Clinical variability of Stickler syndrome: role of exon 2 of the collagen COL2A1 gene.

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.