LAUSR

Dyskeratosis congenita (DC), which is characterized by a classical triad of reticular skin pigmentation, nail dystrophy and oral leukoplakia, is an inherited bone marrow failure (BMF) syndrome (Walne & Dokal, 2009; Nishio & Kojima, 2010). BMF is a common clinical feature that usually develops within the first decade of life. DC is caused by germline mutations in telomere-associated genes and results in excessive telomere attrition. The length of telomeres in most patients with DC is less than the first percentile of telomere length in age-matched healthy individuals (Alter et al, 2007). To date, 14 genes involved in telomere biology have been identified in approximately 70% of the patients (WegmanOstrosky & Savage, 2017). DC is also a cancer predisposition syndrome; patients with DC are at high-risk for malignancies, such as head and neck squamous cell carcinoma (SCC), anogenital SCC, myelodysplastic syndrome (MDS) and acute myeloid leukaemia (Alter et al, 2018). The risk of BMF in DC patients is exceedingly high with a cumulative incidence of about 50% by the age of 40 years and it is the primary cause of death in these patients, followed by pulmonary fibrosis and malignant disease. Allogeneic haematopoietic stem cell transplantation (HSCT) is the only curative treatment for BMF in patients with DC; however, this cannot correct other systemic defects of telomere maintenance. Allogeneic HSCT accelerates telomere shortening (Wynn et al, 1998), thereby increasing transplant–related toxicities, including pulmonary/liver complications in patients with DC. Moreover, the risk for developing solid tumours is higher in transplanted patients than in patients without transplants (Calado & Cl e, 2017). In the current issue, Fioredda et al (2018) analyse the outcome of 94 patients with DC who underwent HSCT between 1979 and 2015. A non-myeloablative conditioning regimen (NMAC) was administered to all patients. The 5-year overall survival (OS) rate was 59%; 39 patients died, accounting for a crude mortality rate of 41%. The OS curve showed a continuous decline over time; in particular, a sudden decline was observed after 8 years, with 10-year OS estimates of only <30%. The causes of death were infection (43%), organ damage (25%), rejection/graft failure (8%), secondary malignancy (8%) and others (8%). Infection and rejection/graft failure were the main causes of early deaths (i.e. within 24 months after transplantation). The incidence of organ damage particularly pulmonary fibrosis, and secondary malignancies increased later after transplantation, without reaching a plateau. Although clinical haematologists are particularly interested in the haematological findings in DC and their correction, neglecting the complex phenotype in DC patients as outlined above will most likely prove unfavourable and harmful if an allogeneic HSCT is under consideration. Traditionally, the endpoints of patients who underwent HSCT were 3to 5year OS; however, a continuous decline in the OS and an increase in late mortalities, even after 10 years from HSCT, were also observed in other large cohort studies involving DC patients who underwent HSCT (Gadalla et al, 2013; Barbaro & Vedi, 2016). The long-term outcome was disappointing, with an estimated OS of <20%. Underlying pulmonary and hepatic disease may predispose the patients to increased transplantation-related morbidity and mortality. Early results with NMAC were promising for improving the short-term survival (Nishio et al, 2011); however, there was no positive impact on long-term survival (Barbaro & Vedi, 2016). These disappointing results raise the question; “Should we consider HSCT as the first-line treatment for patients with DC?” The treatment of DC should aim at not only curing BMF but also prevent other organ damage and reduce the risk for cancer in affected patients. Since the 1960’s, androgens have been a therapeutic option for both inherited and acquired BMF syndromes when there is no evidence of progression to MDS or acute leukaemia. An in vitro study reported that androgen up-regulates both telomerase reverse transcriptase gene expression and telomerase enzymatic activity of human lymphocytes and CD34 haematopoietic cells (Calado et al, 2009). In a prospective phase 1/2 study, Townsley et al (2016) administered danazol to 27 patients Correspondence: S Kojima, Department of Paediatrics, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showaku, Nagoya 466-8550, Japan. E-mail: [email protected] editorial comment