Congenital anaemia associated with loss-of-function variants in DNA polymerase epsilon 1.

DNA polymerase epsilon (Pol ε), a component of the core replisome, is involved in DNA replication. Although genetic defects of Pol ε have been reported to cause immunodeficiency syndromes, its role in haematopoiesis remains unknown. Here, we identified compound heterozygous variants (p.[Asp1131fs];[Thr1891del]) in POLE, encoding Pol ε catalytic subunit A (POLE1), in siblings with a syndromic form of severe congenital transfusion-dependent anaemia. In contrast to Diamond-Blackfan anaemia, marked reticulocytopenia or marked erythroid hypoplasia was not found. Their bone marrow aspirates during infancy revealed erythroid dysplasia with strongly positive TP53 in immunostaining. Repetitive examinations demonstrated trilineage myelodysplasia within 2 years from birth. They had short stature and facial dysmorphism. HEK293 cell-based expression experiments and analyses of patient-derived induced pluripotent stem cells (iPSCs) disclosed a reduced mRNA level of Asp1131fs-POLE1 and defective nuclear translocation of Thr1891del-POLE1. Analysis of iPSCs showed compensatory mRNA upregulation of the other replisome components and increase of the TP53 protein, both suggesting dysfunction of the replisome. We created Pole-knockout medaka fish and found that heterozygous fishes were viable, but with decreased RBCs. Our observations expand the phenotypic spectrum of the Pol ε defect in humans, additionally providing unique evidence linking Pol ε to haematopoiesis.

Diagnostic delay of MYH9-related disorder in Japan.

MYH9-related disorder (MYH9-RD) is characterized by congenital macrothrombocytopenia and granulocyte inclusion bodies. MYH9-RD is often misdiagnosed as chronic immune thrombocytopenia. In this study, we investigated age at definitive diagnosis and indicative thrombocytopenia in 41 patients with MYH9-RD from the congenital thrombocytopenia registry in Japan. Our cohort comprises 54.8% adults over 18 years at confirmed diagnosis. We found a significant difference (p < 0.0001) between the median age at definitive diagnosis of 25.0 years and for indicative thrombocytopenia it was 9.0 years. Our findings strongly suggest diagnostic delay of MYH9-RD in Japan. Our registry system will continue to contribute to this issue.

The clinical and genetic landscape of early-onset thrombophilia in Japan.

OBJECTIVES: To determine the optimal management for early-onset thrombophilia (EOT), the genetic and clinical features of protein C (PC)-, protein S (PS)-, or antithrombin (AT)-deficient patients of ≤20 years of age were studied in Japan. METHODS/RESULTS: Clinical and genetic information of all genetically diagnosed cases was collected through the prospective, retrospective study, and literature review. One-hundred-one patients had PC (n = 55), PS (n = 29), or AT deficiency (n = 18). One overlapping case had PC- and PS-monoallelic variant. Fifty-five PC-deficient patients (54%) had 26 monoallelic or 29 biallelic variant(s), and 29 (29%) PS-deficient patients had 20 monoallelic or nine biallelic variant(s). None of the patients had AT-biallelic variants. The frequent low-risk allele p.K193del (PC-Tottori) was found in five patients with monoallelic (19%) but not 29 with biallelic variant(s). The most common low-risk allele p.K196E (PS-Tokushima) was found in five with monoallelic (25%) and six with biallelic variant(s) (67%). One exceptional de novo PC variant was found in 32 families with EOT. Only five parents had a history of thromboembolism. Thrombosis concurrently developed in three mother-newborn pairs (two PC deficiency and one AT deficiency). The prospective cohort revealed the outcomes of 35 patients: three deaths with PC deficiency and 20 complication-free survivors. Neurological complications were more frequently found in patients with PC-biallelic variants than those with PC-, PS-, or AT-monoallelic variants (73% vs. 24%, p = .019). CONCLUSIONS: We demonstrate the need for elective screening for EOT targeting PC deficiency in Japan. Early prenatal diagnosis of PC deficiency in mother-infant pairs may prevent perinatal thrombosis in them.

Feasibility of discontinuing immunosuppression in children with idiopathic nephrotic syndrome.

