Kiichiro Kanamitsu

Verification of risk scores to predict i.v. immunoglobulin resistance in incomplete Kawasaki disease

A recent study indicated the efficacy of the addition of prednisolone to i.v. immunoglobulin (IVIG) as initial treatment in patients with higher risk of IVIG resistance. Several different risk scores for predicting IVIG resistance have been proposed, mainly based on typical Kawasaki disease (KD) patients. We investigated the utility of the risk scores to predict IVIG resistance in incomplete KD.

Relapsed infant MLL-rearranged acute lymphoblastic leukemia with additional genetic alterations

Acute lymphoblastic leukemia (ALL) in infants is a rare and aggressive disease, and has poor prognosis. Approximately 80% of patients with infant ALL harbor a mixed lineage leukemia (MLL, also known as KMT2A) gene rearrangement, which is a strong independent predictor of poor outcome.1,2 Although MLL rearrangement is considered a strong driver mutation, it may not be sufficient for leukemogenesis.3 We report two relapsed cases of infant ALL with MLL rearrangement. Case 1 is a 3-month-old female who was diagnosed as infant ALL with MLL-ENL, and Case 2 is a 4-month-old male who was diagnosed as infant ALLwithMLL-AF4. Both patients experienced a relapse twice. Somatic DNA was obtained from bone marrow at diagnosis and each episode of relapse, while germline DNA was obtained from buccal swab. Targeted sequencing was performed on MiSeq (Illumina, San Diego, CA) using HaloPlex custom panels (Agilent, Santa Clara, CA), with 163 known mutated genes in hematological diseases, which are customized to detect cancer-related genes (Supplementary Table S1). Read alignment and variant calling were performed using the MiSeq reporter (Illumina), and variants were annotated using SureCall software (Agilent). Synonymous or noncoding variants were excluded, and single nucleotide polymorphisms (SNPs) and germline polymorphisms were reported to dbSNP, unless they were found in the COSMIC database. Among the remaining variants with a variant allele frequency higher than 0.1, recurrentlymutated genes reported in a larger cohort4 were considered as candidate genes and validated by conventional Sanger sequencing. Sanger sequencingwasperformedafterPCR using specific primers, and mutations were detected by ABI PRISM 3100 (Thermo Fisher Scientific,Waltham,MA) using the primers listed in Supplementary Table S1. Thus, we identified additional gene alterations (Fig. 1). Only two mutations were detected in diagnostic samples, indicating that small number of mutations cooperate with MLL rearrangement. Among them, mutations in KRAS and FLT3 have also been recurrently reported in a study by Andersson et al. using wholegenome or whole-exome sequencing .4 To date, their study has been the largest describing the mutational profile of infant ALL. It is notable that many mutations other than those involved in the tyrosine kinasePI3K-RAS signaling pathways, which are found in approximately half of the patients, are found with low frequency. We could monitor our

Adults with germline CBL mutation complicated with juvenile myelomonocytic leukemia at infancy

Juvenile myelomonocytic leukemia (JMML) appears to be a life-threatening disease and showed poor prognosis even after hematopoietic stem cell transplantation (HSCT) because of high relapse rate. On the other hand, recent molecular analysis revealed the heterogeneity of JMML. Here we report that two JMML patients survived >20 years without HSCT and both patients had uniparental disomy of 11q23 where CBL is located without the phenomenon found in neither Noonan syndrome nor Noonan syndrome-like disorder. We think that some JMML patients with CBL mutation might show the good prognosis in later life after remission of JMML.

Transient myeloproliferative disorder with partial trisomy 21.

