Experimental Eye Research 90 (2010) 472e473
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Letter to the Editor
Dyskeratosis congenita and limbal stem cell deficiency Deniz Aslan a, *, Rustu Fikret Akata b a b
Section of Hematology, Department of Pediatrics, Faculty of Medicine, Gazi University, Ankara, Turkey Department of Ophthalmology, Faculty of Medicine, Gazi University, Ankara, Turkey
a r t i c l e i n f o
a b s t r a c t
Article history: Received 11 December 2009 Accepted in revised form 14 December 2009 Available online 27 December 2009
In light of the latest developments in the field of molecular hematology, we herein discuss the reported cases that have presented dyskeratosis congenita as one of the inherited stem cell diseases causing limbal stem cell deficiency. Ó 2009 Elsevier Ltd. All rights reserved.
Keywords: limbal stem cell telomerase dyskeratosis congenita
We read with great interest the recent article by Notara et al. (2009). This article describes in detail the characteristics of the limbal stem cell, the changes on the cornea that are seen with limbal stem cell deficiency (LSCD), the diseases causing LSCD, and the current treatment modalities. With this letter, we want to draw the attention of ophthalmologists to an additional stem cell disease, dyskeratosis congenita (DC), which has been demonstrated to cause LSCD but was not mentioned in Notara's article, in view of its potential impact on treatment choice and success. Our window to the world is the eye, specifically the cornea on the front surface of the eye. The health of the outermost corneal epithelium is vital for clear vision. The maintenance of a healthy corneal epithelium under both normal and disease state is achieved by a population of stem cells residing in the corneoscleral junction, also known as the limbus (Schlötzer-Schrehardt and Kruse, 2005; Secker and Daniels, 2008; Takács et al., 2009; Lim et al., 2009). With division and migration of these cells to the cornea, a barrier is formed against conjunctival migration and as a result, the transparent and avascular state of the cornea is maintained. Any acquired or hereditary disease that disrupts this constant process causes LSCD. Though not commonly encountered, these inherited diseases, especially stem cell diseases, need to be considered by ophthalmologists. We noticed that only one of the inherited diseases, aniridia, was reviewed in the article by Notara et al. (2009). A similar situation is true for the other remarkable reviews on LSCD (Daniels et al., 2001; Hatch and Dana, 2009). DC, a stem cell disease in itself, has not yet been included in the inherited
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LSCD-causing diseases. However, latest developments in the field of molecular hematology have shown that DC is an inherited stem cell disorder (Hiyama and Hiyama, 2007; Mason, 2003), and a recent publication has demonstrated the development of LSCD in DC (Aslan et al., 2009). In addition, it would probably not be wrong to consider that some clinical findings (e.g. corneal vascularization) and symptoms (e.g. excessive tearing) described in the previously reported DC cases are due to the presence of LSCD. In cases determined to have LSCD, the presence of DC as an underlying disorder is an important factor for therapy success and therefore for the choice of treatment. In particular, autologous transplants may not produce satisfactory results in those cases, given the nature of systemic stem cell insufficiency of this disease. Therefore, we would like to draw the attention of ophthalmologists to this genetic disorder. DC, initially described as a bone marrow failure syndrome, is a multisystem disorder with a very broad range of clinical presentations (Dokal, 2000; Kirwan and Dokal, 2009; Walne and Dokal, 2009). Classically, the disease is defined by a triad of mucocutaneous features: nail dystrophy, oral leukoplakia and abnormal skin pigmentation. However, this triad is not always observed in a clinical setting. A wide spectrum of disorders affecting every system in the body, including the eyes, has been described in this disease. DC is principally a disease due to lack of telomerase in stem cells (Hiyama and Hiyama, 2007; Kirwan and Dokal, 2009; Mason, 2003; Walne and Dokal, 2009; Vulliamy, 2009). Telomerase is an enzyme complex and is important in the elongation and protection of the telomeric end. It adds telomeric repeats onto the chromosome ends, and prevents the replicationdependent loss of telomere and cellular senescence in highly proliferative cells. Thus, telomerase is important in maintaining cellular lifespan and replicative potential in human organs. In the
D. Aslan, R.F. Akata / Experimental Eye Research 90 (2010) 472e473
absence of telomerase, telomeres shorten progressively due to the problem of the telomeric end processing. All DC patients have very short telomeres and the genetically characterized cases of DC have mutations in six genes that either encode components of the telomerase complex (DKC1, TERC, TERT, NOP10, NHP2) or shelterin (TINF2); these are important in the elongation and protection of the telomeric end, respectively (Kirwan and Dokal, 2009; Walne and Dokal, 2009). Telomere length is a major determinant of stem cell maintenance. It acts as a mitotic clock, counting and limiting the number of times a cell can divide (Vulliamy, 2009). Short telomeres lead to decreased round number of cell division and limited tissue renewal (Carroll and Ly, 2009; Hao et al., 2005). It is noticeable that the tissues that are affected in DC are those that are turning over most rapidly. This is consistent with the thought that erosion of telomeres has its greatest effect in the stem cell pool. The corneal epithelium has the capacity to renew itself through a population of stem cells residing in the limbus. Recently, it was shown that the limbal stem cell population has telomerase activity (Chen et al., 2005). It is not surprising, therefore, to observe clinical findings and symptoms of LSCD in DC since it is a disease due to lack of telomerase in stem cells. Indeed, DC has already been reported to cause corneal limbal stem cell insufficiency (Aslan et al., 2009). The LSCD findings reported in DC are loss of transparency of the cornea and corneal neovascularization, as detailed in the article by Notara et al. (2009). We have encountered cases who presented with similar LSCD findings, and which were later diagnosed as DC according to the current criteria of Vulliamy et al. (2006) (unpublished results). In addition, clinical findings of deep and superficial corneal vascularization, keratinized corneal surface and corneal perforation, and clinical symptoms of epiphora and photophobia described in the previously reported DC cases could be considered to be LSCD. One of the currently available treatment options for LSCD is transfer of limbal stem cells from the healthy eye to the diseased eye. Another is to obtain alternative epithelial cells from the patient's own tissues, culturing them and transferring these cells to the diseased eye (Liang et al., 2009; Notara et al., 2009; Torres et al., 2008). In cases with underlying DC, these autologous transplants may not be successful since even in the absence of clinical findings, harvested cells are genetically affected and have insufficient replicative potential. Similarly, the presence of a genetic disease causing limited tissue renewal may in the long run cause failure of the commonly used method of using cells derived from the amniotic membrane due to insufficiency of the microenvironment. In DC, the tissue microenvironment is also altered by the accumulation of senescent cells that are changed in function, morphology and gene expression (Vulliamy, 2009).
