Limbal stem cell deficiency in patients with inherited stem cell disorder of dyskeratosis congenita

Abstract

The aim of this study is to present the limbal stem cell deficiency (LSCD) cases with features resembling dyskeratosis congenita (DC), a heritable disease of stem cells principally caused by telomerase deficiency. The clinical, laboratory and molecular findings of four cases are presented. A complete systemic examination was performed in a standardized manner for each patient. Laboratory measurements included investigations of the tests used for screening DC. All eight known disease-causing genes in DC (DKC1, TERC, TERT, NOP10, NHP2, TINF2, C16orf57, and TCAB1) were screened for mutations. The family members of the cases were also assessed, when possible. In all four patients, multisystem involvement was present, along with the disorder affecting corneal LSCs. The affected tissues were mainly the skin and its adnexa, the oral cavity and the hematopoietic system, which are rapidly renewing tissues, consistent with the presence of a stem cell disorder. Similarly affected cases were seen in different generations in families, suggesting an underlying inherited disorder. No mutation was detected in any of the known disease-causing genes in these patients. Based on the presented cases and with the contribution of the review of previously reported DC cases available, we suggest that DC is one of the inherited causes of LSCD and that those cases presenting with LSCD might represent a subgroup of DC caused by mutations in an as yet undefined gene.

Presentation, diagnosis and management of limbal stem cell deficiency

“…Diseases in the congenital category include; aniridia,67 keratitis associated with multiple endocrine deficiency,89 dyskeratosis congenita,1011 and epidermal dysplasia 1213. Common causes in acquired LSCD include chemical and thermal burns, multiple ocular surgeries involving the limbal region, contact lens wear, and ocular surface inflammatory diseases 6814–17.…”

“…Aniridia is a congenital disorder in which the abnormal LSC niche cannot sustain the proliferation and differentiation of LSCs 22. In dyskeratosis congenita, the defect in stem cells is principally caused by telomerase deficiency 10. In most of the acquired LSCD, it is likely that both LSCs and their niche are affected 23…”

Limbal epithelial stem cells in regeneration of corneal epithelium – clinical and molecular aspects

“…U człowieka może być on elementem zespołów zwią-zanych z mutacjami genu PAX6, takich jak wrodzony brak tęczówki [33,34] czy anomalia Petersa [35]. Innymi genetycznymi zaburzeniami, w których wykazano związek z niedoborem LESC, są: zespół EEC (ektrodaktylia, dysplazja ektodermalna, rozszczep wargi i podniebienia) [36,37], zespół KID (zapalenie rogówki, rybia łuska, głuchota) [38], skóra pergaminowa [39], dziedziczone autosomalnie dominująco zapalenie rogówki [40], zespół Turnera [41], wrodzona dyskeratoza [42,43,44] oraz zapalenie rogówki związane z zespołem niedoczynności wielogruczoło-wej [45,46]. Częstymi wtórnymi przyczynami LSCD są oparzenia chemiczne i termiczne powierzchni gałki ocznej oraz stany po uprzednich zabiegach operacyjnych lub krioterapii w obszarze rąbka rogówki [47,48].…”

Expansion und Transplantation limbaler Stammzellen zur Regeneration der kornealen Oberfläche

“…Die Ursachen einer limbalen Stammzellinsuffizienz können, wie bei der kongenitalen Aniridie [10] und der Dyskeratosis congenita [11]…”