Clinical Variability of Stickler Syndrome

SURVEY OF OPHTHALMOLOGY VOLUME 48 • NUMBER 2 • MARCH–APRIL 2003

CURRENT RESEARCH EDWARD COTLIER AND ROBERT WEINREB, EDITORS

Clinical Variability of Stickler Syndrome: Role of Exon 2 of the Collagen COL2A1 Gene Larry A. Donoso, MD, PhD,1 Albert O. Edwards, MD, PhD,2 Arcilee T. Frost, MA,1 Robert Ritter III,2 Nina Ahmad, PhD,1 Tamara Vrabec, MD,1 Jerry Rogers, OD,3 David Meyer, MD,3 and Scott Parma, MD4 1

Henry and Corinne Bower Laboratory, the Eye Research Institute, Wills Eye Hospital, Philadelphia, Pennsylvania; Department of Ophthalmology and McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, Texas; 3The Vitreoretinal Foundation, Memphis, Tennessee; and 4 University of Louisiana, New Orleans, Louisiana, USA 2

Abstract. Stickler syndrome (progressive arthro-ophthalmopathy) is a genetically heterogeneous disorder resulting from mutations in at least three collagen genes. The most common disease-causing gene is COL2A1, a 54-exon–containing gene coding for type II collagen. At least 17 different mutations causing Stickler syndrome have been reported in this gene. Phenotypically, it is also a variably expressed disorder in which most patients present with a wide range of eye and extraocular manifestations including auditory, skeletal, and orofacial manifestations. Some patients, however, present without clinically apparent systemic findings. This observation has led to difficulty distinguishing this Stickler phenotype from other hereditary vitreoretinal degenerations, such as Wagner syndrome and Snowflake vitreoretinal degeneration. In this regard, review of the literature indicates type II collagen exists in two forms resulting from alternative splicing of exon 2 of the COL2A1 gene. One form, designated as type IIB (short form), is preferentially expressed in adult cartilage tissue. The other form, designated as type IIA (long form), is preferentially expressed in the vitreous body of the eye. Because of this selective tissue expression, mutations in exon 2 of the COL2A1 gene have been hypothesized to produce this Stickler syndrome phenotype with minimal or absent extraocular findings. We review the evidence for families with exon 2 mutations of the collagen COL2A1 gene presenting in a distinct manner from families with mutations in the remaining 53 exons, as well as other hereditary vitreoretinal degenerations without significant systemic manifestations. (Surv Ophthalmol 48:191–203, 2003. © 2003 by Elsevier Science Inc. All rights reserved.) Key words. alternative splicing • COL2A1 • exon 2 • genealogy • mitral valve prolapse • retinal detachment • Stickler syndrome • stop codon • vitreoretinal degeneration • vitreous • Wagner syndrome

Introduction

His mother was blind and also had joint problems. Five generations of this family were subsequently studied, and the condition was described as a domi-

In 1960, Gunnar Stickler, MD, examined a child with high myopia and enlargement of several joints. 191 © 2003 by Elsevier Science Inc. All rights reserved.

0039-6257/03/$–see front matter doi:10.1016/S0039-6257(02)00460-5

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nantly inherited progressive arthro-ophthalmopathy.52,53 Since its original description, this disorder has become commonly known as Stickler syndrome (Table 1).44,51 It has been shown to be a genotypically and phenotypically heterogeneous disorder with the majority (approximately 75%) of families having mutations in the gene coding for type II collagen (COL2A1)*.1,2,10,24,25,44,57 The COL2A1 gene has 54 exons (Table 1) and is located on chromosome 12.3 A minority of Stickler syndrome families have mutations in COL11A131,43 and COL11A248 genes, respectively (Table 1). In this regard, the mutation in the original family studied by Stickler involves an A to G transition in the COL2A1 gene (A-2 → G at the 3 acceptor splice site of IVS17) that produces a frame shift mutation in exon 18 leading to a premature stop codon as is typical of other mutations associated with this disorder.61 In the eye, posterior findings are prominent and include pigmentary degeneration, vitreous degeneration, and retinal breaks and detachments. A characteristic perivascular pigmentary degeneration is an ever-present finding in this condition as is vitreous degeneration. Several reports37,41 indicate there are two vitreous phenotypes. One is described as a retrolenticular membranous phenotype, which is associated with mutations in the COL2A1 gene. The other is a beaded phenotype, which arises from mutations in the COL11A1 gene (Table 1). Retinal detachments, including giant tears, occur in more than 60% of Stickler patients over their lifetime.54 Myopia (90%), early onset cataracts, and glaucoma are also common (Table 1). The extraocular features of Stickler syndrome include loose joints and joint pain (90%), hearing loss (70%), and some form of facial abnormality (84%), such as midline clefting and midfacial hypoplasia.35, 36,40,51,54 However, these clinical features are highly variable between and among families. Recent reports of Stickler syndrome have appeared that describe patients without clinically apparent articular, hearing, and facial findings leading to confusion between this Stickler syndrome phenotype and other vitreoretinal degenerations.12,17,38,42 The relatively recent discovery that the COL2A1 gene undergoes tissue specific, alternative splicing6 of exon 2 resulting in two forms of type II collagen may explain this phenotype (Fig. 1). Type IIB, coded by 53 exons of the gene (exon 2 is deleted), represents the shorter form of the molecule which predominates in cartilaginous tissues. On the other hand, type IIA, coded by all 54 exons of the gene (exon 2 is retained), represents the longer form of the molecule that predominates in the vitreous gel. Hence, mutations in exon 2 of the COL2A1 gene might be expected to produce a Stickler syndrome phenotype with predominately oc-