BACKGROUND: Despite adverse events associated with the long-term use of immunosuppressants, their long-term discontinuation remains challenging in children with idiopathic nephrotic syndrome. Relapse and resumption of immunosuppressants after discontinuation and associated risk factors were analyzed. METHODS: This single-center retrospective cohort study included children with frequently relapsing/steroid-dependent nephrotic syndrome (FRNS/SDNS) or steroid-resistant nephrotic syndrome (SRNS) who initiated immunosuppressant treatment between 2010 and 2020. Patients treated with immunosuppressants for less than two years, those with genetic SRNS, and those with continuation of immunosuppressants were excluded. RESULTS: Sixty-eight patients with FRNS/SDNS or SRNS discontinued immunosuppressants. Discontinuation of immunosuppressants was more frequently tried in patients with less relapse on initial immunosuppressants and less rituximab administration. Of 68 patients who discontinued immunosuppressants, 45 (66%) relapsed and 31 (46%) resumed immunosuppressants with a median follow-up of 39.8 months (IQR 24.6-71.2 months) after discontinuation. The relapse-free survival rates were 40.0%, 35.3%, and 35.3% in 1, 2, and 3 years from discontinuation of immunosuppressants, respectively. Relapse on initial immunosuppressants (HR 2.038, 95%CI 1.006-4.128, P = 0.048) and the relapse-free interval before discontinuation of immunosuppressants (HR 0.971, 95%CI 0.944-0.998, P = 0.037) were significant risk factors associated with relapse after the discontinuation of immunosuppressants, adjusting for sex, age at immunosuppressant treatment initiation, SRNS, and rituximab use. CONCLUSIONS: Long-term discontinuation of immunosuppressants can be feasible in patients without a relapse on initial immunosuppressants, those with longer relapse-free interval before discontinuation of immunosuppressants, and those without a relapse for one year after discontinuation of immunosuppressants. TRIAL REGISTRATION: Not applicable.

Characteristics of urinary tract infections in children with positive urine culture for Aerococcusurinae.

Urinary tract infections caused by Aerococcus urinae have rarely been reported in children, and the clinical characteristics remain unclear. We reviewed medical records of children whose urine cultures grew A. urinae (≥104 CFU/mL) at a tertiary children's hospital in Tokyo, Japan. We found 17 pediatric patients in a review of 22,769 urine cultures between June 2006 and May 2022. The median age of 17 patients was 10.7 years (IQR 8-13 years), and males represented 76.5 % of the patients. Sixteen patients (94.1 %) had underlying urological conditions (neurogenic bladder, vesicoureteral reflux, urethral stenosis, bladder exstrophy, or urinary catheterization). The chief symptoms were fever (35.3 %), malodorous urine (23.5 %), nausea (11.8 %), and back pain (5.9 %). Ten patients were asymptomatic. Pyelonephritis was diagnosed in five male patients. All of them had underlying abnormal conditions of the bladder, and two had malodorous urine. All patients had favorable outcomes after 10-14 days of ampicillin/amoxicillin-based antimicrobial therapy.

Neck Point-of-Care Ultrasound for the Identification of Tongue-Base Cysts in Infants With Stridor: A Case Series.

ABSTRACT: Tongue-base cysts, which are occasionally categorized as vallecular cysts, are a rare yet potentially life-threatening cause of stridor in pediatric patients. Studies reporting the use of point-of-care ultrasound (POCUS) to identify tongue-base cysts are lacking. We present the case series of four infants in whom tongue-base cysts were detected using neck POCUS.

Changes in Patterns of Infection Associated with Pediatric Idiopathic Nephrotic Syndrome: A Single-Center Experience in Japan.

OBJECTIVE: We studied infection rates and risk factors for infection in current patients with idiopathic nephrotic syndrome (INS). STUDY DESIGN: This retrospective cohort study included the clinical data for children with diagnosed INS in our center between January 2010 and December 2020. The infection rates and risk factors were analyzed. RESULTS: We enrolled 187 patients, including 85 cases with steroid-dependent/frequently relapsing nephrotic syndrome and 45 with steroid-resistant nephrotic syndrome. Infection was observed a total of 84 times in 55 patients (95.5 per 1000 person-years). Pneumonia was the most common infection (21 cases, 23.9 per 1000 person-years), followed by febrile neutropenia (12 cases, 13.7 per 1000 person-years), whereas peritonitis and bacteremia were observed in only 3 and 2 cases, respectively. The multivariate analyses by logistic regression showed that rituximab treatment was significantly associated with infections in pediatric INS (P = .001). The infection rate during the B-cell-depleted state with immunosuppressants (318 per 1000 person-years) was greater than that with normal B-cell count with immunosuppressants (109 per 1000 person-years) or without immunosuppressants (76 per 1000 person-years). CONCLUSION: Common infections, such as peritonitis and bacteremia, decreased, whereas infections associated with medication (eg, rituximab) increased. The rate of infection increases during B-cell depletion after treatments with rituximab and other immunosuppressants.

