Alternative titles; symbols
SNOMEDCT: 268158009; ORPHA: 91489; DO: 0060305;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| Xq23 | Megalocornea 1, X-linked | 309300 | X-linked recessive | 3 | CHRDL1 | 300350 |
A number sign (#) is used with this entry because of evidence that megalocornea (MCG1) is caused by mutation in the CHRDL1 gene (300350) on chromosome Xq23.
Megalocornea is an inherited eye disorder in which the corneal diameter is bilaterally enlarged (greater than 13 mm) without an increase in intraocular pressure. It may also be referred to as 'anterior megalophthalmos,' since the entire anterior segment is larger than normal. Features of megalocornea in addition to a deep anterior chamber include astigmatic refractive errors, atrophy of the iris stroma, miosis secondary to decreased function of the dilator muscle, iridodonesis, and tremulousness, subluxation, or dislocation of the lens. Whereas most affected individuals exhibit normal ocular function, complications include cataract development and glaucoma following lenticular dislocation or subluxation. X-linked recessive inheritance is the most common pattern, accounting for the male preponderance of the disorder (summary by Skuta et al., 1983).
Megalocornea sometimes occurs as part of the Marfan syndrome (154700).
Genetic Heterogeneity of Megalocornea
Autosomal recessive megalocornea has been reported (249300).
In a family reported by Riddell (1941), affected males showed large cornea as an isolated defect. Heterozygous women may show slight increase in corneal diameter. Two presumed homozygous females occurred in this family.
Skuta et al. (1983) studied 2 brothers with megalocornea and their 2 affected maternal uncles. The deceased maternal great-grandfather was reported to have had large eyes and cataracts. Examination of the 4 affected individuals revealed corneal diameters ranging from 13 to 15.5 mm, deep anterior chambers, and normal intraocular pressure. Additional features included atrophy of the iris stroma, iridodonesis, astigmatic refractive errors in the vertical meridian, lens subluxation, and cataract formation. Two of the patients exhibited transillumination of the irides, a feature not previously reported in this disorder, and the oldest patient, aged 54 years, displayed posterior 'crocodile shagreen' bilaterally, believed to represent opacities of the central stroma. Endothelial specular microscopy of affected individuals disclosed normal endothelial cell densities and morphologic characteristics and increased total endothelial cell populations, suggesting that the process involved in the development of megalocornea is one of primary overgrowth rather than secondary distention. Eye examination of 3 daughters of 1 of the affected men showed normal results except for amblyopia in 1 of them, and there was no history of women in the family with unusually large eyes or other ocular problems.
Mackey et al. (1991) studied 16 affected males from 5 unrelated families, including a large 5-generation family ('family 1') with linkage to Xq21.3-q22 (Chen et al., 1989), and found that affected males had corneal diameters between 13.0 and 16.5 mm. Arcus juvenilis, mosaic corneal dystrophy, and cataracts were found only in adult affected males. No abnormality was identified in carrier females.
Webb et al. (2012) ascertained 6 families segregating X-linked megalocornea. Affected individuals had corneal diameters ranging from 14 mm to 16 mm, large anterior chamber depths, decreased central corneal thickness, mosaic corneal degeneration ('shagreen'), corneal arcus juvenilis, and, in older patients, cataract. Iris transillumination with pigment dispersion was seen in all patients examined. No patient had glaucoma or significant vision loss, and no neurologic or systemic abnormalities were detected. Carrier females had no clinical signs of megalocornea.
