Corneal Thinning Phenotypes—An Alternative Perspective

Abstract

We were very interested to read of a second mutation in the seed region of miR-184 resulting in EDICT syndrome. 1 We were unsure after reading the paper, however, of how the corneal findings should be classified and of the statement that the family "does not demonstrate a keratoconus phenotype." Keratoconus, the commonest disorder of corneal thinning and steepening, has been linked with VSX1 and SOD1 in single studies and up to 14 different genetic loci.2 It has a variable phenotype, and while few would dispute the diagnosis in classic cases with central corneal thinning, identifying variants such as forme fruste disease (where a cone may not be present) may be more challenging. A less common disorder of corneal thinning is keratoglobus, in which the thinning is global and often most pronounced in the periphery. Iris hypoplasia with keratoglobus has been described. 3 Similarly, the occurrence of keratoglobus with a corneal endothelial disease, posterior polymorphous corneal dystrophy, has also been recognized.

C.57 C > T Mutation in MIR 184 is Responsible for Congenital Cataracts and Corneal Abnormalities in a Five-generation Family from Galicia, Spain

“…This is the case with c.57 C>U mutation which already has been documented with a significant heterogeneity of ocular abnormalities across different families (Table 2). This observation led to an extensive discussion in an effort to explain this phenotypic variability by potential phenotype misclassification or additional genomic variants [8], [9], [10, 11]. In the Galician family there is also a clear heterogeneity of corneal defect between a proband and his maternal female relatives (keratoconus vs. corneal thinning, Figure 1), and of lens defect between a proband and Northern Irish and EDICT families (posterior vs. anterior cataracts).…”

Megalocornea, anterior megalophthalmos, keratoglobus and associated anterior segment disorders: A review

“…12 Although an acquired form is reported which is associated with vernal keratoconjunctivitis and chronic marginal blepharitis. 12,13,56,[61][62][63] Severe keratoconus is a separate entity that can also take on a 'globular' form, but it is typically a progressive disease that presents around puberty, with central or paracentral asymmetric corneal thinning, severe irregular astigmatism, striae and corneal scarring with a normal cornea diameter. 64,65 Notably, Pouliquen et al, among others, have suggested that the acquired form of keratoglobus should be considered a variant of keratoconus, 66 and Karabatsas et al have also highlighted that in adults, keratoglobus, pellucid margical degeneration and keratoconus may represent a spectrum of disease.…”

“…Most cases are sporadic, though pedigrees suggestive of autosomal dominant and recessive inheritance have been reported. 61,83,84 Keratoglobus may be present in brittle cornea syndrome 1 (BCS1) (OMIM#229200), 85 brittle cornea syndrome 2 (BCS2) (OMIM#614170), 86 EDICT syndrome (OMIM#614303) 62 and distal arthrogryposis type 5 (DA5) (OMIM#108145). 87 The association of keratoglobus and keratoconus with brittle cornea syndrome and Rubinstein-Taybi syndrome may suggest a correlation of genetic abnormalities in connective tissues with keratoglobus and some forms of keratoconus.…”

“…Keratoglobus presents principally in a congenital form, which may be associated with blue sclera syndromes, osteogenesis imperfecta, Ehlers‐Danlos type VI, brittle cornea syndrome, Rubenstein Taybi Syndrome, Marfan Syndrome and Leber congenital amaurosis 12 . Although an acquired form is reported which is associated with vernal keratoconjunctivitis and chronic marginal blepharitis 12,13,56,61–63 . Severe keratoconus is a separate entity that can also take on a ‘globular’ form, but it is typically a progressive disease that presents around puberty, with central or paracentral asymmetric corneal thinning, severe irregular astigmatism, striae and corneal scarring with a normal cornea diameter 64,65 .…”