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ular manifestations as is commonly seen in other vitreoretinopathies (Table 1). We review the recent developments in the clinical and genetic features of exon 2 mutations of the COL2A1 gene in Stickler syndrome. Families with exon 2 mutations present in a distinct manner from families with disease-causing mutations in the other exons of the gene and may simulate other hereditary vitreoretinal degenerations.

Collagen and the Collagen Genes COLLAGEN

Collagens are a family of proteins consisting of a minimum of 35 types and are encoded by at least 17 genes.59 They are ubiquitous molecules distributed throughout the body and are characterized based on their tissue specific properties (Table 2). TYPE II COLLAGEN

Type II collagen is the major collagen component found in the adult vitreous, cartilage, and nucleus pulposus of the intervertebral disk of adults.13,33,55 Type II collagen accounts for approximately 70–90% of the total collagen in these tissues. The collagen molecule itself is composed of a triple helix formed by three  or  helical protein chains. The integrity of the  helix appears important for the overall integrity of the molecule. Type II collagen is an interstitial collagen synthesized as a procollagen molecule, assembled intracellularly into trimers within the cell, secreted, and then processed extracelluarly, resulting in the final form of the protein. Each  or  chain is formed from a precursor peptide in the form of a preprocollagen polypeptide. These precursor molecules contain portions at each end called registration peptides and an additional area called a signal peptide. At the site of assembly the signal peptide is removed resulting in the procollagen polypeptide molecule. Three such molecules are intertwined as a triple helix to form procollagen. Finally, the registration peptide is removed resulting in an intact collagen molecule existing as a triple helix with each chain being made up of a repetitive (Gly-X-Y) sequence. This finding may be important clinically as well. Richards and associates41 correlated the clinical appearance of the vitreous with mutations that alter the X position in the Gly-X-Y triple helix. They found that alterations in the triple helix structure of collagen give rise to differences in the phenotypic appearance of the vitreous gel. For example, a L467F mutation produces an afibrillar vitreous gel devoid of all normal lamellar structure.41 ALTERNATIVE SPLICING

As already noted, type II collagen exists in two forms, type IIA and type IIB. These two forms arise by alterna-

Systemic  Eye Systemic  Eye Systemic Cleft palate, Hearing loss, Flattened facies, Arthropathy

Predominately Eye Minimal to Absent

50% or more

Preretinal avascular membranes, presenile cataract, glaucoma

Visual fields normal unless pronounced chorioretinal atrophy, Progressive abnormalities of dark adaption and rod and cone ERG

Other

Visual Physiology

None

None

None

None

None

Optically empty vitreous, Vitreous veils and bands, Membranous membranes

Optically empty vitreous, vitreous veils and bands, beaded vitreous membranes Sheathing of peripheral vessels, choriocapallaris atrophy, perivascular pigmentation pattern

None

High Myopia, Astigmatism

66

68

53

exon 2

6/COL11A2

1/COL11A1

12/COL2A1

Stickler Syndrome

Retinal Detachment

Vasculature

Chromosome /Gene Number of exons Systemic status Systemic Finding Refractive Error Vitreous

Feature

Preretinal avascular membranes, Presenile cataract Peripheral field loss or ring scotoma, Progressive abnormalities of dark adaption and rod and cone ERG (85%)

