Dyskeratosis Congenita

Dyskeratosis Congenita is a rare multisystem disease belonging to the genodermatosis family, ie dermatological diseases caused by genetic defects.
It manifests early in infancy with the typical triad represented by nail dystrophy (abnormal growth of the fingernails and toenails), skin pigmentation changes and oral leukoplakia (appearance of whitish spots in the oral mucosa).
Affected subjects can also undergo severe bone marrow dysfunctions, such as to cause the possible onset of aplastic anemia (which leads to a strong reduction in the number of blood cells), myelodysplastic syndromes (due to abnormalities of hematopoietic cells) and leukemia. Other possible consequences of DC are the increased predisposition to develop different types of cancer, pulmonary fibrosis, dental and ocular complications, osteoporosis and other bone disorders, liver disease and urethral strictures (in males).
The extent of the symptoms varies from individual to individual: there are, in fact, milder forms of DC and quite severe variants that can affect the functions of the cerebellum (Hoyeraal Hreidarsson Syndrome) and of the retina (Revesz Syndrome).
At the basis of the disease are mutations in genes coding for proteins involved in the maintenance of telomeres (the ends of chromosomes). In most cases, these mutations affect the TERT, TERC, DKC1 or TINF2 genes, while in some individuals no mutations attributable to known genes have been found. The biological function of telomeres is fundamental for the integrity of chromosomes, as they protect the ends from unwanted recombination and degradation phenomena. With each DNA replication in adult cells, however, the telomeres tend to shorten more and more, to the point of becoming so short that they push the cell into apoptosis. This is one of the mechanisms behind aging, among others. In fetal cells (which are actively replicating), however, this shortening is counterbalanced by the action of enzymes called telomerases, which add small, repeated sequences to the telomeric ends.
Alterations of the proteins involved in telomere maintenance will therefore have consequences on the stability of the DNA. This leads to aberrant phenomena especially in rapidly proliferating cells such as those of the hair follicles, skin, oral mucosa and bone marrow. Hence the typical systemic manifestations of Dyskeratosis Congenita.
DC can be inherited in an autosomal dominant, recessive and X-linked manner. In this case, the responsible gene is DKC1.