Association between residents' scholarly activities and publication requirement policy.

BACKGROUND: Scholarship is recognized as important in residency training worldwide. The Japan Pediatric Society (JPS) enacted a reform in 2017 to require publication of an article as a prerequisite for taking the board certification test, with the goal of increasing scholarly activity. METHODS: The purpose of this study was to provide a detailed description of the trends in residents' scholarly activities related to the JPS reform. A secondary analysis was performed on the cross-sectional database of pediatrics residents who took the certification test in 2015-2018. RESULTS: The enrolled participants were 2399 residents of which 79.7% passed the test. Publication of any type of article increased significantly (21%-22% to 100%; 0.1 to 0.3/person-year) after the implementation of the JPS reform, whereas academic presentations did not (89% to 91%; 1.2 to 1.3/person-year), both in terms of the percentage of the number of those who created them and the average rate of research production. Not only Japanese articles (11%-13% to 49%-53%; 0.04 to 0.15-0.17/person-year) or case reports (10%-14% to 51%-52%; 0.03-0.05 to 0.16-0.17/person-year), but also English articles (4%-5% to 15%-16%; 0.01-0.02 to 0.05/person-year) and original articles (5% to 11%-17%; 0.01 to 0.03-0.05/person-year) increased significantly. The number of each type of article publication was correlated with success in the board certification test (odds ratio 1.5-1.8). CONCLUSIONS: Scholarly activities of pediatrics residents were enhanced by the JPS implementation of the article requirement policy, which is crucial to fostering a scholarly culture. The most efficient measures to promote scholarship need to be persistently investigated.

Natural course of acute COVID-19 among healthy children in a tertiary hospital.

BACKGROUND: Previous studies have reported the clinical and epidemiological characteristics of children with coronavirus disease 2019 (COVID-19) in a cross-sectional fashion; however, the natural course of each symptom based on a daily basis during the acute phase has not yet been clarified. This retrospective study aimed to describe the natural course of COVID-19 in children according to dominant variants. METHODS: We conducted our study on symptomatic children with COVID-19 who were hospitalized at the National Center for Child Health and Development, in Japan. We excluded patients who were observed for less than 9 days and those with underlying disease, COVID-19 vaccination, coinfection, complications, or therapeutic intervention. We collected the data on each participant's age at admission, sex, medical history, observation period, hospitalization period, SARS-CoV-2 test results, and 10 daily symptoms in the first 9 days from the illness onset. RESULTS: Eventually, 115 children were included in this study. The prevalence of fever during the omicron era declined more rapidly over time than that during the pre-omicron era. The prevalence of cough and rhinorrhea did not decline during the observation period, and these clinical manifestations were more common during the pre-omicron era at any point. The prevalence of dysgeusia and/or dysosmia steadily increased over time in the pre-omicron era. This study demonstrated that the prevalence of some symptoms differed not only at the onset but also over time during the acute phase. CONCLUSION: Details of the natural clinical course of children with COVID-19 help primary care physicians to manage these patients.

Genomic SELEX Reveals Pervasive Role of the Flagella Master Regulator FlhDC in Carbon Metabolism.

Flagella are vital bacterial organs that allow microorganisms to move to favorable environments. However, their construction and operation consume a large amount of energy. The master regulator FlhDC mediates all flagellum-forming genes in E. coli through a transcriptional regulatory cascade, the details of which remain elusive. In this study, we attempted to uncover a direct set of target genes in vitro using gSELEX-chip screening to re-examine the role of FlhDC in the entire E. coli genome regulatory network. We identified novel target genes involved in the sugar utilization phosphotransferase system, sugar catabolic pathway of glycolysis, and other carbon source metabolic pathways in addition to the known flagella formation target genes. Examining FlhDC transcriptional regulation in vitro and in vivo and its effects on sugar consumption and cell growth suggested that FlhDC activates these new targets. Based on these results, we proposed that the flagella master transcriptional regulator FlhDC acts in the activation of a set of flagella-forming genes, sugar utilization, and carbon source catabolic pathways to provide coordinated regulation between flagella formation, operation and energy production.