15%

Sheathing of peripheral vessels. Choriocapillaris atrophy, bone spicule pigmentation pattern

Low to moderate myopia Optically empty vitreous, vitreous veils and bands

Eye Only None

Unknown

5/Unknown

Wagner’s Disease

Features of Autosomal Dominant Hereditary Vitreotetinal Degenerations

TABLE 1

Stage 1, extensive white without pressure Stage 2, snowflakes Stage 3, retinal vessel sheathing, pigmentation Stage 4, disappearance of peripheral retinal vessels Common in eyes with aphakia and lattice degeneration Presenile cataract Preretinal neovascularization Peripheral visual field defects, Progressive abnormalities of dark adaption and rod and cone ERG

Liquified with condensations

Myopia

Eye Only None

Unknown

Unknown

Snowflake Degeneration

CLINICAL VARIABILITY OF STICKLER SYNDROME

193

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Fig. 1. Schematic diagram of the COL2A1 gene containing 54 exons. Procollagen arises from mRNA in which exon 2 has been retained (type IIA) or spliced out (type IIB). Type IIA collagen is predominately expressed in the vitreous gel, whereas type IIB collagen predominates in cartilage. Mutations in exon 2 of type IIA collagen predominately affect the eye. Mutations in the remaining 53 exons predominately affect the eye and systemic tissues giving rise to typical Stickler syndrome.

tive splicing of the COL2A1 gene, a cellular mechanism whereby not all exons of a gene are processed in creating the final form of the protein. This process produces a related set of mRNA (messenger RNA) which codes for a family of related proteins that are often tissue specific. Alternative splicing represents a means of producing protein diversity in eukaroytes. With regard to type II collagen, alternative splicing appears to have an important role in the integrity of the chondrocyte. For example, the expression of exon 2 correlates with changes in cell morphology during tissue development, suggesting that alternative splicing regulates the expression of a protein domain in the type II procollagen molecule. This tissue specific protein expression may play an important role in development and determining cellular function as well as an important factor in chondrogenesis.45

This observation that exon 2 is not expressed in adult cartilage suggest patients with exon 2 mutations might be expected to show limited systemic manifestations. However, in the embryo exon 2 containing COL2A1 is transiently expressed during axial and appendicular skeletal growth, as well as the optic capsule and nasal septum.34 Thus, this transient expression and subsequent lack of expression of exon 2 COL2A1 may help explain the dramatic reduction in systemic manifestations in this Stickler syndrome phenotype.

Reported Families with Exon 2 Mutations We found reports for nine families with vitreoretinal degeneration and documented mutations in exon 2 of the COL2A1 gene (Table 3). Richards and associates42 reported the first three families (Family 1, 3 generations; Family 2, 3 generations; Family 3, 3 gen-

195

CLINICAL VARIABILITY OF STICKLER SYNDROME TABLE 2

Summary of Collagen Types Type

Feature

I IIA IIB III IV V VI VII VII IX X XII XIV

Fibrillar; tendon, skin, ligament Cartilage Vitreous Skin, vessels, tendon Network forming, basement membrane Fetal membranes (associated with type I) Cartilage (associated with type II); vessels, skin Anchoring, anchoring filaments Decements membrane Fibril associated, cornea Hypertorphic Embryonic tendon Fetal skin, tendon

erations). Two additional families have been reported, including a French-Canadian (Family 4, 6 generations)17 and a Dutch family (Family 5, 4 generations, personal communication).56 We have ascertained four additional families (Family 6, 12 generations; Family 7, 12 generations; Family 8, 6 generations; and Family 9, 8 generations). Family members from at least two of these families have been reported earlier prior to the identification of the genetic defect, including Family 64 and Family 9.18 CLINICAL DESCRIPTIONS OF EXON 2 FAMILIES—OCULAR Common Clinical Features

