Genotypic and Phenotypic Spectrum of Dyskeratosis Congenita: Results from the Canadian Inherited Marrow Failure Registry

Introduction:
Dyskeratosis congenita (DC) is an inherited bone marrow failure syndrome caused by mutations in one of 13 telomere-related genes, resulting in disruption of normal telomere maintenance; however, about 30% of patients do not have a molecular diagnosis. DC patients are at increased risk for severe bone marrow failure (SBMF), myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), and solid tumours. Life expectancy is compromised by SBMF, malignancy, pulmonary and liver fibrosis, and GI bleeding.

Objectives:
Among patients with DC in Canada, aims were to: (1) characterize the genetic profile of DC in Canada, (2) define the spectrum of clinical features of DC, (3) determine the incidence and age when SBMF, MDS, AML or solid tumours develop, (4) identify factors that are associated with higher mortality risk, and (5) describe the causes of death.

Methods:
Data of patients enrolled in the Canadian Inherited Marrow Failure Registry (CIMFR) and meeting diagnostic criteria for DC between January 1, 2001 and March 1, 2018 were included. The CIMFR is a multicentre registry that captures data on patients with inherited marrow failure syndromes from pediatric tertiary referral centres across all Canadian provinces. We investigated several continuous (e.g. age at diagnosis of SBMF/MDS/AML) and categorical (e.g. mutated gene) variables that are associated with specific outcomes, namely overall survival and development of SBMF. Cox proportional hazard models were used to assess risk of death based on age at diagnosis and presence of SBMF. Kaplan–Meier curves were used to assess overall survival.

Results:
As of March 1^st, 2018, 35 patients with DC were enrolled. The mean age of diagnosis was 10.94 years (0-39.9). The underlying genotypes were: DKC1 (7), TERT (6), TINF2 (5), RTEL1 (3), PARN (2), TERC (2) but remained undetermined in the others (10). Twenty-seven patients were classified as classical DC, 7 had Hoyeraal-Hreidarsson syndrome and 1 patient had Coats plus syndrome. Eight patients (23%) developed SBMF. The mean age of SBMF was 4.22 years (1-8.66). No statistical difference was found between genotypes and progression to SBMF (P=0.1). Modelling death as a function of time varying SBMF status using a cox proportional hazard regression model showed that the presence of SBMF in DC patients was predictive of higher mortality rate (P= 0.009, hazard ratio 5.7, CI 1.54-21.5). None of the patients developed malignancy during childhood (0-18 years). One adult patient developed skin cancer. Eleven patients (31%) received a hematopoietic stem cell transplant (HSCT). The mean age of HSCT was 9.5 years (0.5-37). Ten (29%) patients died, five of whom were recipients of HSCT. Mean age of death was 12.98 years (2-24.6).
Extra-hematological complications included gastrointestinal bleeding (50%), pulmonary fibrosis (40%), overwhelming infection (40%), liver fibrosis (20%), cardiomyopathy (10%), hemolytic uremic syndrome (HUS) (10%) and thrombotic microangiopathy (TMA) (10%). Most patients had more than one organ dysfunction.

Analysis of survival showed that all patients with TINF2 mutations have died (at median age of 10.8 years, range 2.5-23.25) whereas none died in the TERT group. Patients diagnosed at younger age had lower overall survival compared to patients diagnosed at older ages (P= 0.03, HR: 0.72, CI: 0.57-0.90). All deaths were due to organ dysfunction related to DC. Fifty percent of the patients had concurrent SBMF at the time of death.

Conclusion:
In this analysis, we characterised the genetic and phenotypic spectrum of DC patients registered in the CIMFR. We found a high mortality rate mainly related to organ dysfunction and SBMF, and described the impact of genotype, earlier age at diagnosis and presence of SBMF in predicting survival. We found that malignancy is an uncommon complication in the pediatric age group.