Myeloid malignancy with Down syndrome (ML‐DS) is estimated to have a step‐wise leukemogenesis including GATA1 mutation. Trisomy 21 is essential for ML‐DS; however, we do not know exactly which gene or genes located on chromosome 21 are necessary for the ML‐DS. We report a female infant with transient myeloproliferative disorder (TMD) and partial trisomy 21. SNP array analysis showed 10 Mb amplification of 21q22.12–21q22.3, which included DYRK1A, ERG, and ETS but not the RUNX1 gene. With two other reported TMD cases having partial trisomy 21, DYRK1A, ERG, and ETS were the most likely genes involved in collaboration with the GATA1 mutation. Pediatr Blood Cancer

Simultaneous detection of ABL1 mutation and IKZF1 deletion in Philadelphia chromosome‐positive acute lymphoblastic leukemia using a customized target enrichment system panel

Recent clinical outcomes of pediatric Philadelphia chromosome‐positive acute lymphoblastic leukemia (Ph+ALL) vastly improved owing to tyrosine kinase inhibitor (TKI). However, the genetic status would be different in each case with ABL1 gene mutation or copy number variants (CNVs) such as IKZF1 deletion. In particular, the TKI resistant clone with ABL1 kinase mutation remains problematic. The comprehensive assessment of genetic status including mutation, insertion and deletion (indel) and CNVs is necessary.

Desmoid‐type fibromatosis in a boy with Down syndrome

Patients with Down syndrome (DS) have a markedly higher incidence of childhood leukemia, but a lower incidence of most solid tumors, compared with age‐matched euploid individuals. Trisomy 21 might be protective against tumorigenesis because of several tumor suppressive mechanisms. Desmoid‐type fibromatosis (DF) is a rare monoclonal, fibroblastic proliferation characterized by a variable clinical course. In recent reports, almost all cases of DF involved genomic alterations associated with activation of the Wnt/β‐catenin pathway. Here, we report the case of a boy with DS who developed DF without activation of the Wnt/β‐catenin pathway. To the best of our knowledge, this is the first case of DS involving DF.

Pediatric intestinal Behçet disease complicated by myeloid malignancies.

Behçet disease (BD) is rarely seen in children. Its clinical manifestations are believed to differ between pediatric and adult patients. The characteristics of BD complicated by myelodysplastic syndrome (MDS) are well established for adult patients; however, because only a few cases of pediatric-onset BD complicated by MDS have been reported, its clinical characteristics remain unknown. We here retrospectively review pediatric-onset BD complicated by myeloid malignancies in Japan, having identified five such patients. All patients were female and had gastrointestinal involvements, but lacked both major features of BD, i.e., uveitis and association with HLA-B51. All patients had advanced MDS or acute myeloid leukemia and received chemotherapy followed by hematopoietic stem cell transplantation. These five cases suggest that intestinal BD and myeloid malignancies have one or more pathophysiological mechanisms in common.

Suspected early onset of congenital Langerhans cell histiocytosis involving ectopic cervical thymus and mediastinal thymus, simultaneously

To the Editor: Langerhans cell histiocytosis (LCH) is a rare histiocytic disorder characterized by accumulation of Langerhans cells [1,2]. Congenital LCH chiefly affects the skin and is selfhealing (Hashimoto–Pritzker disease), but rare involvements of the lung, bone, or liver have been reported [3]. Thymus is one of the uncommon organs involved by LCH [4]. Ectopic thymus is an extremely rare etiology of a neck mass in an infant which results from abnormal embryogenesis of the thymus [5,6]. We present a case of congenital LCH with simultaneous involvement of ectopic cervical thymus and mediastinal thymus. A 2-month-old female without any significant medical history through the prenatal and neonatal period was brought to a physician complaining of left submandibular swelling. On physical examination, there was an elastic, soft, and poorly movable mass in the left submandibular area. The mass was 3 cm in diameter and had a smooth surface. Computed tomography (CT) revealed cystic and solid components in the mass (Fig. 1A). An open biopsy of the mass was performed. The mass was well demarcated from surrounding tissues and was resected without macroscopic leaving residues. The pathological examination showed proliferation of CD1a positive cells with a round nuclear and rich cytoplasm in an eosinophil rich background (Fig. 1B–D). Diagnosis of LCH was made. Moreover, the resected mass contained ectopic thymic tissue whose architecture was partly effaced by infiltration of Langerhans cells (Fig. 1B and E). Reconfirmation of the CT image revealed the enlarged mediastinal thymus with multiple cysts and punctate calcifications which are specific findings of the thymic involvement of LCH (Fig. 1A) [7]. Although biopsy of the mediastinal thymic LCH