Topical therapy and skin care for transplant-associated atopic dermatitis in children and adolescents.

BACKGROUND: New-onset allergic diseases, such as food allergy or atopic dermatitis, can develop after allogeneic transplantation. There are limited reports of new-onset atopic dermatitis after allogeneic hematopoietic stem cell transplantation in children and adolescents, and its treatment is yet to be established. The pathogenesis may differ from typical atopic dermatitis in terms of alloimmunity including graft-versus-host disease. METHODS: We present five children and adolescents with new-onset atopic dermatitis after allogeneic hematopoietic stem cell transplantation. The characteristics and clinical profiles of skin treatment after hematopoietic stem cell transplantation are summarized. RESULTS: Graft-versus-host disease prophylaxis included systemic tacrolimus for all patients. After hematopoietic stem cell transplantation, all patients achieved complete donor chimerism of the bone marrow and had acute graft-versus-host disease of the skin. After engraftment, all patients had skin lesions that met the international consensus diagnostic criteria for atopic dermatitis. None of the patients met the diagnostic criteria for chronic graft-versus-host disease. Topical therapy and skin care based on atopic dermatitis guidelines improved skin condition and atopic dermatitis severity scores in all patients. In addition, type 2 inflammatory markers improved accordingly. CONCLUSION: Topical therapy and skin care may be effective for transplant-related atopic dermatitis after hematopoietic stem cell transplantation. When extensive dermatitis is observed after hematopoietic stem cell transplantation, this treatment may avoid excessive immunosuppressive therapy if it meets the diagnostic criteria for atopic dermatitis.

Clinical conditions and risk factors for inhibitor-development in patients with haemophilia: A decade-long prospective cohort study in Japan, J-HIS2 (Japan Hemophilia Inhibitor Study 2).

BACKGROUND: Inhibitor-development is a serious complication in patients with haemophilia (PwH). Previous studies reported that therapeutic and genetic factors could be associated with these alloantibodies. Relevant clinical features such as genetic-background and different treatment regimens in Japan remain unclear, however. AIMS: To analyse a nation-wide Japanese registry for PwH, and to examine risk factors for inhibitor-development. METHODS AND RESULTS: Newly diagnosed patients with haemophilia A (PwHA) or haemophilia B (PwHB) without inhibitors after 2007, and with treatment records traceable from 0 to 75 exposure days (ED), were enrolled in the Japan Hemophilia Inhibitor Study 2 (J-HIS2) initiated in 2008. Of 417 patients (340 PwHA, 77 PwHB) from 46 facilities, 83 (76 PwHA, 7 PwHB) were recorded with inhibitors by July 2020. Inhibitors were observed in 31.0% of severe PwHA, 8.0% moderate and 1.6% mild and in 17.1% of severe PwHB. The majority of inhibitors (89.7% in severe PwHA and 71.4% in severe PwHB) were detected on or before 25ED (median 12ED in PwHA and 19ED in PwHB). Genotyping in these severe patients identified an association between inhibitor-development and null variants of F8 (P < .01) or F9 (P < .05). A lower incidence of inhibitors was recorded in severe PwHA treated with prophylaxis than in those treated on-demand (P < .01). A past-history of intracranial-haemorrhage appeared to be associated with inhibitor-development, while FVIII-concentrates infusion and routine vaccination on the same day was not related to inhibitor-development. CONCLUSION: The J-HIS2 study has identified significant clinical variables associated with inhibitor-development in Japanese PwH, consistent with other global studies.

Mutations in MECOM, Encoding Oncoprotein EVI1, Cause Radioulnar Synostosis with Amegakaryocytic Thrombocytopenia.

Radioulnar synostosis with amegakaryocytic thrombocytopenia (RUSAT) is an inherited bone marrow failure syndrome, characterized by thrombocytopenia and congenital fusion of the radius and ulna. A heterozygous HOXA11 mutation has been identified in two unrelated families as a cause of RUSAT. However, HOXA11 mutations are absent in a number of individuals with RUSAT, which suggests that other genetic loci contribute to RUSAT. In the current study, we performed whole exome sequencing in an individual with RUSAT and her healthy parents and identified a de novo missense mutation in MECOM, encoding EVI1, in the individual with RUSAT. Subsequent analysis of MECOM in two other individuals with RUSAT revealed two additional missense mutations. These three mutations were clustered within the 8(th) zinc finger motif of the C-terminal zinc finger domain of EVI1. Chromatin immunoprecipitation and qPCR assays of the regions harboring the ETS-like motif that is known as an EVI1 binding site showed a reduction in immunoprecipitated DNA for two EVI1 mutants compared with wild-type EVI1. Furthermore, reporter assays showed that MECOM mutations led to alterations in both AP-1- and TGF-ß-mediated transcriptional responses. These functional assays suggest that transcriptional dysregulation by mutant EVI1 could be associated with the development of RUSAT. We report missense mutations in MECOM resulting in a Mendelian disorder that provide compelling evidence for the critical role of EVI1 in normal hematopoiesis and in the development of forelimbs and fingers in humans.