The most common clinical features of affected exon 2 family members is posterior perivascular degeneration and vitreous degeneration. In our experience (over 30 years; Family 6 and Family 9; 194 affected individuals), the earliest retinal changes described by the subjects’ physician (DM) are white, glistening, “cystic-like” lesions followed by pigmentation along the radial posterior blood vessels (Fig. 2 and Fig. 3; Table 4). These lesions were observed in

individuals as young as 3 to 4 years of age (personal observation) and progressed over time so that essentially all subjects demonstrated this finding by age 21 years.38 It is also of interest to note that such fundus changes were described by Hagler and Crosswell in 196818 in a series of 33 patients with perivascular chorioretinal degeneration identical to those reviewed herein. In their series 91% of the subjects were found to have perivascular degeneration located only adjacent to the veins. It is now known that several of these patients are part of Family 9. Similarly, in 1965 Alexander and Shea4 reported a series of two families (Family 1; 45 members, 13 affected, 5 generations; and Family 2, 142 members, 47 affected, 7 generations) residing in Canada with identical fundus features. Patients from these families are now known to be members of the family (Family 4) described by Gupta and associates.17 Although perivascular pigmentation is one of most consistent findings in these families, it is not pathopneumonic as this finding has been associated in other conditions such as syphilis, tuberculosis, and variants of retinitis pigmentosa.11,18,49 Despite this, this finding should alert the ophthalmologist to suspect Stickler syndrome particularly in the presence of vitreous degeneration. Vitreous Changes Vitreous changes including syneresis and band formation is another consistent clinical finding in exon 2 families. As shown in Table 4, virtually all patients, except those reported by Gupta and co-workers,17 had an optically empty vitreous. In our experience, the presence of vitreous bands (Fig. 3) or veils is also common. Several groups have extensively characterized the vitreous phenotype in subjects with exon 2 and other mutations in the collagen gene.37,42,50 They have classified the vitreous gel into two different phenotypes, the most common being membranous, which is associated with mutations in the COL2A1 gene, and, less frequently a beaded vitreous phenotype has been associated with muta-

TABLE 3

Summary of Families With Exon 2 Mutations Family # 1 (MS11) 2 (MS13) 3 (MS62) 4 (French-Canadian) 5 (Dutch) 6 (Present report) 7 (Present report) 8 (Present report) 9 (Present report)

Mutation

Result

Reference

Frameshift; 4 base pair duplication Frameshift; 2 base pair deletion G→A Frameshift A→C C→A C→A C→A C→A

Stop in exon 2 Stop in exon 2 Stop in exon 2 Cys57 stop in exon 2 X64 stop in exon 2 Cys86 stop in exon 2 Cys86 stop in exon 2 Cys86 stop in exon 2 Cys86 stop in exon 2

Richards42 Richards42 Richards42 Gupta17 van der Hout56 Donoso12 Present Present Parma38

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fected patients within the exon 2 families (Table 4). Although some patients present with simple tears and uncomplicated retinal detachments, others present with multiple posterior tears and complicated retinal detachments (Fig. 4). In one series (Family 9) the surgical failure rate was 36%.38 Another common feature of this group of patients is the presence of proliferative vitreoretinopathy, as illustrated in Fig. 5. In this group of patients the mean age of detachment was less than 21 years of age. In our series (Family 6), the mean age of detachment was 15.2 years, which compares to Family 9 (11 years) and is often associated with a family history of retinal detachment (Figs. 6 and 7). Fig. 2. Fundus photograph showing early fundus changes. Note presence of chorioretinal atrophy, perivascular whitish lesions, and mild pigmentary changes adjacent to retinal vessels.

tions in the COL11A1 gene.37 Two of the authors of this review (Edwards and Vrabec) examined five affected patients in one branch of a family and concluded that four had a membranous phenotype, and the remaining patient had a posterior vitreous detachment where a retrolenticular membrane could not be observed. This clinical feature of the disorder appears important and worthy of continued evaluation. Retinal Detachment and Tears Complicated retinal detachment and tears occur with a high incidence in exon 2 families and is characteristic of this condition. Retinal tears and detachments occurred in between 57% and 91% of af-

Myopia and Presenile Cataract Other ocular features include myopia and presenile cataract. A history of moderate to high myopia is a frequent finding in these families. Parma and associates38 found 83% of patients in their series have refractive errors greater than 6.00 diopters (D). Similar results were found by Gupta and associates17 (9.50 D in patients without prior surgery). Presenile cataracts (occurrence before age 40 years) have also been reported with an increased frequency of 78% by Parma and associates38 in these families. Exon 2 Stickler Syndrome Families Compared with Non-Exon 2 Stickler Syndrome Families The frequency and severity of the ocular features resulting from mutations in the COL2A1 gene are approximately the same for exon 2 mutations as compared with other non exon 2 mutations in the COL2A1 gene54 as far as can be determined. This would be expected because exon 2 is expressed in the eye. CLINICAL DESCRIPTIONS OF EXON 2 FAMILIES—EXTRAOCULAR Frequency

Fig. 3. Retinal perivascular pigmentary degeneration. Vitreous band is also present.

