Advertisement

Trauma-induced exacerbation of epithelial-stromal TGFBI lattice corneal dystrophy

      Introduction

      Several heritable diseases of the cornea known as corneal dystrophies are caused by mutations within the human genome. With the advent of genetic sequencing, it is possible to link most corneal dystrophies to a specific gene mutation.
      • Weiss J.S.
      • Møller H.U.
      • Aldave A.J.
      • et al.
      IC3D classification of corneal dystrophies—edition 2.
      While Transforming Growth Factor Beta I (TGFBI) is the most studied gene, with over 60 documented single point mutations,
      • Lakshminarayanan R.
      • Chaurasia S.S.
      • Anandalakshmi V.
      • Chai S.M.
      • Murugan E.
      • Vithana E.N.
      • et al.
      Clinical and genetic aspects of the TGFBI-associated corneal dystrophies.
      without sequencing the patient’s DNA it is difficult to determine if mutations within TGFBI are causal when a patient has symptoms of the disease. In symptomatic cases where the genotype of the individual is unknown, a DNA sequencing method such as next-generation sequencing (NGS) can provide the clinician with a genetic diagnosis. Furthermore, NGS can be used to distinguish which TGFBI mutation the patient may have or if other mutations in other genes that are known to cause other types of corneal dystrophy are present.
      • Weiss J.S.
      • Møller H.U.
      • Aldave A.J.
      • et al.
      IC3D classification of corneal dystrophies—edition 2.
      Classic lattice corneal dystrophy (LCD), one of the TGFBI corneal dystrophies caused by the R124C mutation,
      • Weiss J.S.
      • Møller H.U.
      • Aldave A.J.
      • et al.
      IC3D classification of corneal dystrophies—edition 2.
      commonly presents as radially oriented linear opacities in the anterior stroma corresponding to amyloid accumulation.
      • Dark A.J.
      • Thomson D.S.
      Lattice dystrophy of the cornea: a clinical and microscopic study.
      It is often referred to as LCD type 1. In addition to type 1, there exist several different subtypes of LCD linked to mutations within TGFBI.
      • Weiss J.S.
      • Møller H.U.
      • Aldave A.J.
      • et al.
      IC3D classification of corneal dystrophies—edition 2.
      We present two cases of LCD in a mother and son, both with a rare TGFBI variant mutation. The underlying LCD was discovered during a LASIK procedure, and trauma from a tree branch, in the mother and son respectively. To our knowledge, these are among the first reported cases of lattice dystrophy to be revealed by trauma. In order to uncover the underlying genetic mutation that was causal for this mother and son pair, we sequenced the patients’ entire exome utilizing a NGS platform.

      Materials and Methods

      Institutional review board approval was waived for this retrospective case series, and permission to publish clinical findings was obtained from both patients. The two patients underwent full ophthalmic examination. Genetic testing was conducted on epithelial cells collected from the inner cheeks with an iSWAB collection kit (Mawi DNA Technologies, Hayward, Calif, USA). Genomic DNA was extracted with a QIAGEN QIAamp® DNA blood mini kit (Hilden, Germany), and whole-exome sequencing was carried out with the ACE platform™ (Personalis Inc., Menlo Park, Calif, USA) on a HiSeq 2000 (Illumina Inc., San Diego, Calif, USA). Real-time PCR (RT-PCR) was carried out on a 7500 FAST PCR System (Thermo Fisher Scientific, Waltham, Mass, USA) by Avellino Lab USA, Inc., (Menlo Park, Calif, USA).