Amelioration of inflammation and tissue damage in sickle cell model mice by Nrf2 activation.

Sickle cell disease (SCD) is an inherited disorder caused by a point mutation in the ß-globin gene, leading to the production of abnormally shaped red blood cells. Sickle cells are prone to hemolysis and thereby release free heme into plasma, causing oxidative stress and inflammation that in turn result in damage to multiple organs. The transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2) is a master regulator of the antioxidant cell-defense system. Here we show that constitutive Nrf2 activation by ablation of its negative regulator Keap1 (kelch-like ECH-associated protein 1) significantly improves symptoms in SCD model mice. SCD mice exhibit severe liver damage and lung inflammation associated with high expression levels of proinflammatory cytokines and adhesion molecules compared with normal mice. Importantly, these symptoms subsided after Nrf2 activation. Although hemolysis and stress erythropoiesis did not change substantially in the Nrf2-activated SCD mice, Nrf2 promoted the elimination of plasma heme released by sickle cells' hemolysis and thereby reduced oxidative stress and inflammation, demonstrating that Nrf2 activation reduces organ damage and segregates inflammation from prevention of hemolysis in SCD mice. Furthermore, administration of the Nrf2 inducer CDDO-Im (2-cyano-3, 12 dioxooleana-1, 9 diene-28-imidazolide) also relieved inflammation and organ failure in SCD mice. These results support the contention that Nrf2 induction may be an important means to protect organs from the pathophysiology of sickle cell-induced damage.

Onset of Hemophagocytic Lymphohistiocytosis during Piperacillin-Tazobactam Therapy in Three Children with Acute Focal Bacterial Nephritis.

Hemophagoytic lymphohistiocytosis (HLH) is a rare life-threatening disorder caused by overactivation of the immune system, associated with infections, autoimmune disorders, and malignancies. The pathological hallmark of HLH is phagocytosis of blood cells and platelets by activated macrophages and histiocytes. In this report, we describe the onset of HLH in three children, aged 2, 5 and 7 years old, during the treatment of acute focal bacterial nephritis (AFBN) with an antibiotic, piperacillin-tazobactam (PIPC-TAZ). AFBN is acute localized bacterial infection of the kidney without abscess formation. PIPC-TAZ was chosen for the treatment of AFBN, because it not only has indications for complicated urinary tract infections, but also covers most of the causative bacteria of urinary tract infections, including ß-lactamase-producing Escherichia coli. The clinical courses of the three patients were similar, and they were treated with PIPC-TAZ and amikacin (AMK) for AFBN. Fever went down 2 to 5 days later, and AMK was discontinued by day 6. However, fever recurred on 13 to 15 days after introduction of PIPC-TAZ therapy, even though all of the patients had no signs of recurrence of AFBN. The clinical features and laboratory tests of two patients fulfilled the criteria of HLH, whereas the other patient had initiated therapy before fulfilling the criteria. Cessation of PIPC-TAZ combined with corticosteroid therapy improved clinical symptoms. HLH of our patients was probably induced by PIPC-TAZ, as judged by the timing of the onset of HLH and the positivity of the drug-lymphocyte stimulation test. In conclusion, prolonged antibiotic therapy with PIPC-TAZ could be a cause of HLH.

Analyses of Genetic and Clinical Parameters for Screening Patients With Inherited Thrombocytopenia with Small or Normal-Sized Platelets.