Extraocular manifestations occur less frequently in families with exon 2 mutations, as compared to classic Stickler syndrome families. Extraocular manifestations in classic Stickler syndrome occur with a high incidence and include some form of orofacial (84%), hearing loss (70%), and joint problems (90%)54 (Table 4). These features are less prominent and often subtle in exon 2 families.42 For example, in Family 6 and Family 9 orofacial features including midfacial hypoplasia, depressed nasal bridge, anteverted nares, and micrognathia were conspicuously reduced or absent. This was true for the series reported by Gupta and associates.17 In addition, Richards42 found that 6 of 16 patients in his series of three exon 2 families had mild midfacial hy-

197

CLINICAL VARIABILITY OF STICKLER SYNDROME TABLE 4

Summary of Clinical Features Exon 2 Families 12

Reference Donoso Family # 6 Year 2002 Perivascular 100 pigmentation (%) Vitreous 100 syneresis (%) Retinal 57 detachment (%) Presenile 10 cataract (%) Oralfacial (%) 0 Skeletal (%) 5 Hearing loss 7.5 (%) Cleft palate (%) 1 Affected 95 examined (%) Total members 2,384 (No.) Generations 12 ERG Normal

38

Parma 9 2002 100

Other Families 42

Richards 1,2,3 2001 NR

17

Gupta 4 2002 100

56

van der Hout 5 NR

52

Stickler — 1965 NR

Stickler54 Wagner58 Graemiger16 — — — 2001 NR NR 54

100

100

71

100

NR

NR

NR

93

65

75

91a

NR

20

60

0

14

78

NR

NR

NR

NR

NR

NR

43

0 2 2

38 13 19

0 0 NR

0 0 0

20 NR

84 90 70

NR NR NR

NR NR NR

3 100

NR 16

NR 32

NR 25

3 20

NR 0

NR 21

NR 28

2,500

39

218

NR

65

316**

67

60

8 Normal

3 NR

6 NR

NR NR

6 NR

NR NR

3 Abnormal

5

NR  none reported **  represents a survey result References correspond to #52 original Stickler family, #54 follow-up of Stickler families, #58 original Wagner family, #16 follow-up of original Wagner family.

poplasia. Similarly, early onset hearing loss was infrequent and varied from 7–19%, as was true for skeletal problems (2–13%). Cleft palate has also been associated with Stickler syndrome.19,20,26 We found four patients from two different family branches with a history of cleft palate. In one case, this patient also had multiple, complicated, retinal surgeries for retinal detachment secondary to giant retinal tear. In addition to this patient, Parma and associates38 reported three cases of cleft palate occurring in the same family (mother, daughter, and son of the same immediate family). Mitral Valve Prolapse Mitral valve prolapse occurs in several connective tissue disorders. In one series of Stickler syndrome patients studied by Liberfarb and Goldblatt,27 they reported an incidence of 46%. This is in contrast to other series42 that have been unable to document this finding. In this regard, we observed a high incidence of mitral valve prolapse in one branch of Family 6. We also noted that mitral valve prolapse was present among several nonaffected family members, including the proband. These results suggest that the mitral valve prolapse that occurs in this family, occurs independently of the Cys86Stop mutation in exon 2 in the COL2A1 gene. It also raises the issue

that more than one gene may be responsible for the systemic effects seen in these families as well. CLINICAL DESCRIPTIONS OF FAMILIES—GENEALOGICAL

All reported families with exon 2 Stickler syndrome transmit the disease in an autosomal dominate mode of inheritance. In addition, direct DNA sequence analysis revealed a C to A transition (Fig. 8) at position 4363 within exon 2 of the COL2A1 gene, leading to the creation of a stop at codon 86 (TGA) in four of the nine families described herein (Families 6, 7, 8, and 9) raising the possibility as to whether these four families are related. In this regard, we conducted an extensive genealogical search and have been able to trace family members from Family 6 back to the year 1570 (Fig. 9; I:3). Other family members include direct descendants from the Mayflower voyage in 1620 (Fig. 9, II: 1). One author of this review (Parma) is a member of Family 9 and has personal knowledge of the clinical features of many members of this branch. However, our records indicate that an individual who was born in 1704 (Figure 9; IV:13) was, by inference, the family member from whom Cys86Stop, exon 2 mutation in the United States could be first documented. This individual was exempt from pay-