      Results

      Case 1

      A 26-year-old male presented with symptoms of recurrent corneal erosions in his right eye 4 years after a tree branch injury. His family history was significant for LCD on the maternal side, including two relatives who had had corneal transplants. Best corrected visual acuity was 20/25 bilaterally. He had 3 epithelial defects within an area of lattice-like changes in his right eye (Fig. 1A). His left eye was unremarkable (Fig. 1B). He had mild Meibomian gland dysfunction and rosacea facies. He was treated with a bandage contact lens, preservative-free hyaluronic acid eye drops 6 times daily, and was started on Doxycycline 100mg daily. Genetic testing revealed a sequence variation (H626R c.1877A>G) in exon 14 of the TGFBI gene.
      • Lai K.
      • Reidy J.
      • Bert B.
      • Milman T.
      Spheroidal degeneration in H626R TGFBI variant lattice dystrophy: a multimodality analysis.
      RT-PCR analysis confirmed the presence of the H626R variant.
      Fig. 1
      Fig. 1Slit lamp photograph of the son. (A) Three epithelial defects within an area of lattice-like changes were found in the right eye. (B) A clear cornea with no lattice-like changes was found in the left eye.

      Case 2

      The patient’s 62-year-old mother was in attendance with him at consultation. In view of the findings and family history, she was examined. Her best corrected visual acuity was 20/20 OD and 20/70 OS. She had bilateral LASIK performed in 2003, with central lattice-like changes at the flap interface in the right eye (Fig. 2A) and diffuse interface lattice-like changes in the left eye (Fig. 2B). She did not report to have had known corneal pathology before the LASIK procedure. The remainder of her eye exam was normal. Genetic testing as described above confirmed the same mutation in the TGFBI gene as her son.
      Fig. 2
      Fig. 2Slit lamp photograph of the mother. (A) Lattice lines were noted in the center of the LASIK flap in the right eye. (B) Diffuse interface lattice-like changes were noted in the left eye.

      Discussion

      LCD is a common epithelial-stromal corneal dystrophy.
      • Lisch W.
      • Seitz B.
      Lattice corneal dystrophy type 1: an epithelial or stromal entity?.
      It is most often associated with a mutation in TGFBI on chromosome 5q31.
      • Weiss J.S.
      • Møller H.U.
      • Aldave A.J.
      • et al.
      IC3D classification of corneal dystrophies—edition 2.
      • Stone E.M.
      • Mathers W.D.
      • Rosenwasser G.O.
      • et al.
      Three autosomal dominant corneal dystrophies map to chromosome 5q.
      Typically, lesions are thin branching lines and/or subepithelial whitish ovoid dots and involve the central cornea with peripheral and posterior corneal sparing.
      • Weiss J.S.
      • Møller H.U.
      • Aldave A.J.
      • et al.
      IC3D classification of corneal dystrophies—edition 2.
      Patients are prone to recurrent corneal erosions and vision loss due to irregular astigmatism, and eventually confluence of the lesions. Treatment involves management of the recurrent erosions through traditional methods and visual rehabilitation through phototherapeutic keratectomy,
      • Aldave A.J.
      • Sonmez B.
      Elucidating the molecular genetic basis of the corneal dystrophies: are we there yet?.
      contact lenses, and ultimately corneal transplantation, if necessary.
      The mutation identified in our patients has been associated with a late-onset (fourth to fifth decade) form of LCD that was asymmetric in manifestation and possibly linked to minor corneal trauma in one case.
      • Stewart H.
      • Black G.C.
      • Donnai D.
      • et al.
      A mutation within exon 14 of the TGFBI (BIGH3) gene on chromosome 5q31 causes an asymmetric, late-onset form of lattice corneal dystrophy.
      The patients in our series were asymptomatic until they sustained trauma to their eyes, and the son had an earlier unilateral presentation. In a patient where a significant family history of transplantation without known cause is present, genetic testing may be warranted. Given the late onset of this subtype of lattice dystrophy, genetic testing of the mother may have dissuaded her surgeon from performing LASIK.

