Advances in the understanding of dyskeratosis congenita

Abstract

Dyskeratosis congenita (DC) is a rare inherited syndrome exhibiting marked clinical and genetic heterogeneity. It is characterised by mucocutaneous abnormalities, bone marrow failure and a predisposition to cancer. Bone marrow failure is the principal cause of premature mortality. Studies over the last 10 years have demonstrated that DC is principally a disease of defective telomere maintenance. All DC patients have very short telomeres and the genetically characterised cases of DC have mutations in six genes which 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. These advances have led to the recognition of cryptic forms of DC, such as presentations with aplastic anaemia and myelodysplasia. They have also increased our understanding of normal haematopoiesis and provided new insights to the aetiology of some cases of aplastic anaemia and related haematological disorders.

Fig 1

Photographs showing the classical mucocutaneous features of DC. (A) reticular skin pigmentation, (B) nail dystrophy of the fingers, (C) nail dystrophy of the toes, (D) tongue leucoplakia.

Fig 2

Schematic representation highlighting the varying presentations of DC: Classical, severe variant and ‘cryptic’ forms. The year (in brackets) indicates when mutations in these variants were identified linking them to the DC phenotype.

Fig 3

Schematic representation of the telomerase and shelterin complexes involved in telomere maintenance. Protein names in bold are mutated in DC and associated disorders as listed. No human mutations have been described in the other components. AA, aplastic anaemia; AD-DC, autosomal dominant dyskeratosis congenita; AR-DC, autosomal recessive dyskeratosis congenita; ET, essential thrombocythaemia; HH, Hoyeraal Hreidarsson syndrome; PF, pulmonary fibrosis; MDS, myelodysplastic syndrome; PNH, paroxysmal nocturnal haemoglobinurea; RS, Revesz syndrome; S-DC, sporadic dyskeratosis congenita.