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Fig. 4. A 68-year-old man presented in 1980 with a past history of four retinal detachments in the right eye. The phthisical left eye had previously been enucleated. On examination the patient’s visual acuity was 20/400 in the right eye. Funduscopic examination revealed a retinal detachment. There were eight tears present, seven of which were predominately located posterior to the equator.

ing taxes after the revolutionary war because he was blind. His marriage resulted in five children. The eldest son migrated to the mid south following the Civil War and was also exempt from paying taxes because of blindness(Fig. 9; V:4). Descendants from another son (Fig. 9; V:5) moved to the southeastern part of the United States following the Cherokee Land Grant of 1813, thus joining Family 6 with Family 7 (Fig. 9). A third son (Fig. 9; V:5) joined Family 8 to this family. At the present time we are continuing to join Family 9 to this family. It is likely they are part of this larger family since they reside within the same narrow geographic location as Families 6, 7, and 8 and share some overlapping surnames. SUMMARY Stop Codons One of the unifying features of all nine families with exon 2 mutations of the COL2A1 gene is that all of the mutations resulted in stop codons (Table

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Fig. 5. Patient at age 20 who presented with a history of decreased vision in her right eye. Funduscopic evaluation of the right eye revealed extensive vitreous traction and massive preretinal membrane proliferation. The patient underwent a scleral buckling and encircling band procedure. Detachment persisted in spite of surgery. Her vision at last follow-up was light perception in the right eye and/ 20/60 in the left eye. The retina in the left eye detached 9 years later.

3). Premature stop codons signal the early termination of transcription and may occur by several different mechanisms. Frameshift mutations creating stop codons occur either by the addition or deletion of nucleotide base pairs as is the case in three of the reported nine families with exon 2 mutations (Table 3). Conversely, nucleotide transitions can give rise to stop codons. In this case a single nucleotide is mutated from one base to another creating a new stop codon. Such mutations have been found in the six remaining exon 2 mutation families (Table 3). Stop codons may be highly relevant because such altered proteins may not interact with other proteins properly, or they may not be translated (leading to haplo insufficiency). This may be particularly important for structural proteins, like collagen, since an altered protein may not form the required three dimensional structure required for function. This

CLINICAL VARIABILITY OF STICKLER SYNDROME

199

Fig. 6. A 12-year-old boy in January 2000 presented with a 1-month history of decreased vision in the right eye. Past medical history was significant for retinal detachment repair in both the patient’s father and grandmother. Furthermore, the patient’s great-grandmother and grandfather were blind, by history, from retinal detachment. His vision was light perception in the right eye and 20/40 in the left eye, respectively.

change may have an effect on the overall structure of collagen. Biosynthesis of fibrillar collagens, such as type II, requires synthesis of precursor chains known as procollagen alpha chains. Folding of procollagen involves association of three of these alpha chains (identical in the case of type II, encoded by the COL2A1 gene), which are disulfide linked through their globular carboxy (COOH) terminal propeptides. On forming this nucleus, there is a zipper-like propagation of the triple helix from the COOH to the amino (NH2) terminus. The premature stop codons reported to date would all cause synthesis of a truncated polypeptide lacking the carboxy terminus which therefore could not participate in the triple helix formation or may not be expressed at all leading to haploid insufficiency.14,59 Hence, it is likely these stop codons would reduce the synthesis of type II procollagen and thereby exert their overall effect on the vitreous structure leading to an altered vitreous phenotype which can be observed clinically.

Simulating Conditions and Nomenclature Historically, the first vitreoretinal degeneration was described by Wagner in 1938.58 He described a Swiss family with a vitreoretinal degeneration consisting of 18 affected members. Phenotypic features in this family included low myopia, vitreoretinal degeneration, and “bone spicule” pigmentary changes resembling that seen in retinitis pigmentosa. Dark adaptation was abnormal and the b-wave of the ERG was reduced. He described this entity as “degeneration hyaloideo-retinalis hereditaria” and is now commonly referred to as

Fig. 7. Top: Preoperative and Bottom: postoperative B-scan ultrasonogram of the right eye from patient illustrated in Fig. 6 showing attached retina following pars plana vitrectomy and fluid-air exchange. The patient underwent a trans pars plana vitrectomy, endo laser photocoagulation, gas fluid exchange for a 360-degree giant retinal tear. The retina was attached at last follow-up visit.