BACKGROUND: Childhood thrombocytopenias include immune thrombocytopenic purpura (ITP) and inherited thrombocytopenia; the former is caused by autoantibodies to platelets, whereas the latter can be distinguished by platelet size and underlying genetic mutations. Due to limited methods for the definite diagnosis of ITP, genetic and clinical parameters are required for diagnosing inherited thrombocytopenias with small or normal-sized platelets. PROCEDURE: In total, 32 Japanese patients with thrombocytopenia with small or normal-sized platelets from 29 families were enrolled. All the patients were under 20 years of age, with family histories of early-onset thrombocytopenia and/or poor response to conventional therapies for ITP. Genotypes and clinical parameters were retrospectively evaluated according to the disease type. RESULTS: Twelve cases of inherited thrombocytopenia were observed. We identified chromosomal deletions within the WASP gene in two patients with Wiskott-Aldrich syndrome; a missense mutation in a patient with X-linked thrombocytopenia; and mutations in the RUNX1 gene of five patients with familial platelet disorder with propensity to acute myelogenous leukemia, and in the ANKRD26 gene of four patients with autosomal dominant thrombocytopenia-2. All 12 carried germline mutations, three of which were de novo. Furthermore, we observed significantly elevated serum thrombopoietin (TPO) levels and dysplasia of megakaryocytes in patients carrying the RUNX1 and ANKRD26 mutations. CONCLUSIONS: Genetic analyses and detection of TPO levels and dysmegakaryopoiesis were clinically useful for screening patients with inherited thrombocytopenias, irrespective of the family history. We hypothesize that the WASP, RUNX1, and ANKRD26 genes are important for normal TPO signaling and the network underlying thrombopoiesis.

Pharmacokinetics, efficacy, and safety of caspofungin in Japanese pediatric patients with invasive candidiasis and invasive aspergillosis.

The antifungal agents approved in Japan for pediatric use are limited and many unapproved drugs are actually used without clear instruction for dosage. We investigated the pharmacokinetics of caspofungin for the treatment of invasive candidiasis and invasive aspergillosis in 20 Japanese pediatric patients using a pediatric-specific dosage based on body surface area. Caspofungin was administered intravenously over 60 min as 70 mg/m(2) on Day 1, followed by 50 mg/m(2) per day. Five or 4 point blood sampling were done in 15 patients on Day 4-5 to calculate AUC0-24 h. The geometric means (95% confidence interval) of C24 h and AUC0-24 h in the pediatric patients were 3.3(2.5, 4.4) µg/mL and 175.1 (139.3, 220.1) µg hr/mL, respectively, which were comparable to those in Japanese adult patients [3.2 (2.8, 3.5) µg/mL and 144.9 (131.7, 159.3) µg hr/mL, respectively]. Among the 20 patients, 10 (50%) had at least 1 drug-related adverse event which was considered related to caspofungin therapy. No drug-related serious adverse event and no death occurred. The most common drug-related adverse events were events relating to hepatic function (mainly increases in ALT and AST). The overall success in efficacy was observed in 13 of 20 patients. In conclusion, once daily administration of caspofungin (70 mg/m(2) on Day 1, followed by 50 mg/m(2) [maximum daily dose not to exceed 70 mg]), which is the same dosage being used in overseas, achieved sufficient drug exposure and a favorable efficacy and acceptable safety profile in Japanese pediatric patients with invasive fungal infections.

Gene alterations involving the CRLF2-JAK pathway and recurrent gene deletions in Down syndrome-associated acute lymphoblastic leukemia in Japan.

In Western countries, gene alterations involving the CRLF2-JAK signaling pathway are identified in approximately 50-60% of patients with Down syndrome-associated acute lymphoblastic leukemia (DS-ALL), and this pathway is considered a potential therapeutic target. The frequency of BTG1 deletions in DS-ALL is controversial. IKZF1 deletions, found in 20-30% of DS-ALL patients, are associated with a poor outcome and EBF1 deletions are very rare (∼2%). We analyzed 38 patients to determine the frequencies and clinical implications of CRLF2-JAK pathway genetic alterations and recurrent gene deletions in Japanese DS-ALL patients. We confirmed a high incidence of P2RY8-CRLF2 (29%) and JAK2 mutations (16%), though the frequency of P2RY8-CRLF2 was slightly lower than that in Western countries (∼50%). BTG1 deletions were common in our cohort (25%). IKZF1 deletions were detected in 25% of patients and associated with shorter overall survival (OS). EBF1 deletions were found at an unexpectedly high frequency (16%), and at a significantly higher level in P2RY8-CRLF2-positive patients than in P2RY8-CRLF2-negative patients (44% vs. 4%, P=0.015). Deletions of CDKN2A/B and PAX5 were common in P2RY8-CRLF2-negative patients (48 and 39%, respectively) but not in P2RY8-CRLF2-positive patients (11% each). Associations between these genetic alterations and clinical characteristics were not observed except for inferior OS in patients with IKZF1 deletions. These results suggest that differences exist between the genetic profiles of DS-ALL patients in Japan and in Western countries, and that P2RY8-CRLF2 and EBF1 deletions may cooperate in leukemogenesis in a subset of Japanese DS-ALL patients.