Pfirrmann et al. (2015) studied a 4-generation family exhibiting megalocornea with broad intrafamilial phenotypic variability. There were 4 affected males related to each other by carrier females, with no male-to-male transmission, consistent with X-linked recessive inheritance. The proband was a 14-year-old boy who was noted at birth to have remarkably large eyes; there were no other systemic anomalies, and the eye phenotype showed no progression over time. At age 14, he had bilateral corneal diameters of 16 mm with dome-shaped corneas and very deep anterior chambers, but intraocular pressures were normal and no other ocular anomalies were detected. Corneas of an affected maternal uncle and maternal first cousin once removed had a keratoconus-like appearance. The uncle, whose corneal diameter was 14.5 mm, also exhibited congenital cataract and iris hypoplasia with transillumination and intraocular straylight, causing moderate photophobia, as well as iridodonesis, mild displacement of the pupils, slight arcus lipoides, and Krukenberg spindle pigment dispersion at the inner corneal surface (see GPDS1, 600510). The affected male cousin underwent removal of a congenital cataract in his twenties; he also had unilateral spontaneous retinal detachment due to vitreous degeneration. All 3 affected males had reduced corneal thicknesses, ranging from 350 to 405 micrometers. The proband's deceased maternal great-grandfather, who was the first affected family member, had also undergone bilateral cataract surgery at age 56 years. Examination of obligate carrier females and unaffected brothers showed flat corneas with normal diameters. Pfirrmann et al. (2015) noted that severity of biometric abnormalities does not correlate with congenital cataract or pigment dispersion, and that retinal detachment due to vitreous degeneration must be considered.
Distinguishing megalocornea from primary congenital glaucoma (see 231300) in infants is clinically challenging due to overlapping phenotypic features. Davidson et al. (2014) ascertained 10 unrelated families with X-linked megalocornea and mutations in the CHRDL1 gene (see MOLECULAR GENETICS). Examination of these and 8 previously reported mutation-positive probands (Webb et al., 2012; Han et al., 2015) demonstrated that patients with MGC1 have a large corneal diameter and thin cornea, but no corneal edema or breaks in the Descemet layer. The authors also stated that the depth of the anterior chamber in MGC1 is typically significantly greater than in patients with primary congenital glaucoma, and that ultrasonography could reliably distinguish between the 2 conditions: if the ratio of the anterior chamber depth to the total axial length is greater than 0.19 mm by ultrasound, then a diagnosis of MGC1 is extremely likely, unless there is coexisting gross axial myopia (greater than 36 mm).
In linkage studies in a large 5-generation family with X-linked megalocornea, Chen et al. (1989) demonstrated close linkage to DXS87 (maximum lod = 3.91 at theta = 0.00) and DXS94 (maximum lod = 3.34 at theta = 0.00) in Xq21.3-q22.
Using dense X chromosome-specific array CGH, Webb et al. (2012) identified an approximately 250-kb segmental deletion on Xq23 in an affected male from a 4-generation family ('family 1') with megalocornea. The deletion encompassed the 3-prime end of the CHRDL1 gene, extending proximally 238 kb from intron 5 of CHRDL1, and segregated with disease in the family. Analysis of CHRDL1 in affected individuals from 5 additional families with megalocornea revealed 5 different mutations, including 1 missense, 1 splice site, 1 nonsense, and 2 frameshift mutations (300350.0001-300350.0005, respectively). In a large 5-generation Tasmanian family with megalocornea mapping to Xq21.3-q22, originally studied by Chen et al. (1989), Webb et al. (2012) identified a 270- to 600-kb deletion, encompassing the entire CHRDL1 gene; this deletion did not share breakpoints with the previously identified segmental deletion in family 1. None of the patients had developmental or cognitive problems. Electrophysiologic evaluation of 2 affected individuals from family 1 revealed mild generalized cone system dysfunction, and 1 of them also showed interhemispheric asymmetry in visual evoked potentials; Webb et al. (2012) stated that evaluation of additional patients would be necessary to determine the association of a visual pathway or cone system phenotype with CHRDL1 mutations.
Davidson et al. (2014) analyzed the CHRDL1 gene in 10 probands with megalocornea and identified 2 missense, 4 nonsense, and 2 frameshift mutations, as well as 2 large deletions encompassing the entire gene. In addition, they sequenced the CHRDL1 gene in a 10-year-old boy with megalocornea, intellectual disability, facial dysmorphism, and a history of hypotonicity and seizures (see MMR syndrome, 249310) and identified a missense mutation that was also present in his unaffected mother. However, Davidson et al. (2014) stated that it was unlikely that his extraocular features were caused by the CHRDL1 mutation because no other patients with CHRDL1 mutations exhibited developmental delay or any of the other extraocular phenotypes associated with MMR syndrome. Furthermore, his deceased maternal grandfather was reported to have had 'large eyes,' cataracts, and glaucoma, whereas 2 paternal half sibs had seizures and intellectual disability. Whole-exome sequencing in the patient revealed several plausible variants that might have caused his extraocular phenotype, but due to lack of familial DNA samples, the potential pathogenicity of those variants could not be tested.
