**1. Introduction**

Originally described in 1965, Stickler syndrome is a multiorgan system connective tissue disorder with an estimated incidence between 1:7500–1:9000 births [1, 2].

To date, Stickler syndrome has been reported to be caused by mutations in seven genes including COL2A1, COL11A1, COL11A2, COL9A1, COL9A2, COL9A3, and LOXL3 [3]. Mutations in the first three genes are inherited in an autosomal dominant pattern, while mutations in the latter four genes are inherited in an autosomal recessive pattern. These genes are associated with formation of collagen type II, IX, and XI [4].

Ocular manifestations of Stickler syndrome can be seen in 95% of patients [3]. The hallmark ocular finding of Stickler syndrome is vitreous abnormalities, seen in 40% of patients [4, 5]. Patients also present with high myopia (90%) and congenital cataracts (30%) [4, 5]. 40–80% of Stickler syndrome patients can develop retinal

detachments, which makes it the most common cause of inherited pediatric retinal detachments [4–9].

Given its multisystem manifestations, as ophthalmologists, it is important to be aware of both the ocular and systemic clinical manifestations of this disease. Additional common clinical findings often include craniofacial abnormalities (84%), hearing loss (70%), and arthropathy (90%) [3]. Finally, early arthritis is common among all patients with Stickler syndrome. Other spinal abnormalities have also been reported including scoliosis and kyphosis with resulting chronic back pain affects the majority of adults [3].

Stickler syndrome Type 1 (STL1) is primarily due to autosomal dominant mutations in *COL2A1* and accounts for 80–90% of cases [3, 10]. While the majority of individuals with *COL2A1* mutations exhibit systemic signs, individuals with other variants of the COL2A1 mutation may present with only ocular symptoms. Craniofacial abnormalities are common and are typically due to underdevelopment of the maxilla and result in midface hypoplasia, micrognathia, and Pierre Robin Sequence. Sensorineural hearing loss is the most common type of hearing loss seen in Stickler syndrome, however STL1 typically has a milder presentation of hearing loss. On the other hand, STL1 is associated with the highest rate of RD (60–74%) of all the subtypes [7]. A summary of the prevalence of each type of Stickler syndrome and the associated retinal detachment rate can be found in **Table 1**.

Stickler syndrome Type 2 (STL2) is less common than STL1 but is due to autosomal dominant mutations in *COL11A1*. Craniofacial abnormalities such as midfacial and nasal bridge flattening are typically less pronounced. Approximately 1/3 of patients have variable manifestations of midline clefting (for example bivid uvula, high arched palate, or cleft palate). On the other hand, more severe early onset hearing loss is much more common in type 2 than type 1. 45% of patients with STL2 have been estimated to have hearing loss, 80% of whom had high frequency sensorineural hearing loss [8]. STL2 has a reported incidence of RD of 42–50%, 19% of which are bilateral, making it the subtype with the second highest RD rate [8].

Mutations in COL11A2, which cause Stickler Syndrome Type 3 is the only gene not associated with ocular manifestations [4]. It primarily affects joints and can cause mild to moderate hearing loss [9].


*\* Retinal detachments have been reported in patients with this mutation. However, these reports have only been from case reports of families with these disorders.*

#### **Table 1.**

*Incidence of retinal detachment by Stickler syndrome subtype.*

*Approaches to Retinal Detachment Prophylaxis among Patients with Stickler Syndrome DOI: http://dx.doi.org/10.5772/intechopen.107289*

Finally, mutations in *COL9A1, COL9A2, COL9A3* result in the autosomal recessive variants of Stickler syndrome (Stickler syndrome type 4-6). There is more limited data on these rarer forms of Stickler syndrome. Unlike the autosomal dominant forms of Stickler syndrome, cleft palates are commonly not seen in Stickler Syndrome Type 4-6 [4]. Among the recessive types of Stickler syndrome (STL4-6), mild to moderate hearing loss has been reported in STL5, while STL4 and 6 tend to have more severe hearing loss [3].

STL4 has been associated with moderate sensorineural hearing loss most pronounced at higher frequencies, femoral head epiphyseal dysplasia, and spinal abnormalities similar to those seen in STL1-3. Retinal detachments have been reported in the literature in a case series of patients with STL4 but because of how rare STL4 is, incidence is unknown. STL4 has also been associated with exudative retinal detachments exudative retinal detachment [4, 11, 12].

In STL5, hearing loss, midface hypoplasia, and a small chin have been reported in small case series. Retinal detachments have also been reported in patients with this subtype [13].

Finally, STL6 has been associated with moderate to profound progressive sensorineural hearing loss and moderate to high myopia. This rarer type of Stickler syndrome has only been reported in seven total families with the biallelic recessive COL9A3 mutation. Cataracts and retinal detachment have also been reported. In contrast to other subtypes, skeletal involvement appears more variable in STL6 [14].

#### **2. Rationale for prophylactic treatment**

Unfortunately, surgical repair of RRDs in patients with Stickler syndrome is technically challenging because of the vitreous abnormalities and early presentation of these patients [7]. Stickler syndrome patients are likely to develop giant retinal tears and have a propensity for developing proliferative vitreoretinopathy [15]. Pediatric retinal surgeons are highly aware of the extensive and often multiple surgeries that these patients may require. Anatomic success rate after one surgery can vary from 19 to 78%, while 97% achieve successful reattachment with an average of 2.3 surgeries [15].

Visual outcomes after these extensive surgeries are moderate at best. One case series reported that best corrected visual acuity at last follow up (>1 year) was 20/103 [15]. Further discussion regarding the best surgical approach to managing these complex retinal detachments is out of the scope of this chapter. Given the long-term impact these extensive pediatric retinal detachments can have on Stickler syndrome patients, many pediatric retinal surgeons have explored approaches to prevent these complex retinal detachments from occurring. In particular, the use of prophylactic treatment to prevent or reduce the morbidity of retinal detachments has become increasingly employed.

Although definitive evidence supporting prophylactic treatment is lacking, several systemic review articles have suggested a decreased incidence of RD with prophylactic treatment [7, 16, 17]. However, there have been no prospective randomized control trials performed looking at prophylactic treatment of patients with Stickler syndrome. In addition, retrospective case series have not found a clear benefit from prophylactic laser retinopexy in reducing the rate of RDs in their patient cohort [18].

One challenge in developing a consensus regarding prophylactic treatment is that wide variability in treatment modality, technique, and timing varies from study to

study. In addition, many studies often rely on a clinical diagnosis of Stickler syndrome that has not been verified with genetic testing given lack of access. This makes headto-head comparison of these different studies challenging from both a treatment and patient selection perspective [19]. The three common approaches for prophylactic treatment include scleral buckle, laser retinopexy, and cryotherapy retinopexy. Some have even reported combined use of these approaches, for example, use of both cryotherapy and scleral buckle [20]. Others, in particular those who report use of laser retinopexy, employ a variety of laser treatment protocols that make it difficult to compare efficacy of one treatment approach to another. Much of the early literature regarding prophylactic treatment stem from robust trials using the Cambridge prophylactic cryotherapy protocol, however, cryotherapy is not widely used, especially the U.S. [11].

Given the wide variation in prophylactic treatment approaches, the purpose of this chapter is to provide an overview of the three primary types of prophylactic treatment (laser retinopexy, cryotherapy, and scleral buckle) and review the literature supporting these approaches.
