Outcome after Stem Cell Transplant in Patients with Dyskeratosis Congenita

Dyskeratosis congenita is a rare inherited bone marrow failure and cancer predisposition syndrome with multisystem involvement. While allogeneic hematopoietic stem cell transplant (HSCT) can cure the bone marrow failure, reported survival is low, with patients suffering unusual complications post HSCT. We describe the long term outcome in 6 patients with mutation proven DC following an allo-HSCT at our institution between 1997–2011. To our knowledge this is the first report to begin to correlate genotype to phenotype post HSCT. The median age was 4 years (range: 2–13). 4 patients had mutations in the TINF2 gene, 1 in DKC1 and 1 had a homozygous TERT mutation. 4/6 patients received reduced intensity conditioning (RIC) regimens and 2 received myeloablative conditioning regimens (MAC). Patients received HSCT from MRDs (4) and MMUDs (2). 5/6 patients engrafted with the 1^st HSCT. One patient had primary engraftment failure and was rescued with a 2^nd HSCT from the same donor using MAC.  3/6 six patients developed GVHD (acute GVHD – 2, chronic extensive GVHD -1). 4/6 patients are alive (OS: 67%) with a median follow up of 1753 days (range: 92–5963). However, all 4 patients with TINF2 mutations suffered unusual multi-system complications which developed late (4–5 years) after HSCT. The 2 patients with DKC1 and TERT mutation had no such atypical complications and are doing well at last follow up. Recent reports describe a more severe phenotype in patients with TINF2 mutations and the extra-hematopoietic manifestations that continue after transplantation suggest that HSCT can have only limited impact on the natural course of their disease and on their long-term outcome. These patients require close multi-disciplinary follow up after HSCT to ensure early detection of complications. Future improvements could focus on the use of less toxic RIC regimens, measurement of biomarkers to predict complications and perhaps novel therapies to correct the underlying telomere defect.

Age (yrs)	Sex	Mutation	Complications post HSCT	Survival
5	F	TINF2	Pulmonary: Pulmonary fibrosis Renal: Hemolytic uremic syndrome, CKD Vascular: Venous malformations Heme: Hypocellular marrow Other DC related: Leukoplakia, nail dystrophy, alopecia, lacrimal duct stenosis, vaginal stenosis, osteoporosis, femur fracture	Alive
4	F	TINF2	Pulmonary: Pulmonary fibrosis GI: Massive GI bleeding, ascites Renal: Hepatorenal syndrome Heme/BMT: Hypocellular marrow Other DC related: Lacrimal duct stenosis	Dead
5	M	TINF2	GI: Massive GI bleeding, ascites Heme/BMT: Hypocellular marrow, oral GVHD ID: Disseminated adenovirus	Alive
2	M	TINF2	GI: Massive GI bleeding, intestinal obstruction and perforation Renal: Thrombotic microangiopathy, AKI Heme/BMT: Acute GVHD (gut, liver,skin) Other DC related: Urethral meatus stenosis ID: HHV6,  C difficile colitis	Dead
13	M	DKC1	GI: Esophageal stricture	Alive
3	M	TERT	Heme/BMT: Acute gut GVHD	Alive