TUBB1 mutation disrupting microtubule assembly impairs proplatelet formation and results in congenital macrothrombocytopenia.

This report describes a family with TUBB1-associated macrothrombocytopenia diagnosed based on abnormal platelet ß1-tubulin distribution. A circumferential marginal microtubule band was undetectable, whereas microtubules were frayed and disorganized in every platelet from the affected individuals. Patients were heterozygous for novel TUBB1 p.F260S that locates at the α- and ß-tubulin intradimer interface. Mutant ß1-tubulin was not incorporated into microtubules with endogenous α-tubulin, and α-tubulin expression was decreased in transfected Chinese hamster ovary cells. Transduction of mutant ß1-tubulin into mouse fetal liver-derived megakaryocytes demonstrated no incorporation of mutant ß1-tubulin into microtubules with endogenous α-tubulin and diminished proplatelet formation, leading to the production of fewer, but larger, proplatelet tips. Furthermore, mutant ß1-tubulin was not associated with endogenous α-tubulin in the proplatelets. Deficient functional microtubules might lead to defective proplatelet formation and abnormal protrusion-like platelet release, resulting in congenital macrothrombocytopenia.

Selective expansion of donor-derived regulatory T cells after allogeneic bone marrow transplantation in a patient with IPEX syndrome.

IPEX syndrome is a rare and fatal disorder caused by absence of regulatory T cells (Tregs) due to congenital mutations in the Forkhead box protein 3 gene. Here, we report a patient with IPEX syndrome treated with RIC followed by allogeneic BMT from an HLA-matched sibling donor. We could achieve engraftment and regimen-related toxicity was well tolerated. Although the patient was in mixed chimera and the ratio of donor cells in whole peripheral blood remained relatively low, selective and sustained expansion of Tregs determined as CD4+CD25+Foxp3+ cells was observed. Improvement in clinical symptoms was correlated with expansion of donor-derived Tregs and disappearance of anti-villin autoantibody, which was involved in the pathogenesis of gastrointestinal symptoms in IPEX syndrome. This clinical observation suggests that donor-derived Tregs have selective growth advantage in patients with IPEX syndrome even in mixed chimera after allogeneic BMT and contribute to the control of clinical symptoms caused by the defect of Tregs.

Reduced-intensity conditioning is effective for allogeneic hematopoietic stem cell transplantation in infants with MECOM-associated syndrome.

Mutations in the MECOM encoding EVI1 are observed in infants who have radioulnar synostosis with amegakaryocytic thrombocytopenia. MECOM-associated syndrome was proposed based on clinical heterogeneity. Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment for progressive bone marrow failure. However, data regarding allogeneic HSCT for this rare disease are limited. We retrospectively assessed overall survival, conditioning regimen, regimen-related toxicities and long-term sequelae in six patients treated with allogeneic HSCT. All patients received a reduced-intensity conditioning (RIC) regimen consisting of fludarabine, cyclophosphamide or melphalan, and rabbit anti-thymocyte globulin and/or low-dose total body/thoracic-abdominal/total lymphoid irradiation, followed by allogeneic bone marrow or cord blood transplantation from unrelated donors between 4 and 18 months of age. All patients survived and achieved stable engraftment and complete chimerization with the donor type. Moreover, no patient experienced severe regimen-related toxicities, and only lower grades of acute graft-versus-host disease were observed. Three patients treated with low-dose irradiation had relatively short stature compared to three patients not treated with irradiation. Therefore, allogeneic HSCT with RIC is an effective and feasible treatment for infants with MECOM-associated syndrome. Future studies are needed to evaluate the use of low-dose irradiation to avoid risks of other long-term sequelae.

Fatigue in survivors of childhood acute lymphoblastic and myeloid leukemia in Japan.