“Wagner’s disease.” No patient in this original family was reported to have a retinal detachment,32 and none of the original patients was observed to detach in a later follow-up study including 10 new patients by Bohringer.8 Graemiger and coworkers16 in a later follow-up study reported four patients with tractional retinal detachment (incidence 15%), and 87% of subjects showed abnormal b-wave amplitudes of the rod and cone system on electroretinography. Thus rhegmatogenous retinal detachment is not a prominent feature of Wagner syndrome. More recently the disease has been linked to chromosome 5q13-14.9,39 Two other conditions, erosive vitreoretinopathy,9 which is similar to the Wagner syndrome, and a novel hereditary developmental vitreoretinopathy with multiple ocular abnormalities7 have also been linked to 5q113-14 and may represent an allelic variant. The gene, however, has not been identified to date.

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Fig. 8. Mutation screening of exon 2 of the COL2A1 gene in a family branch demonstrating C to A transition creating stop codon. The position is indicated by nucleotide location within the COL2A1 gene (Accession No L10347). Amino acids in N-propeptide are numbered from the initiating methionine. Upper graph: Normal. Lower graph: C to A transition indicated by asterisk.

Stickler, on the other hand, in 1965 described a family with three prominent eye findings including high myopia, pigmentary changes, and retinal detachment occurring in the first decade of life that of-

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ten progressed to a blind and/or phthisical eye.52 In addition, these ocular findings occurred in association with progressive arthropathy. Hearing defects were reported in this condition 2 years later.53 In a 2001 survey (316 usable replies) by Stickler, Hughes, and Houchin,54 an incidence of retinal detachment was reported in 60% of patients, myopia in 90% of patients, and blindness in 4% of patients. Since these original descriptions by Wagner and Stickler, there have been a number of reports of patients with clinical features of either or both of these conditions as well as other vitreoretinal degenerations.21,46 These two conditions have been described under a variety of names, including “Wagner–Stickler,”15,28,29,30 “Stickler-like,”5 “Wagner syndrome with arthropathy,”15 and “primarily ocular Stickler syndrome.”42 Recent refinements in clinical descriptions of the various phenotypes and advancements in molecular techniques such as linkage analysis, gene identification, and mutation screening may aid in distinguishing the various phenotypes. In this regard, the presence of an optically empty vitreous, typical perivascular pigmentary changes, or

Fig. 9. Simulated family pedigree of a 14-generation family with autosomal dominant vitreoretinal degeneration. Affected individuals can be traced to generation 4, by inference. Squares represent males and circles represent females. Filled squares or circles represent affected individuals. The marriage between individual IV:13 and IV:14 gave rise to five offspring. Each offspring is designated as a branch. The earliest individual that can be inferred to be affected is IV:13. Descendants of three of his children are shown and give rise to Family 6, Family 7, and Family 8 respectively. Individual II:1 was a member of the Mayflower voyage in 1620.

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CLINICAL VARIABILITY OF STICKLER SYNDROME

early onset retinal detachment with minimal or absent systemic findings should alert the ophthalmologist to suspicion of exon 2 Stickler syndrome. Although these exon 2 Stickler patients resemble the Wagner syndrome patients, several important phenotypic distinctions should be noted. The unifying feature of all the exon 2 families is the presence of perivascular pigmentation and vitreous degeneration. Although not pathopneumonic, it is distinctly different from the bone spicule pigmentation seen in Wagner syndrome. In addition to the perivascular pigmentation, retinal detachment (often complicated) is one of the most striking differences between the two conditions. As noted, none of the original members of the family examined by Wagner presented with retinal detachment.58 When the original family was examined by Bohringer and associates,8,16 none of the patients in the original family had a retinal detachment (28 patients in 5 generations). Years later, only 10–15% of patients had a history of detachment, all of which occurred over the age of 45 years. This is in marked contrast to Stickler syndrome patients in whom 50% or more of patients will develop a retinal detachment during their lifetime and up to 75% of cases will be bilateral.38 Although not all series of the exon 2 families reported ERG changes, Parma and associates38 noted normal ERG findings in all of those patients tested (20), which is in marked contrast to the findings of Graemiger16 who reported that 87% of Wagner syndrome patients showed reduced b-wave changes. Linkage analysis provides an additional method to distinguish Wagner and Stickler syndromes. Although the disease causing gene for Wagner’s disease has not been identified, it has been linked to chromosome 5q13-14.7,9,62 This finding provides a method to distinguish these conditions if the size of the pedigree is large enough. In contrast, direct DNA sequencing for mutations in exon 2 (or the other collagen genes) can be performed. Furthermore, because essentially all known mutations in this condition result in a stop codon, several investigators have devised simple and rapid screening tests for stop codons.14,60

Patient Management The management of hereditary vitreoretinal degenerations can be separated into treatment of affected patients, genetic counseling, and reducing the risk of transmitting the disease gene to offspring. SURGICAL TREATMENT

Early in the course of this study detached retinas repaired with scleral buckling remained attached in fewer than 50% of cases (personal observation).

