Evaluation and Management of Hematopoietic Failure in Dyskeratosis Congenita

Abstract

Dyskeratosis congenita (DC) is a rare, inherited bone marrow failure (BMF) syndrome characterized by variable manifestations and ages of onset, and predisposition to cancer. DC is one of a spectrum of diseases caused by mutations in genes regulating telomere maintenance, collectively referred to as telomere biology disorders (TBDs). Hematologic disease is common in children with DC/TBD. Timely diagnosis of underlying TBD in patients with BMF affects treatment and has been facilitated by increased awareness and availability of diagnostic tests in recent years. This article summarizes the pathophysiology, evaluation, and management of hematopoietic failure in patients with DC and other TBDs.

Keywords: Aplastic anemia; Bone marrow failure; Bone marrow transplantation; Dyskeratosis congenita; Telomeres.

Fig. 1.

Components of telomere biology disrupted in DC. Telomeres are composed of thousands of TTAGGG repeats. The telomere repeats are bound by several proteins (TRF1, TRF2, TIN2, RAP1 [not shown], TPP1, and POT1), collectively called shelterin. The telomere ends in a loop (t loop) with a 3′ overhang, which must be unwound by RTEL1 for telomere replication. The figure depicts the unwound telomere end bound by telomerase, a ribonucleoprotein (RNP) complex that elongates telomeres by reverse transcription. Telomerase is composed of the reverse transcriptase TERT and the RNA template TERC, which add telomere repeats to the 3′ end. Several other proteins make up the telomerase RNP (dyskerin, NOP10, NHP2, GAR1, TCAB1), and are responsible for stabilizing and trafficking telomerase to the Cajal body, where telomeres are elongated. NAF1 is responsible for early assembly of the dyskerin RNP but is replaced by GAR1 in the mature RNP. PARN is required for maturation and stabilization of nascent TERC RNA. Components of the CST (CTC1, STN1, TEN1) complex are responsible for filling in the lagging C-strand of the elongating telomere end. Components of the telomere maintenance machinery that have been found to be disrupted in DC are shown in color with bold labels.