In a 4-generation family exhibiting X-linked recessive megalocornea with broad intrafamilial phenotypic variability, Pfirrmann et al. (2015) identified hemizygosity for a 2-bp deletion in the CHRDL1 gene (300350.0006) that segregated fully with disease in the family.
Chen, J. D., Mackey, D., Fuller, H., Serravalle, S., Olsson, J., Denton, M. J. X-linked megalocornea: close linkage to DXS87 and DXS94. Hum. Genet. 83: 292-294, 1989. [PubMed: 2571565] [Full Text: https://doi.org/10.1007/BF00285176]
Davidson, A. E., Cheong, S.-S., Hysi, P. G., Venturini, C., Plagnol, V., Ruddle, J. B., Ali, H., Carnt, N., Gardner, J. C., Hassan, H., Gade, E., Kearns, L., and 11 others. Association of CHRDL1 mutations and variants with X-linked megalocornea, Neuhauser syndrome and central corneal thickness. PLoS One 9: e104163, 2014. Note: Electronic Article. [PubMed: 25093588] [Full Text: https://doi.org/10.1371/journal.pone.0104163]
Gronholm, V. Ueber die Vererbung der Megalokornea nebst einem Beitrag zur Frage des genetischen Zusammenhanges zwischen Megalokornea und Hydrophthalmus. Klin. Monatsbl. Augenheilkd. 67: 1-15, 1921.
Han, J., Young, J. W., Frausto, R. F., Isenberg, S. J., Aldave, A. J. X-linked megalocornea associated with the novel CHRDL1 gene mutation p.(Pro56Leu*8). Ophthal. Genet. 36: 145-148, 2015. [PubMed: 24073597] [Full Text: https://doi.org/10.3109/13816810.2013.837187]
Mackey, D. A., Buttery, R. G., Wise, G. M., Denton, M. J. Description of X-linked megalocornea with identification of the gene locus. Arch. Ophthal. 109: 829-833, 1991. [PubMed: 2043071] [Full Text: https://doi.org/10.1001/archopht.1991.01080060093033]
Pfirrmann, T., Emmerich, D., Ruokonen, P., Quandt, D., Buchen, R., Fischer-Zirnsak, B., Hecht, J., Krawitz, P., Meyer, P., Klopocki, E., Stricker, S., Lausch, E., Seliger, B., Hollemann, T., Reinhard, T., Auw-Haedrich, C., Zabel, B., Hoffmann, K., Villavicencio-Lorini, P. Molecular mechanism of CHRDL1-mediated X-linked megalocornea in humans and in Xenopus model. Hum. Molec. Genet. 24: 3119-3132, 2015. [PubMed: 25712132] [Full Text: https://doi.org/10.1093/hmg/ddv063]
Riddell, W. J. B. Uncomplicated hereditary megalocornea. Ann. Eugen. 11: 102-107, 1941.
Skuta, G. L., Sugar, J., Ericson, E. S. Corneal endothelial cell measurements in megalocornea. Arch. Ophthal. 101: 51-53, 1983. [PubMed: 6849653] [Full Text: https://doi.org/10.1001/archopht.1983.01040010053007]
Webb, T. R., Matarin, M., Gardner, J. C., Kelberman, D., Hassan, H., Ang, W., Michaelides, M., Ruddle, J. B., Pennell, C. E., Yazar, S., Khor, C. C., Aung, T., and 11 others. X-linked megalocornea caused by mutations in CHRDL1 identifies an essential role for ventroptin in anterior segment development. Am. J. Hum. Genet. 90: 247-259, 2012. [PubMed: 22284829] [Full Text: https://doi.org/10.1016/j.ajhg.2011.12.019]