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Marfan syndrome (MFS) is an autosomal dominant syndrome resulting from mutations in the fibrillin-1 gene (FBN1) on chromosome 15q21.1. Ectopia lentis is the major ocular criterion. Minor ocular criteria include flat corneas, increased axial length (>23.5 mm), and iris hypoplasia with miosis. We report the first genetically confirmed case of microcornea in MFS with a novel FBN1 mutation.1
This female patient with MFS (including tall stature, positive wrist and thumb signs, joint hypermobility, highly arched palate, frontal bossing, and mitral valve prolapse) demonstrated progressive inferotemporal lens subluxations(Figure 1A and B) and increasing myopic astigmatism in both eyes. Her keratometry readings were 42.35 diopters OU, and axial lengths were 25.7 mm OU. She refused spectacle correction and became contact lens intolerant as a result of poor hygiene.
A and B, Preoperative appearance of the right eye seen by direct illumination (A) and of the left eye seen by retroillumination (B), showing significant inferotemporal lens subluxation. C and D, Postoperative appearance of the right eye (C) (with iris atrophy due to the attempt to place a 13-mm anterior chamber intraocular lens [AC-IOL]) and of the left eye (D), showing 12-mm AC-IOLs.
At age 14 years, she underwent lensectomy with insertion of an anterior chamber intraocular lens (AC-IOL) in both eyes. A suturable IOL was not used to help avoid retinal detachment and subluxation from suture degradation. Microcornea (horizontal diameter, 10 mm OU) was identified on the right eye during surgery because it was b oth subtle and unexpected in a patient with MFS. An attempt was made to insert a 13-mm AC-IOL, but ultimately, a 12-mm AC-IOL was inserted into each eye (Figure 1C and D). Six months after surgery, her best-corrected visual acuity was 20/20 OU. The AC-IOLs were centered, her pupils were round, peripheral iridectomies were patent, and intraocular pressures were 15 mmHg OU.
Sequencing of the patient's complementary DNA synthesized from RNA harvested from explanted dermal fibroblasts revealed a novel mutation in intron 63, resulting in deletion of exon 64 (nucleotides 8052 through 8227 deleted) in the FBN1 messenger RNA. In translation, the deletion of exon 64 results in a premature termination of translation after 8 nonsense amino acids are added to the carboxy terminus, shortening the protein by 184 amino acids (Figure 2). Genomic DNA from the patient was used to amplify and sequence exon 64 and the surrounding intronic sequence in introns 63 and 64. This sequencing revealed an A to G transition in one allele at position −2 of the 3′ splice site in intron 63 in the genomic DNA. The parents of the patient did not have MFS, and sequencing of their genomic DNA failed to reveal an alteration in the 3′ splice site.
Genetic mutation in the fibrillin-1 gene results in the deletion of the entire carboxy-terminal domain. EGF indicates epidermal growth factor domain; TGF-BP, transforming growth factor binding protein domain.
Mutations in the FBN1 gene result in a wide range of clinical phenotypes, with classic MFS being one of these phenotypes.2 This first reported case, to our knowledge, of a genetically confirmed MFS with ectopia lentis and microcornea, has occurred in the setting of a novel mutation in FBN1. Comparing the lens subluxation and the corneal diameter in our case of MFS with the study by Cross and Jensen, 3 and the study by Maumanee, 4 the lenses subluxated in a very unusual direction, inferotemporally. Classically, the lens in MFS subluxates superiorly.3,4 Maumenee4 stated that the corneal diameter is classically increased but can be normal. Both reviews revealed several patients with corneal diameters up to 13.0 mm but not a single patient with microcornea.3,4 In this case, the patient's DNA had a heterozygous mutation in the FBN1 protein that truncated the protein, removing the entire C-terminal domain. There have been no proven links between microcornea and specific genetic mutations. Genotype-phenotype correlations may be possible in the future and may assist in predicting these abnormalities.
This research was supported in part by unrestricted grants from the Hermann Eye Fund and the J. M. West Texas Corp, Houston, Tex (Dr Mintz-Hittner), from Research to prevent Blindness Inc, New York, NY (Dr Mintz-Hittner), grant EY10608 from Vision Core, National Insitutes of Health (NIH), Bethesda, Md(Dr Mintz-Hittner), and grant RO1AR43626 from the NIH (Dr Milewicz).
Corresponding author and reprints: Helen A. Mintz-Hittner, MD, University of Texas–Houston Medical School, Department of Ophthalmology and Visual Science, 6410 Fannin, Suite 920, Houston, TX 77030-5204 (e-mail: email@example.com).
Vital MC, Mintz-Hittner HA, Milewicz DM. Microcornea and Subluxated Lenses Due to a Splicing Error in the Fibrillin-1 Gene in a Patient With Marfan Syndrome. Arch Ophthalmol. 2003;121(4):579-581. doi:10.1001/archopht.121.4.579