Corneal ectasia associated with Cohen syndrome: a role for COH1 in corneal development and maintenance?

Cohen syndrome¹ is a rare autosomal recessive condition with a pleiotropic phenotype. Ocular findings of high myopia and early onset retinochoroidal dystrophy are almost universal. The extraocular manifestations include developmental delay, a typical facial gestalt, and granulocytopenia. Elsewhere, we have described the identification of the COH1 gene which is mutated in this condition² and have reported an extensive genotype‐phenotype screen.³

We report a case of corneal ectasia in a patient with confirmed Cohen syndrome, who is now 50 years of age. She presented at age 17 with high myopia, astigmatism, and retinochoroidal dystrophy; refractive error was −11.50/+3.50@90 in the right eye and −13.00/+3.00@80 in the left. By the age of 30 she had developed posterior subcapsular cataracts associated with a mild progression of myopia (−16.00/+4.00@90 in the right eye and −17.00/+2.50@80 in the left). Early keratoconus was noted in the left cornea (fig 1), along with subluxation of both the lenses. The corneal ectasia has subsequently worsened in the left eye and has been repeatedly confirmed on slit lamp examination. Further details of the ectasia could not be established as accurate topography and pachymetry have not been possible because of poor cooperation. For the same reason, subtle signs of ectasia cannot be excluded in the right eye. At age 42 her corrected visual acuities were 6/24 right eye, hand movement in the left eye. She underwent bilateral lensectomy with pars plana vitrectomy, for lens subluxation and progression of the lenticular opacities. The reduced visual acuity in the left eye was caused by the combination of retinochoroidal dystrophy, cataract and corneal ectasia.

Figure 1 Corneal ectasia in patient with Cohen syndrome with COH1 mutations confirmed on molecular analysis.

The patient has clinical features typical of classic Cohen syndrome. These include moderate to severe learning difficulties associated with microcephaly, characteristic facial dysmorphism, truncal obesity with slender extremeties, and a neutropenia leading to frequent episodes of cellulitis. Mutation screening of COH1 was carried out by sequencing the full length cDNA which revealed the proband had compound heterozygous mutations (c.5613_5614insA, p.Lys1872fsX10; and c.11169_11172dupGGAC, p.Arg3725fsX7). The protein for Cohen syndrome is of unknown function. This case suggests that it may be involved in corneal development or collagen metabolism.

Elsewhere we have described the ophthalmic findings associated with Cohen syndrome.⁴ These are mainly early in onset and most patients develop high myopia (often severe) and a progressive retinal dystrophy. Myopia in Cohen syndrome has been attributed to high corneal and lenticular refractive power in the presence of a normal axial length.⁵ This is indicative of a specific abnormality of emmetropisation, largely as a result of a defect of corneal development. In view of our finding of unilateral corneal ectasia in an older patient with Cohen syndrome it is possible that these findings indicate early or subtle formes fruste of keratoconus.

Three keratoconus loci have been mapped.⁶,⁷,⁸ The condition can be associated with connective tissue disorders such as Marfan and Ehlers‐Danlos syndromes. Other features of Cohen syndrome including hypermobility of joints, skeletal abnormalities, and postural abnormalities also suggest a generalised disorder of connective tissue.

Analysis of the visual problems associated with Cohen syndrome emphasises their importance in a condition associated with developmental delay. This report highlights that progressive visual deterioration may result from corneal ectasia as well as retinal dystrophy. When considering cataract extraction in patients with Cohen syndrome it is important to recognise that refractive error (in particular myopia) usually results from corneal and lenticular abnormalities. Lastly, as patients with Cohen syndrome have evidence of a generalised connective tissue disorder, the COH1 protein may have a role in extracellular matrix metabolism and suggests that its study may shed light on pathways important in the maintenance of corneal integrity and the development of corneal ectasia.

Acknowledgements

GCMB is a Wellcome Trust Senior Clinical Research Fellow.