BACKGROUND: Fatigue in cancer survivors is a serious problem in pediatric oncology, but reports on this issue are limited, especially in Asian countries. METHODS: Sixty-three patients with acute lymphoblastic leukemia and 18 patients with acute myeloid leukemia who attended a follow-up outpatient clinic were enrolled. Participants were required to be >8 years of age, in remission, and without any cancer treatment for at least the previous 1 year. A control group consisted of 243 subjects whose age and gender were matched with the patient group. A questionnaire consisting of 12 items was devised for fatigue measurement. RESULTS: Principal factor analysis identified three dimensions, defined as physical fatigue, decreased function, and altered mood. The mean total and the three fatigue dimension scores tended to be higher in the control group, but significant differences between the scores were seen only in the total and physical fatigue scores. Multiple regression analysis indicated an association of present older age or shorter duration after completion of treatment with total and physical fatigue, and an association of presence of total body irradiation with decreased function. CONCLUSION: Pediatric leukemia survivors in Japan experience equal or less fatigue compared with that of controls in different fatigue dimensions. Elucidation of underlying mechanisms of cancer-related fatigue including the differences of cultural background among different countries is necessary for future study of this issue.

Favorable prognosis of vaccine-associated immune thrombocytopenia in children is correlated with young age at vaccination: Retrospective survey of a nationwide disease registry.

Childhood vaccine-associated immune thrombocytopenia (ITP) has a mostly favorable prognosis. To identify factors associated with prognosis, a retrospective survey was conducted with children with ITP who were registered in the Japanese Society of Pediatric Hematology/Oncology registry from 2008 to 2011. A total of 477 patients were categorized into four groups by event preceding ITP onset: vaccine-precedence (VP; n = 43), vaccine/infection-precedence (VIP; n = 34), infection-precedence (IP; n = 162), and no vaccine/infection-precedence (NVI; n = 238). Compared to IP and NVI, VP and VIP were significantly younger at diagnosis, with the age distribution peaking at infancy, and more frequently had favorable prognosis. Time to platelet recovery to 100 × 103/µL was significantly faster for VP and VIP than NVI. Multivariate Cox regression analysis with sex, age at diagnosis, infection-precedence, and vaccine-precedence as variables revealed age < 36 months (HR 0.992, 95% CI 0.989-0.995; p < 0.001) and male sex (HR 0.770, 95% CI 0.623-0.952; p = 0.015) as associated factors, but not infection-precedence (p = 0.149) or vaccine-precedence (p = 0.650). In subgroup analysis in patients < 36 months, age at diagnosis (p < 0.001) was the only associated factor. Favorable prognosis of childhood vaccine-associated ITP is correlated with young age at vaccination, but not with vaccination itself.

Identification of FOXP3-negative regulatory T-like (CD4(+)CD25(+)CD127(low)) cells in patients with immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome.

Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is an autoimmune disorder caused by mutations in the FOXP3 gene, which plays a key role in the generation of CD4(+)CD25(+)regulatory T (Treg) cells. We selected CD127 as the surface marker of Treg cells to illustrate the development and function of Treg cells in IPEX syndrome. CD4(+)CD25(+)FOXP3(+) T cells, the putative Treg cells, were almost completely absent in all patients. Importantly, a substantial number of CD4(+)CD25(+)CD127(low) T cells were observed in 3 IPEX patients with hypomorphic mutations in the FOXP3 gene. We demonstrated that CD4(+)CD25(+)CD127(low) T cells isolated from these 3 patients exhibited an appreciable suppressive activity on effector T cell proliferation, although less than that displayed by Treg cells from healthy controls. These results suggest that genetically altered FOXP3 can drive the generation of functionally immature Treg cells, but that intact FOXP3 is necessary for the complete function of Treg cells.

Prospective study of a therapeutic regimen with all-trans retinoic acid and anthracyclines in combination of cytarabine in children with acute promyelocytic leukaemia: the Japanese childhood acute myeloid leukaemia cooperative study.

In childhood acute promyelocytic leukaemia (APL), the efficacy of therapy combining cytarabine with all-trans retinoic acid (ATRA) and anthracyclines remains unclear in terms of long-term prognosis. Between August 1997 and March 2004, 58 children with APL (median age: 11 years) were enrolled into an acute myeloid leukaemia (AML) study (AML99-M3) and followed up for a median time of 86 months. The regimen included ATRA and anthracyclines combined with cytarabine in both induction and consolidation. In induction, two patients died of haemorrhage and four patients developed retinoic acid syndrome. Of 58 patients, 56 (96·6%) achieved complete remission, two of whom relapsed in the bone marrow after 15 and 19 months respectively. Sepsis was a major complication, with an incidence of 5·6-10·9% in the consolidation blocks, from which all but one of patients recovered. Consequently, 7-year overall and event-free survival rates were 93·1% and 91·4% respectively, and cumulative incidence of relapse plateaued at 3·6% after 2 years. Follow-up survey of 54 patients revealed no patients with late cardiotoxicity or secondary malignancy, except one with asymptomatic prolongation of QTc interval. This study suggests that the combination of cytarabine with ATRA and anthracycline-based therapy may have useful implications in the perspective of long-term prognosis and late adverse effects for childhood APL.

