BackgroundDyskeratosis congenita (DC) is an inherited telomeropathy characterized by mucocutaneous dysplasia, bone marrow failure, cancer predisposition, and other somatic abnormalities. Cells from patients with DC exhibit short telomere. The genetic basis of the majority of DC cases remains unknown.MethodsA 2 generational Chinese Han family with DC was studied using targeted capture and next-generation sequencing to identify the underlying DC-related mutations.ResultsIn this study, we identified a unique homozygous WD repeat containing antisense to TP53 (WRAP53) Arg298Trp mutation in the proband with DC and heterozygous WRAP53 Arg298Trp mutations in his asymptomatic, consanguineous parents and his sister, indicating an autosomal recessive inheritance mode. The proband with the homozygous WRAP53 Arg298Trp mutation had short telomere, classic clinical symptoms, and no response to danazol, glucocorticoid or cyclosporin A.ConclusionsThus, we reported for the first time that a unique homozygous WRAP53 mutation site underlies the development of DC.

Immune-mediated quantitative and qualitative defects of hematopoietic stem/ progenitor cells (HSPCs) play a vital role in the pathophysiology of acquired aplastic anemia (AA). Autophagy is closely related to T cell pathophysiology and the destiny of HSPCs, in which autophagy-related gene 5 (ATG5) is indispensably involved. We hypothesized that genetic variants of ATG5 might contribute to AA.We studied six ATG5 polymorphisms in a Chinese cohort of 176 patients with AA to compare with 157 healthy controls. A markedly decreased risk of AA in the recessive models of rs510432 and rs803360 polymorphisms (adjusted odds ratio [OR], 95% confidence interval [CI] = 0.467 [0.236-0.924], P = 0.029 for ATG5 rs510432; adjusted OR [95% CI] = 0.499 [0.255-0.975], P = 0.042 for ATG5 rs803360) was observed. Furthermore, the decreased risk was even more pronounced among nonsevere AA compared with healthy controls under recessive models (adjusted OR [95% CI] = 0.356 [0.141-0.901], P = 0.029 for ATG5 rs510432; adjusted OR [95% CI] = 0.348 [0.138-0.878], P = 0.025 for ATG5 rs803360; adjusted OR [95% CI] = 0.352 [0.139-0.891], P = 0.027 for ATG5 rs473543). Above all, rs573775 can strongly predict the occurrence of newly onset hematological event in patients with AA. Our results indicate that genetic ATG5 variants contributed to AA, which may facilitate further clarifying the underlying mechanisms of AA and making a patient-tailored medical decision. K E Y W O R D S anemia, aplastic, autophagy-related gene 5, hematological event, polymorphism, risk

Rationale: Systemic forms of chronic active Epstein-Barr virus infection (CAEBV) can predispose a patient to a protracted course of fulminant hemophagocytic lymphohistiocytosis, which has a poor prognosis. Epstein-Barr virus (EBV) infection may persist even after theoretically curative hematopoietic stem cell transplantation. Patient concerns: A female patient with CAEBV underwent chemotherapy followed by allogeneic hematopoietic stem cell transplantation from her human leukocyte antigen-matched sister. Neutrophil and platelet engraftment was observed on day +12 and +10. Full donor chimerism (DC) was achieved on Day +21. Diagnoses: From day +38, EBV-DNA in the blood was persistently positive, and DC declined. We attempted empirical interventions such as withdrawal of immune suppression, multiple donor lymphocyte infusion, stem cell boost, and interferon-α treatment. However, EBV-DNA copies continued to increase aggressively, whereas DC decreased rapidly and then reached a nadir of 63.27%. Interventions: Salvage programmed death 1 (PD-1) antibody treatment was administered as salvage therapy at +69 and +84. Outcomes: EBV-DNA was negative on day +97 and was ultimately undetectable. Equivalently, a full and stable DC was obtained at +97. Lessons: We summarize a case of PD-1 antibody used as salvage treatment in a post-transplant patient with CAEBV, which was eradicated and full DC was obtained. This case suggests that the PD-1 antibody appears to be a promising option for fighting EBV and mixed DCs.

Acquired bone marrow failure syndromes (aBMFS) encompass a wide range of diseases. A study to investigate WT1 expression in BM was conducted in 387 patients with aBMFS in China. The WT1 level in patients with aplastic anemia (AA) was significantly lower than that in patients with paroxysmal nocturnal hemoglobinuria (PNH, p = .023) and myelodysplastic syndrome (MDS, p < .001). In addition, the WT1 level in patients with MDS significantly increased as the disease progressed to an advanced stage. Patients with hypoplastic MDS had a differentiated expression level of WT1 compared with that of NSAA (p < .001). Furthermore, post-treatment patients of AA with partial response (PR) or complete response (CR) status had relatively higher WT1 levels than those with naive AA (p = .017, p = .003, respectively). Thus, the WT1 expression level could be a useful genetic marker for routine clinical work in aBMFS.