Many of these cases presented with complicated retinal detachments, including multiple posterior tears, which in some cases led to inoperable proliferative vitreoretinopathy. Following the introduction of vitrectomy techniques, permanent re-attachment was achieved in over 70% of eyes. Based on these observations, a case-controlled study of surgical intervention may be a consideration for future treatment of these patients. GENETIC COUNSELING

Genetic counseling should be offered to all affected patients, and family members as well as those at risk for inheriting the disease gene. Family members should be told this disease is autosomal dominant with the chance that 50% of their offspring will inherit the disease-causing gene. Patients should be told that most patients who inherit the disease gene will be affected. The penetrance of autosomal dominant vitreoretinal degeneration is very high with over 90% of patients being affected by the age of 20.38 RISK REDUCTION

The availability of preimplantation diagnosis raises the possibility of eradication of this disorder. Although this would commit potential couples to in vitro fertilization (IVF), the opportunity to reduce the risk of having an affected child from 50% to near 0% might be attractive to some couples. To our knowledge diagnostic tests have yet to be developed for IVF. GENE THERAPY

Several transgenic mouse models22,23,47 demonstrate mutations in the pro alpha (II) collagen chain. These investigators have been able to demonstrate that both wild and transgenic mRNA underwent alternative splicing of exon 2 in the eye. Such studies provide a basis for developing mouse models for arthrophthalmopathies. These studies may eventually provide a basis for gene directed therapy for this condition.

Summary Vitreoretinal degenerations are important conditions to study not only because of the implications in the care and treatment of patients but also because the study of these disorders may provide important information concerning the pathogenesis of retinal detachment. The phenotypic and genotypic heterogeneity of inherited vitreoretinal degenerations with or without systemic manifestations has created problems with syndrome definitions, nomenclature, classification, and clinical management. Recent advancement in the molecular biology of the genes coding for collagen may help resolve some of the is-

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sues, particularly once the disease causing gene for Wagner’s disease is known. Physicians need to be aware that unlike Wagner syndrome in which retinal detachment is uncommon, perivascular pigmentation, vitreous degeneration due to COL2A1 exon 2 mutations is extremely high and retinal detachment is likely to occur in childhood. Prompt diagnosis and treatment may prevent complicated retinal detachments in children and other family members. The COL2A1 gene should be considered a candidate for the disease locus in such families until it can be excluded by linkage analysis or DNA sequencing of exon 2. Mutation detection provides a basis for better genetic counseling in this condition and for the opportunity of earlier intervention in this potentially blinding disorder.

Method of Literature Search PubMed (www.ncbi.nlm.gov/PubMed) was used as the primary literature search using the terms Stickler syndrome and Wagner’s disease covering the years 1966 to present. All languages were used. Additional citations were identified from the PubMed screen and from articles presently in the authors’ possession.

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The authors reported no proprietary or commercial interest in any product mentioned or concept discussed in this article. Supported, in part, by the Vitreoretinal Foundation, Memphis, the Henry and Corinne Bower Laboratory, the Eye Research Institute, the Elizabeth C. King Trust, the Ruebin and Mollie Gordon Foundation, the estates of Margaret Mercer, Martha W. S. Rogers, Dorothy R. Hartman, and Harry B. Wright, the Foundation Fighting Blindness (Dr Edwards), and Research to Prevent Blindness, Inc, and NIH Grant EY 12699 (Drs Edwards and Donoso). Synthia R. Lewis, RN, and Mike Gerkovich assisted with the study participants. Shizhao Xu, MD, and John Lynn, MD, provided helpful discussions. Reprint address: Larry A. Donoso, MD, PhD, Wills Eye Hospital, Research, 900 Walnut Street, Philadelphia, PA 19107. Nomenclature: COL2A1; COL in capitals refers to human collagen; 2 refers to type II; A refers to an alpha chain; and 1 refers to identical subunits in the triple helix.