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Front Immunol. 2017 May 1;8:449. doi: 10.3389/fimmu.2017.00449. eCollection 2017.

Clinical and Molecular Heterogeneity of RTEL1 Deficiency.

Author information

1
Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology, Medical Centre, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
2
Center for Chronic Immunodeficiency, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
3
Spemann Graduate School of Biology and Medicine, University of Freiburg, Freiburg, Germany.
4
Department of Rheumatology and Clinical Immunology, Medical Centre, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
5
Department of Paediatrics, Univeristy of Bern, Bern, Switzerland.
6
Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria.
7
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
8
Department of Pediatric Hematology and Oncology, Children's Hospital, University of Cologne, Cologne, Germany.
9
Department of Medical Genetics, Biozentrum, University of Wuerzburg, Wuerzburg, Germany.
10
Telomere Replication and Stability Group, MRC London Institute of Medical Sciences (LMS), London, UK.
11
Institute for Transfusion Medicine, Institute for Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Service Baden-Wuerttemberg - Hessen, University Ulm, Ulm, Germany.
12
Department of Human Genetics, Hannover Medical School, Hannover, Germany.
13
Department of Pediatric Hematology and Oncology, Justus-Liebig-University, Giessen, Germany.
14
Clinic of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
15
Hemato-Oncology Clinic Hamburg, Hamburg, Germany.
16
Faculty of Medicine, Institute of Pathology, Medical Center, University of Freiburg, Freiburg, Germany.
17
German Cancer Consortium (DKTK), Freiburg, Germany.
18
German Cancer Research Center (DKFZ), Heidelberg, Germany.
19
Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.
20
St. Anna Kinderspital and Children's Cancer Research Instutute, Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.

Abstract

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, three patients with homozygous mutations p.Trp456Cys or 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 patients 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.

KEYWORDS:

RTEL1; bone marrow failure; dyskeratosis congenita; immunodeficiency; lymphopenia

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