Pneumococcal Serotype-specific Opsonophagocytic Activity in Interleukin-1 Receptor-associated Kinase 4-deficient Patients.

BACKGROUND: The antibody response after pneumococcal vaccines and their effectiveness against invasive pneumococcal disease (IPD) in patients with interleukin-1 receptor-associated kinase 4 (IRAK4) deficiency have not been fully evaluated. Here, we evaluated pneumococcal serotype-specific opsonophagocytic activity (OPA) in IRAK4-deficient patients along with their clinical course. METHODS: We investigated 6 IRAK4-deficient patients in Japan, whose attending physicians could be contacted. We performed OPA measurements using stored and more recent serum samples obtained from these patients. RESULTS: All patients had received pneumococcal vaccination. Among the 3 patients who had IPD, 2 had an episode of pneumococcal meningitis and the other developed pneumococcal bacteremia 3 years after the occurrence of pneumococcal meningitis. Only one episode of invasive bacterial infection was caused by a Streptococcus pneumoniae vaccine-type strain. An increased opsonization index was found in the sera after vaccination for all IRAK-deficient patients, including when the 23-valent pneumococcal polysaccharide vaccine was used. CONCLUSIONS: A significant increase in levels of OPA against most of the pneumococcal vaccine antigens was observed for all IRAK4-deficient patients. However, IPD could not be prevented by pneumococcal vaccination alone. Therefore, adequate prophylaxis should be provided with antibiotics at least until 8 years of age, along with regular immunoglobulin therapy, particularly during the infantile period.

Mutation analysis of the SHOC2 gene in Noonan-like syndrome and in hematologic malignancies.

Noonan syndrome is an autosomal dominant disease characterized by dysmorphic features, webbed neck, cardiac anomalies, short stature and cryptorchidism. It shows phenotypic overlap with Costello syndrome and cardio-facio-cutaneous (CFC) syndrome. Noonan syndrome and related disorders are caused by germline mutations in genes encoding molecules in the RAS/MAPK pathway. Recently, a gain-of-function mutation in SHOC2, p.S2G, has been identified as causative for a type of Noonan-like syndrome characterized by the presence of loose anagen hair. In order to understand the contribution of SHOC2 mutations to the clinical manifestations of Noonan syndrome and related disorders, we analyzed SHOC2 in 92 patients with Noonan syndrome and related disorders who did not exhibit PTPN11, KRAS, HRAS, BRAF, MAP2K1/2, SOS1 or RAF1 mutations. We found the previously identified p.S2G mutation in eight of our patients. We developed a rapid detection system to identify the p.S2G mutation using melting curve analysis, which will be a useful tool to screen for the apparently common mutation. All the patients with the p.S2G mutation showed short stature, sparse hair and atopic skin. Six of the mutation-positive patients showed severe mental retardation and easily pluckable hair, and one showed leukocytosis. No SHOC2 mutations were identified in leukemia cells from 82 leukemia patients. These results suggest that clinical manifestations in SHOC2 mutation-positive patients partially overlap with those in patients with typical Noonan or CFC syndrome and show that easily pluckable/loose anagen hair is distinctive in SHOC2 mutation-positive patients.

A 9-month-old infant with acquired idiopathic thrombotic thrombocytopenic purpura caused by inhibitory IgG-autoantibody to ADAMTS13.

Although acquired idiopathic thrombotic thrombocytopenic purpura (ai-TTP) is rare in children, the authors present the case of a 9-month-old boy with ai-TTP showing severe deficiency of ADAMTS13 activity by its inhibitory IgG-autoantibody (4.8 Bethesda units/mL). Plasma exchange therapy was clinically effective but transient. Deficient activity of ADAMTS13 with the presence of its inhibitor persisted for 7 months after the initial diagnosis. However, other laboratory findings improved gradually with steroid (pulse) therapy. The hitherto insufficiently characterized clinical settings of ai-TTP during early childhood underscore the importance of measuring ADAMTS13 activity and its inhibitors for differential diagnosis in patients with thrombocytopenia of unknown etiology.