Compound Heterozygous p.(R124C) (Classic Lattice Corneal Dystrophy) and p.(R124H) (Granular Corneal Dystrophy Type 2) in TGFBI: Phenotype, Genotype, and Treatment

Abstract

(1) Background: The phenotypes of classic lattice corneal dystrophy (LCD) and granular corneal dystrophy type 2 (GCD2) that result from abnormalities in transforming growth factor β-induced gene (TGFBI) have previously been described. The phenotype of compound heterozygous classic LCD and GCD2, however, has not yet been reported. (2) Case report: A 39-year-old male (proband) presented to our clinic complaining of decreased vision bilaterally. A slit-lamp examination revealed corneal opacities consistent with classic LCD. Contrast sensitivity (CS) was decreased. A genetic analysis performed with commercially available real-time polymerase chain reaction (PCR) showed both homozygous classic LCD and homozygous GCD2. Sanger sequencing performed in our lab suggested compound heterozygosity for c.370C>T and c.371G>A variants, which was confirmed by the TA cloning of exon 4 of TGFBI and sequencing of clones. Phototherapeutic keratectomy (PTK) was performed on the right eye of the proband, and the CS improved. (3) Conclusions: Compound heterozygous classic LCD and GCD2 produces clinical findings like that of severe, classic LCD. PTK can improve VA and CS, delaying the need for keratoplasty.

Keywords: TA cloning; classic lattice corneal dystrophy (LCD); compound mutation of TGFBI; granular corneal dystrophy type 2 (GCD2).

Figure 1

Slit-lamp photographs and Fourier-domain anterior segment optical coherence tomographs (FD-OCT) of the proband. Slit-lamp photographs of the right eye (A,B) and left eye (D,E) are also shown. Diffuse grayish-white opacities in the subepithelial and superficial stroma ((A,D); black arrows) and distinct refractile lattice lines spreading to the periphery ((B,E); magnified views are shown at the upper right) were observed in both corneas of the proband. FD-OCT images of the right eye (C) and left eye (F) are shown. Diffuse grayish-white opacities in the subepithelial and superficial stromal area (black arrowheads) and many distinct refractile lattice lines spreading to the periphery (green arrowheads) were observed.

Figure 2

Slit-lamp photographs of the right eye (A) and left eye (B) of the proband are shown. Many distinct refractile lattice lines spreading to the periphery near to the limbus (green arrowheads) were observed (A). Dense, thick lattice lines are seen in the mid-peripheral cornea (B). Slit-lamp photographs using retro-illumination of the right eye (C) and left eye (D) show 35 lines in the temporal half OD and 33 in the nasal half OS. Many dot-shaped opacities (40 OD and 23 OS) under retro-illumination (red arrows) and distinct refractile lattice lines spreading to the periphery (green arrowheads) were observed in both corneas of the proband (magnified views are shown at the right upper corners).

Figure 3

Slit-lamp photographs and Fourier-domain anterior segment optical coherence tomographic (FD-OCT) images of genetically confirmed classic LCD heterozygotes ((A,D,G); 32-year-old) ((B,E,H); 43-year-old) ((C,F,I); 40-year-old). Diffuse grayish-white opacities in the subepithelial and superficial stromal area (black arrows) are shown (A–C). Distinct refractile lattice lines (green arrowheads), which are less confluent (15, 12, and 14 lines in each half cornea of (D–F)) and thinner than those of the proband, spreading to the periphery are observed (D–F). The dot-shaped opacities are less numerous than those of the proband (13, 9, and 5 dots in each (D–F)) (red arrows). FD-OCT images of heterozygotes show fewer lattice lines (green arrowheads), while diffuse grayish-white opacities in the subepithelial and superficial stromal area (black arrows) were observed at various depths (G–I).

Figure 4

Slit-lamp photographs of other genetically confirmed GCD2 heterozygotes. Granular deposits (yellow arrows) and linear deposits (red arrowhead) were observed in the corneas of 40-year-old (A), 38-year-old (B), and 37-year-old heterozygotes (C).

Figure 5

Genetic analysis results of TGFBI in the proband (A,C) and proband’s mother (B,D). The nucleotides changed from normal sequence are shown in red highlight (A,B). The automatic reader reported a change of arginine to tyrosine in the proband (A) and a change of arginine to cysteine in the proband’s mother (B). Partial nucleotide sequences of exon 4 of the TGFBI gene of the proband shows both C and T curves at 370 nucleotide (red star) and both C and A curves at 371 nucleotide (blue star) (C). Partial nucleotide sequences of exon 4 of the TGFBI gene of the proband’s mother shows both C and T curves at 370 nucleotide (green star) (D).

Figure 6

Slit-lamp photographs of the proband’s right eye before PTK (A) and after PTK of 30 μm and additional 10 μm ablations (B,C) performed sequentially on the same day. Since the surgeon could not determine the depth of opacities precisely before PTK, an additional 10 μm ablation was performed with a slit-lamp examination after the 30 µm PTK to remove opacities and still preserve as much of the posterior stroma as possible for future additional PTKs.

Figure 7

Slit-lamp photographs (OD) of the proband 1 month (A) and 6 months (B) after PTK. FD-OCT images taken 1 month after treatment show that superficial opaque deposits in the superior half were removed while some opacities remained in the inferior half of the right eye inside the white dotted oval line ((C), OD). Intact superficial opaque deposits remained inside the white oval line in the left eye, where PTK was not performed ((D), OS). The ‘# of averages’ in the FD-OCT photo refers to the number of repeated scans and automatic averaging performed by the machine as part of its noise-reduction function. The photopic contrast sensitivity testing of the right, the treated eye, of the proband 1 month after PTK showed normal values at 1.5 cycles/degree and slightly low values at other frequencies (E). In contrast, the left eye showed very low contrast sensitivity at all spatial frequencies (F).