      Conclusions

      Whilst there have been a number of cases of granular/mixed granular dystrophy reported to have been exacerbated by LASIK or trauma,
      • Woreta F.A.
      • Davis G.W.
      • Bower K.S.
      LASIK and surface ablation in corneal dystrophies.
      • Lee W.B.
      • Himmel K.S.
      • Hamilton S.M.
      • et al.
      Excimer laser exacerbation of Avellino corneal dystrophy.
      we believe these to be the among the first cases of lattice dystrophy to follow a similar course. The use of genetic analysis in these patients was critical in diagnosing a rare type of LCD and will guide future therapy and disease monitoring. Identifying the specific type of LCD that a patient is genetically susceptible to may help clinicians predict the age of onset, any potentiating factors, and/or the histology and severity of any corneal depositions; however, such associations have yet to be fully elucidated. Additionally, our cases illustrate the role of genetic screening in refractive laser surgery candidates who have a family history of corneal transplantation of known or unknown cause. Prospective studies may clarify the role of genetic screening in such patients in the future.

      Disclosures

      The authors have no proprietary or commercial interest in any materials discussed in this article.

      Supported by

      This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

      Conflicts of interest

      Dr. Clara C. Chan is a consultant for Alcon, Allergan Inc., TearLab Corporation, Bausch + Lomb, Santen Pharmaceutical, and Shire Plc. Ms. Connie Chao-Shern and Dr. Larry DeDionisio are employees of Avellino Labs USA. Prof Tara Moore is a consultant for Avellino Labs USA. For the remaining authors, none were declared.

      Acknowledgments

      The authors would like to acknowledge the contributions of Drs. Armand Borovik, Adi Einan Lifshitz, and Nir Sorkin for their critical review of this manuscript. Author contributions are as follows: literature search (HN, CCS, LD), figure creation (HN, CC), study design (HN, CC), data collection (all authors), data interpretation (all authors), and writing (all authors).

      References

        • Weiss J.S.
        • Møller H.U.
        • Aldave A.J.
        • et al.
        IC3D classification of corneal dystrophies—edition 2.
        Cornea. 2015; 34: 117-159
        • Lakshminarayanan R.
        • Chaurasia S.S.
        • Anandalakshmi V.
        • Chai S.M.
        • Murugan E.
        • Vithana E.N.
        • et al.
        Clinical and genetic aspects of the TGFBI-associated corneal dystrophies.
        Ocul Surf. 2014; 12: 234-251
        • Dark A.J.
        • Thomson D.S.
        Lattice dystrophy of the cornea: a clinical and microscopic study.
        Br J Ophthalmol. 1960; 44: 257-279
        • Lai K.
        • Reidy J.
        • Bert B.
        • Milman T.
        Spheroidal degeneration in H626R TGFBI variant lattice dystrophy: a multimodality analysis.
        Cornea. 2014; 33: 726-732
        • Lisch W.
        • Seitz B.
        Lattice corneal dystrophy type 1: an epithelial or stromal entity?.
        Cornea. 2014; 33: 1109-1112
        • Stone E.M.
        • Mathers W.D.
        • Rosenwasser G.O.
        • et al.
        Three autosomal dominant corneal dystrophies map to chromosome 5q.
        Nat Genet. 1994; 6: 47-51
        • Aldave A.J.
        • Sonmez B.
        Elucidating the molecular genetic basis of the corneal dystrophies: are we there yet?.
        Arch Ophthalmol. 2007; 125: 177-186
        • Stewart H.
        • Black G.C.
        • Donnai D.
        • et al.
        A mutation within exon 14 of the TGFBI (BIGH3) gene on chromosome 5q31 causes an asymmetric, late-onset form of lattice corneal dystrophy.
        Ophthalmology. 1999; 106: 964-970
        • Woreta F.A.
        • Davis G.W.
        • Bower K.S.
        LASIK and surface ablation in corneal dystrophies.
        Surv Ophthalmol. 2015; 60: 115-122
        • Lee W.B.
        • Himmel K.S.
        • Hamilton S.M.
        • et al.
        Excimer laser exacerbation of Avellino corneal dystrophy.
        J Cataract and Refract Surg. 2007; 33: 133-138