Typical features of dyskeratosis congenita (DC) resulting from excessive telomere shortening include bone marrow failure (BMF), mucosal fragility and pulmonary or liver fibrosis. In more severe cases, immune deficiency and recurring infections can add to disease severity. RTEL1 deficiency has recently been described as a major genetic etiology, but the molecular basis and clinical consequences of RTEL1-associated DC are incompletely characterized. We report our observations in a cohort of six patients: five with novel biallelic RTEL1 mutations p.Trp456Cys, p.Ile425Thr, p.Cys1244ProfsX17, p.Pro884_Gln885ins53X13, and one with novel heterozygous mutation p.Val796AlafsX4. The most unifying features were hypocellular BMF in 6/6 and B-/NK-cell lymphopenia in 5/6 patients. In addition, 3 patients with homozygous mutations p.Trp456Cys and p.Ile425Thr also suffered from immunodeficiency, cerebellar hypoplasia and enteropathy, consistent with Hoyeraal-Hreidarsson syndrome. Chromosomal breakage resembling a homologous recombination defect was detected in patient-derived fibroblasts but not in hematopoietic compartment. Notably, in both cellular compartments differential expression of 1243aa and 1219/1300aa RTEL1 isoforms was observed. In fibroblasts response to ionizing irradiation and non-homologous end joining were not impaired. Telomeric circles did not accumulate in patient-derived primary cells and lymphoblastoid cell lines, implying alternative pathomechanisms for telomeric loss. Overall, RTEL1-deficient cells exhibited a phenotype of replicative exhaustion, spontaneous apoptosis and senescence. Specifically, CD34+ cells failed to expand in vitro, B-cell development was compromised, and T-cells did not proliferate in long-term culture. Finally, we report on the natural history and outcome of our patients. While two patients died from infections, hematopoietic stem cell transplantation (HSCT) resulted in sustained engraftment in two patients. Whether chemotherapy negatively impacts on the course and onset of other DC-related symptoms remains open at present. Early onset lung disease occurred in one of our patient after HSCT. In conclusion, RTEL deficiency can show a heterogeneous clinical picture ranging from mild hypocellular BMF with B/NK cell lymphopenia to early-onset, very severe and rapidly progressing cellular deficiency.

Children with refractory or relapsed Burkitt lymphoma have a poor chance to survive. We describe characteristics, outcome, re-induction and transplantation-approaches and evaluate risk factors among children with progression of a Burkitt lymphoma/leukemia included in NHL-BFM studies between 1986 and 2016. Treatment recommendation was re-induction including rituximab from the early 2000s followed by blood stem cell transplantation. The 3-year survival of the 157 children was 18.5{plus minus}3%. Survival significantly improved from 11{plus minus}3% before to 27{plus minus}5% after 2000 (p<.001) allowing for risk factor analyses among the latter 75 patients, of whom 28 had disease progressive during initial therapy. Survival of 14 patients with relapse after initial therapy for low risk disease (R1/R2) was 50{plus minus}13% compared to 21{plus minus}5% for 61 patients progressing after R3/R4-therapy (p<.02). 25 of 28 patients with progression during first-line therapy, 31 of 32 with progression during re-induction, 15 of 16 not reaching a complete remission before transplantation, 9 of 10 treated with rituximab front-line and all 13 patients not receiving rituximab during re-induction died. 46 patients received stem cell transplantation (20 autologous, 26 allogeneic). Survival after a regimen combining Rituximab with continuous-infusion chemotherapy followed by allogeneic transplantation was 67{plus minus}12% compared to 18{plus minus}5% for all other regimen and transplantations (p=.003). Patients with relapsed Burkitt lymphoma/leukemia have a poor chance to survive after current effective front-line therapies. Progression during initial or re-induction chemotherapy and initial high-risk disease are risk-factors in relapse. Time-condensed continuous-infusion re-induction followed by stem cell transplantation forms the basis for testing new drugs.

Pediatric palliative home care (PPHC) provides care for children, adolescents, and young adults with life-limiting illnesses in their own homes. Home care often requires long travel times for the PPHC team, which is available to the families 24/7 during crises. The complementary use of telehealth may improve the quality of care. In this pilot study we identify the needs and concerns of patients, teams, and other stakeholders regarding the introduction of telehealth. As a first step, focus groups were conducted in three teams. For the second step, semi-structured interviews were conducted with patients and their families (n = 15). Both steps were accompanied by quantitative surveys (mixed methods approach). The qualitative data were analyzed using content analysis. A total of 11 needs were identified, which were prioritized differently. Highest priority was given to: data transmission, video consultation, access to patient records, symptom questionnaires, and communication support. The concerns identified were related to the assumption of deterioration of the status quo. Potential causes of deterioration were thought to be the negative impact on patient care, inappropriate user behavior, or a high level of technical requirements. As a conclusion, we define six recommendations for telehealth in PPHC.