Dyskeratosis Congenita and Corneal Refractive Surgery.

Dyskeratosis congenita is a syndrome of bone marrow failure secondary to unstable telomeres. It is characterized by a range of mucocutaneous diseases. Due to premature telomere shortening, these patients have limbal stem cell deficiency leading to poor regeneration and maintenance of the cornea. Many of these patients will require hematopoietic stem cell transplant in their lifetime, which poses a significant risk for acute and chronic graft-versus-host disease with and without ocular manifestations. We advise against elective corneal refractive surgery in patients with dyskeratosis congenita due to the compounded and long-term risks of delayed healing secondary to limbal stem cell deficiency and ocular complications of graft-versus-host disease post-allogeneic hematopoietic stem cell transplant.

Introduction

Dyskeratosis congenita (DC) is a complex syndrome of bone marrow failure (BMF) [1]. Disease prevalence at birth is approximately one in 1 million with mean age at diagnosis of 15 years [2, 3]. However, it is not uncommon for clinicians to treat DC patients in their career. Patients with DC commonly present with features secondary to mucocutaneous involvement. These mucocutaneous features can include the classic triad of dystrophic nails with longitudinal ridges, lacy reticular pigmentation of the skin (especially of the neck and chest), and oral leukoplakia (premalignant) (Fig. 1) [1, 4–6].

Fig. 1

Mucocutaneous triad of DC. a Dystrophic nails. b Lacy reticular pigmentation of the skin. c Oral leukoplakia.

Image adapted from Savage, 2018 under the license of Creative Commons

A defect in telomere stability causes the systemic nature of DC [1, 7, 8]. Telomeres are the redundant strands of DNA at the ends of chromosomes that preserve genetic material cycle after cycle of cellular proliferation [8]. The enzyme telomerase is a DNA polymerase that maintains the integrity of telomeres [8]. The telomerase complex consists of proteins that stabilize the DNA [9]. Therefore, in DC, telomere instability leads to accelerated shortening of DNA, which mainly impacts tissue with high cell proliferation rates such as bone marrow and mucocutaneous tissues [1]. While telomere shortening is a natural process with age, the rate of shortening in DC is higher than normal [8]. The most common inheritance pattern of DC is X-linked recessive with a defect in the DKC1 gene (chromosome q28) that encodes for dyskerin, a component of the telomerase complex [1]. There also exist autosomal dominant and recessive inheritance patterns with other genes affected [7, 10]. Twelve known genes cause DC, and this list continues to grow (Fig. 2) [11].

Fig. 2

Telomerase complex. Note the proteins’ role in stabilization of the telomere complex. Genetic defects in DKC1 (dyskerin), TERC, TERT, TRF1, TRF2, and TIN2 have all been found in DC [8, 9, 11]

DC is phenotypically heterogeneous, and patients also present with features such as developmental delay, pulmonary fibrosis, and diseases affecting multiple organs like the eyes, liver, esophagus, and periodontal areas [1, 5]. Ocular findings in DC vary according to patient phenotype, with common ocular findings of obstruction of the lacrimal system with epiphora (31%), conjunctivitis, entropion and ectropion, trichiasis, blepharitis, cataract, glaucoma, and exudative retinopathy [1, 3, 12]. Specifically, bilateral exudative retinopathy and intracranial calcifications are associated with a subtype of DC named Revesz syndrome [4, 5]. While some of these findings are contraindications themselves to corneal refractive surgery, we will also address additional complications of DC that we believe to be significant contraindications to elective corneal refractive surgery. This article is based on previously conducted studies and does not contain any studies with human participants or animals performed by any of the authors.

Limbal epithelial stem cells (LESCs), located at the junction of the cornea and conjunctiva, maintain and regenerate the corneal epithelium in response to corneal injury or normal wear over time [13]. The stem cells exist in a niche referred to as the limbal palisades of Vogt that provides a protective microenvironment for these cells [13]. LESCs are undifferentiated and have an unlimited proliferative potential owed to the stability of their telomeres. This process is abnormal in patients with DC, a heritable limbal stem cell deficiency (LSCD) disease [13, 14]. Complications of LSCD, both in DC patients and LSCD secondary to other conditions, consist of corneal epithelial defects, corneal pannus, breakdown, neovascularization, and delayed healing capacity (Fig. 3) [14, 15]. Epithelial trauma secondary to corneal refractive surgery in a DC patient, especially in the setting of subclinical LSCD, will likely not heal as well as a patient without DC.

Fig. 3

Corneal pannus and ulceration secondary to limbal stem cell deficiency.

Photo from the author, Majid Moshirfar, MD

Secondary to the underlying genetic cause of DC, patients are highly susceptible to BMF (up to 80% of patients) with hematopoietic stem cell transplantation (HSCT) as definitive therapy [16, 17]. Due to disease-associated eye disorders in addition to the considerable likelihood of BMF with complications of LSCD and graft-versus-host disease (GVHD) post-bone marrow transplant, we must analyze if a patient with DC is an appropriate candidate for corneal refractive surgery [12-14]. We conclude that DC patients are not suitable candidates, and we do not recommend any elective corneal refractive surgery such as laser in situ keratomileusis (LASIK), photorefractive keratectomy (PRK), or small-incision lenticule extraction (SMILE) for DC patients.

At least 80% of patients with DC will experience BMF. Allogeneic HSCT is done to treat this, which puts patients at risk for both acute (< 100 days since transplant) and chronic (> 100 days) GVHD [18, 19]. GVHD is the clinical manifestation of donor T-cells attacking recipient tissue, and ocular manifestations are common [19]. Approximately 40% of individuals who undergo HSCT will experience acute GVHD, and 30% will experience chronic GVHD [20, 21]. Of patients who undergo allogeneic HSCT, 40–60% will have ocular involvement (without GVHD), and 60–90% with acute or chronic GVHD will have ocular manifestations [22]. Ocular GVHD can present as dry eye (most common), keratoconjunctivitis, corneal ulceration, peripheral corneal melting, corneal vascularization, and acquisition of ocular allergy from the donor [19, 22, 23]. Using the mentioned percentages, the lifetime probability of a patient with DC having acute GVHD is 19–29%, and the probability of chronic GVHD with ocular manifestations is 14–22%.

Conclusion

In summary, DC represents a range of mucocutaneous manifestations of BMF secondary to premature telomere shortening. Figure 4 outlines the main clinical manifestations and clinical course in patients with DC.

Fig. 4

Potential clinical course and outcomes of DC

While some patients with DC may not have prominent ocular findings, others will present primarily with eye complaints. Regardless of patient phenotype, the significant likelihood of a DC patient having bone marrow failure and needing hematopoietic stem cell transplant puts these patients at substantial risk for acute and chronic GVHD with or without ocular complications. When considering the impact of limbal stem cell deficiency on healing, in conjunction with allogeneic transplant complications, we do not recommend elective corneal refractive surgery such as LASIK, PRK, or SMILE in patients with DC.