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In summary, when we apply the recent developments in the field of molecular hematology to the practice of ophthalmology, our accumulating evidence dictates that the diagnosis of DC be entertained in cases diagnosed with LSCD. We believe that this awareness by ophthalmologists will help clarify the role of DC in LSCD and lead to the addition of DC to the list of diseases causing LSCD. It may also contribute to achieving better success in the treatment of selected cases facing difficulties in treatment. References Aslan, D., Ozdek, S., Camurdan, O., Bideci, A., Cinaz, P., 2009. Dyskeratosis congenita with corneal limbal insufficiency. Pediatr. Blood Cancer 53, 95e97. Carroll, K.A., Ly, H., 2009. Telomere dysfunction in human diseases: the long and the short of it! Int. J. Clin. Exp. 2, 528e543. Chen, H., Zhang, M.C., Hu, Y.H., 2005. Experimental research of the expression of telomerase in corneal limbal epithelial cells. Zhonghua. Yan. Ke. Za. Zhi. 41, 399e402. Daniels, J.T., Dart, J.K., Tuft, S.J., Khaw, P.T., 2001. Corneal stem cells in review. Wound Repair Regen. 9, 483e494. Dokal, I., 2000. Dyskeratosis congenita in all its forms. Br. J. Haematol. 110, 768e779. Hao, L.Y., Armanios, M., Strong, M.A., Karim, B., Feldser, D.M., Huso, D., Greider, C.W., 2005. Short telomeres, even in the presence of telomerase, limit tissue renewal capacity. Cell. 123, 1121e1131. Hatch, K.M., Dana, R., 2009. The structure and function of the limbal stem cell and the disease states associated with limbal stem cell deficiency. Int. Ophthalmol. Clin. 49, 43e52. Hiyama, E., Hiyama, K., 2007. Telomere and telomerase in stem cells. Br. J. Cancer 96, 1020e1024. Kirwan, M., Dokal, I., 2009. Dyskeratosis congenita, stem cells and telomeres. Biochim. Biophys. Acta 1792, 371e379. Liang, L., Sheha, H., Li, J., Tseng, S.C., 2009. Limbal stem cell transplantation: new progresses and challenges. Eye 23, 1946e1953. Lim, P., Fuchsluger, T.A., Jurkunas, U.V., 2009. Limbal stem cell deficiency and corneal neovascularization. Semin. Ophthalmol. 24, 139e148. Mason, P.J., 2003. Stem cells, telomerase and dyskeratosis congenita. Bioessays 25, 126e133. Notara, M., Alatza, A., Gilfillan, J., Haris, A.R., Levis, H.J., Schrader, S., Vernon, A., Daniels, J.T., 2009. In sickness and in health: corneal epithelial stem cell biology, pathology and therapy. Exp. Eye Res. doi:10.1016/j.exer.2009.09.023. Schlötzer-Schrehardt, U., Kruse, F.E., 2005. Identification and characterization of limbal stem cells. Exp. Eye Res. 81, 247e264. Secker, G.A., Daniels, J.T., 2008. Corneal epithelial stem cells: deficiency and regulation. Stem Cell Rev. 4, 159e168. Takács, L., Tóth, E., Berta, A., Vereb, G., 2009. Stem cells of the adult cornea: from cytometric markers to therapeutic applications. Cytometry A 75, 54e66. Torres, J., Fernández, I., Quadrado, M.J., Murta, J., Herreras, J., Rodríguez-Ares, M.T., Benítez-del-Castillo, J.M., Alió, J., Muñoz, M.F., Calonge, M., 2008. Limbal transplantation: multicenter retrospective case series analysis. Arch. Soc. Esp. Oftalmol. 83, 417e422. Walne, A.J., Dokal, I., 2009. Advances in the understanding of dyskeratosis congenita. Br. J. Haematol. 145, 164e172. Vulliamy, T.J., Marrone, A., Knight, S.W., Walne, A., Mason, P.J., Dokal, I., 2006. Mutations in dyskeratosis congenita: their impact on telomere lenght and the diversity of clinical presentation. Blood 107, 2680e2685. Vulliamy, T.J., 2009. Premature aging. Cell. Mol. Life Sci. 66, 3091e3094.
