formation and of RDD. Furthermore it could prevent blindness due to bilateral RRD. (2) Leiba et al (8) studied prophylactic photocoagulation in Stickler e. Extensive vitreoretinopathy recieved photocoagulation over 360 around the peripheral retina, focal laser treatment was applied around pathologic areas in e with isolated lesions. They concluded that the incidence of RRD was significantly lower in lasered e than in non-lasered e (p < 0.025). In a recent systematic review Carroll et al criticized both studies mentioned above due to the retrospective study design. (3) They concluded that the relative effectiveness of cryotherapy or laser treatment remains uncertain, neither in comparison with each other, nor in comparison with no treatment at all. To improve certainty of relative efficacy, they suggest a nonrandomised, prospective cohort comparison study design to compare laser treatment and cryotherapy with each other and with no treatment. 48

5 Up till now, practical guidelines for follow up or thresholds for initiating treatment have not been formulated. The potential benefit of artificial induction of PVD (by microplasmin) in preventing RRD is to be awaited. (6) CONCLUSION This family report illustrates that Stickler syndrome remains under-diagnosed. Hightened awareness of Stickler syndrome could improve visual outcome in affected individuals and makes genetic counseling possible. REFERENCES (1) Abseysiri P. et al. Outcomes of surgery for retinal detachment in patients with Stickler syndrome: a comparison of two sequential 20- year cohorts. Graefe s Arch Clin Exp Ophtalmol (2007) 245: (2) Ang A et al. Retinal detachment and prophylaxis in Type 1 Stickler syndrome. Ophthalmology (2008); 115: (3) Carroll C et al. 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 2011; vol 15: No. 16 (4) DonosoLAetal. Clinical variability of Stickler syndrome: role of exon 2 of the collagen COL2A1 gene. Survey of Ophthalmology (2003) Volume 48-2 (5) Edwards AO Clinical features of the congenital vitreoretinopathies. Eye (2008) 22: (6) Gandorfer A et al. Posterior vitreous detachment induced by Microplasmin. Investigative Ophthalmology & Visual Sience, Febuary 2004, Vol 45, No 2 (7) Huang F et al. Visual complications of Stickler syndrome in paediatric patients with Robin sequence. Journal of Cranio-Maxillofacial Surgery (2007) 35, (8) Leiba H et al. Prophylactic laser photocoagulation in Stickler syndrome. Eye (1996); 10: (9) Lisi V et al. Linkage analysis for prenatal diagnosis in a familial case of Stickler syndrome. Genet Couns (2002); 13(2): (10) Pacella E et al. Stickler syndrome in Pierre- Robin sequence prenatal ultrasonographic diagnosis and postnatal therapy: two cases report. Eur. Rev. Med. Pharmacol Sci (2010); 14(12): (11) Parke II D W Stickler syndrome: clinical care and molecular genetics. American Journal of Ophthalmology (2002) 134, vol5, (12) Peter S Rose et al Stickler Syndrome: clinical characteristics and diagnostic criteria. American Journal of Medical Genetics 138A: (2005) (13) Richards A J et al. Molecular genetics of rhegmatogenous retinal detachment. Eye (2002) 16, (14) Richards A J et al. Stickler syndrome and the vitreous phenotype: mutations in COL2A1 and COL11A1. Eye (2002) 16, (15) Richards AJetal Variation in the Vitreous Phenotype of Stickler syndrome can be caused by different amino acid substitutions in the X position of the type II collagen Gly-X-Y triple helix. Am. J. Hum. Genet. (2000) 67: (16) Snead MPetal. Clinical and molecular genetics of Stickler syndrome. Journal of Medical Genetics (1999) 36, (17) Stickler GB, Belau PG, Farrell FJ, Jones JD, Pugh DG, Steinberg AG, Ward LE (1965) Hereditary progressive arthro-ophthalmopathy. Mayo Clin Proc 40: (18) Van Camp G et al. A New Autosomal Recessive Form of Stickler syndrome is caused by a mutation in the COL9A1 gene. American journal of Human Genetics (2006) 79, (19) Webb ACetal. The diagnosis and consequences of Stickler syndrome. British Journal of Oral and Maxillofacial Surgery (2002) 40, (20) Zlotogora J et al. Prenatal exclusion of Stickler syndrome. Prenat Diagn (1994); 14(2): zzzzzz Address for correspondence: tomasdekeyzer@hotmail.com ilse.de.veuster@uza.be Erica.smets@uza.be Antwerp University Hospital, Wilrijkstraat 10, 2650 Edegem, Belgium 49