Pre-engraftment syndrome (PES) is poorly characterized, and its clinical significance and the prognostic impact after unrelated cord blood transplantation (CBT) are unclear. To address these issues, we retrospectively analyzed the incidence, risk factors, and clinical outcomes of PES in unrelated CBT recipients. Data of 381 patients who received unrelated CBT from 18 medical centers in Korea were reviewed. PES was defined as unexplained fever >38.3°C not associated with infection, and/or unexplained skin rash with or without evidence of fluid retention before neutrophil recovery. PES developed in 102 patients (26.8%) at a median of 7 days after CBT. Of these patients, 74 patients (72.5%) received intravenous corticosteroid at a median dose of 1 mg/kg/day, and of these, 95% showed clinical improvement. Risk factors for developing PES included low risk disease, myeloablative conditioning, graft-versus-host disease (GVHD) prophylaxis without methotrexate or corticosteroid, and >5.43 x 10(7)/kg infused nucleated cells. Absence of PES was one of the risk factors for graft failure in multivariate analysis. The cumulative incidence of grade II to grade IV acute GVHD by 100 days after CBT was higher in patients with PES than in those without PES (56.0% versus 34.4%, P < .01). PES was not associated with chronic GVHD, treatment-related mortality, relapse, or overall survival. PES seems to be common after CBT and may be associated with enhanced engraftment without significant morbidity.

Ethnically specific data on genetic variation are crucial for understanding human biology and for clinical interpretation of variant pathogenicity. We analyzed data obtained by deep sequencing 1303 Korean whole exomes; the data were generated by three independent whole exome sequencing projects (named the KOEX study). The primary focus of this study was to comprehensively analyze the variant statistics, investigate secondary findings that may have clinical actionability, and identify loci that should be cautiously interpreted for pathogenicity. A total of 495 729 unique variants were identified at exonic regions, including 169 380 nonsynonymous variants and 4356 frameshift insertion/deletions. Among these, 76 607 were novel coding variants. On average, each individual had 7136 nonsynonymous single-nucleotide variants and 74 frameshift insertion/deletions. We classified 13 pathogenic and 13 likely pathogenic variants in 56 genes that may have clinical actionability according to the guidelines of the American College of Medical Genetics and Genomics, and the Association for Molecular Pathology. The carrier frequency of these 26 variants was 2.46% (95% confidence interval 1.73–3.46). To identify loci that require cautious interpretation in clinical sequencing, we identified 18 genes that are prone to sequencing errors, and 671 genes that are highly polymorphic and carry excess nonsynonymous variants. The catalog of identified variants, its annotation and frequency information are publicly available (http://koex.snu.ac.kr). These findings should be useful resources for investigating ethnically specific characteristics in human health and disease.

Familial hemophagocytic lymphohistiocytosis (familial HLH or FHL) is a potentially fatal autosomal recessive disorder. Our previous study demonstrated that UNC13D mutations (FHL3) account for ~90 % of FHL in Korea with recurrent splicing mutation c.754-1G>C (IVS9-1G>C). Notably, half of the FHL3 patients had a monoallelic mutation of UNC13D. Deep intronic mutations in UNC13D were recently reported in patients of European descent. In this study, we performed targeted mutation analyses for deep intronic mutations and investigated on the founder effect in FHL3 in Korean patients. The study patients were 72 children with HLH including those with FHL3 previously reported to have a monoallelic UNC13D mutation. All patients were recruited from the Korean Registry of Hemophagocytic Lymphohistiocytosis. In addition to conventional sequencing of FHL2-4, targeted tests for c.118-308C>T and large intronic rearrangement mutations of UNC13D were performed. Haplotype analysis was performed for founder effects using polymorphic markers in the FHL3 locus. FHL mutations were detected in 20 patients (28 %). Seventeen patients had UNC13D mutations (FHL3, 85 %) and three had PRF1 mutations (FHL2, 15 %). UNC13D:c.118-308C>T was detected in ten patients, accounting for 38 % of all mutant alleles of UNC13D, followed by c.754-1G>C (26 %). Haplotype analyses revealed significantly shared haplotypes in both c.118-308C>T and c.754-1G>C, indicating the presence of founder effects. The deep intronic mutation UNC13D:c.118-308C>T accounts for the majority of previously missing mutations and is the most frequent mutation in FHL3 in Korea. Founder effects of two recurrent intronic mutations of UNC13D explain the unusual predominance of FHL3 in Korea.

Chemoimmunotherapy-based treatments have improved the survival of patients with HLH, but outcomes of the patients are still unsatisfactory. We report here the outcome of Korean children with HLH who underwent HSCT, which was analyzed from the data of a nation-wide HLH registry. Retrospective nation-wide data recruitment for the pediatric HLH patients diagnosed between 1996 and 2008 was carried out by the Histiocytosis Working Party of the Korean Society of Hematology. Nineteen patients who received HSCT among the total of 148 enrolled children with HLH were analyzed for the transplant-related variables and events. The probability of five-yr survival after HSCT was 73.3% with a median follow-up of 57. Two months compared to 54.3% for the patients who were treated with chemoimmunotherapy only (p = 0.05). The reasons for HSCT were active disease after eight wk of initial treatment (n = 9), relapsed disease (n = 5), and FHL (n = 5). Fourteen patients are currently alive without disease after HSCT, four patients died of treatment-related events (infection in two and graft failure in two) at early post-transplant period, and one patient died of relapse at one yr post transplantation. The survival of patients who were transplanted because of active disease after eight wk of initial treatment was worse compared to those patients who had inactive state at that time (60.6% vs. 100%, respectively, p = 0.06). Of the four patients who received transplants using cord blood, three died of graft failure (n = 2) and relapse (n = 1). The five-yr probability of survival after HSCT according to the donor type was 85.7% for the MRDs (n = 6), 87.5% for the MUDs (n = 8), and 40% for the MMUDs (n = 5) (p = 0.03). Other variables such as age, CNS involvement at the time of diagnosis, the etiology of HLH (familial or secondary), and the conditioning regimens had no influence on the five-yr OS of the HLH patients who underwent HSCT. HSCT improved the survival of the patients who had familial, relapsed, or severe and persistent SHLH in the Korean nation-wide HLH registry. Although numbers were small, these results are similar to other reports in the literature. The disease state after initial treatment, the stem cell source of the transplant, and the donor type were the important prognostic factors that affected the OS of the HLH patients who underwent HSCT.