ALS-linked FUS mutations dysregulate G-quadruplex-dependent liquid-liquid phase separation and liquid-to-solid transition.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the accumulation of protein aggregates in motor neurons. Recent discoveries of genetic mutations in ALS patients promoted research into the complex molecular mechanisms underlying ALS. FUS (fused in sarcoma) is a representative ALS-linked RNA-binding protein (RBP) that specifically recognizes G-quadruplex (G4)-DNA/RNAs. However, the effects of ALS-linked FUS mutations on the G4-RNA-binding activity and the phase behavior have never been investigated. Using the purified full-length FUS, we analyzed the molecular mechanisms of multidomain structures consisting of multiple functional modules that bind to G4. Here we succeeded to observe the liquid-liquid phase separation (LLPS) of FUS condensate formation and subsequent liquid-to-solid transition (LST) leading to the formation of FUS aggregates. This process was markedly promoted through FUS interaction with G4-RNA. To further investigate, we selected a total of eight representative ALS-linked FUS mutants within multidomain structures and purified these proteins. The regulation of G4-RNA-dependent LLPS and LST pathways was lost for all ALS-linked FUS mutants defective in G4-RNA recognition tested, supporting the essential role of G4-RNA in this process. Noteworthy, the P525L mutation that causes juvenile ALS exhibited the largest effect on both G4-RNA binding and FUS aggregation. The findings described herein could provide a clue to the hitherto undefined connection between protein aggregation and dysfunction of RBPs in the complex pathway of ALS pathogenesis.

Food-Induced Anaphylaxis among Children Weighing <15 kg: A Single-Center Case Series of the Pediatric Emergency Department.

INTRODUCTION: Food-induced anaphylaxis among infants shows an increasing prevalence; however, the prescription of epinephrine auto-injectors (EAIs) for children weighing <15 kg is associated with issues of the needle length and the epinephrine dose. Several studies have shown age-related differences in food-induced anaphylaxis, although little is known about the weight-related differences in food-induced anaphylaxis. This study aimed to reveal the incidence, clinical characteristics, and management of food-induced anaphylaxis in children weighing <15 kg. METHODS: This chart review included children who visited the pediatric emergency department (ED) of the National Center for Child Health and Development (Tokyo, Japan) from January 2014 to December 2016 and were diagnosed with food-induced anaphylaxis. The severity of anaphylaxis was evaluated using the Sampson Grading Scale. RESULTS: Of 89,232 ED visits, 444 visits included patients with food-induced anaphylaxis, after excluding cases of food-induced anaphylaxis related to oral desensitization therapy. The incidence was 4.98 per 1,000 visits. More than half of the children (n = 247/444, 55.6%) weighed <15 kg. The proportion of grade 3 and higher severity anaphylactic symptoms was 74.5% (184/247) in children weighing <15 kg and 79.2% (156/197) in children weighing 15 kg or more. The recurrence rate of food-induced anaphylaxis was 22.3% (55/247) in children weighing <15 kg and 48.7% (96/197) in children weighing 15 kg or more. Among the children weighing <15 kg, the proportion of those with recurrent food-induced anaphylaxis was 4 times higher in children weighing 10-15 kg than in those weighing <10 kg (32.2% [47/146] vs. 7.9% [8/101]). The proportion of patients who were prescribed EAIs before each visit was 25.5% (14/55) in children weighing <15 kg with a history of food-induced anaphylaxis. CONCLUSION: Food-induced anaphylaxis among children weighing <15 kg occurred as frequently and was as severe as that among children weighing 15 kg or more. However, the proportion of patients prescribed EAIs was very low in children weighing <15 kg with food-induced anaphylaxis. The potential need for EAIs is suggested among children weighing <15 kg, especially among children weighing 10 kg or more but <15 kg.

Incidence and risk factors of rituximab-associated hypogammaglobulinemia in patients with complicated nephrotic syndrome.

BACKGROUND: Hypogammaglobulinemia is a major adverse event after rituximab treatment; however, the precise incidence and risk factors are unclear in complicated steroid-dependent or frequently relapsing nephrotic syndrome (SDNS/FRNS) patients. METHODS: This was a single-center, retrospective, observational study. Patients who received a single dose of rituximab for complicated SDNS or FRNS between February 2007 and May 2019 were enrolled. Serum IgG levels were plotted, and their trends were evaluated after rituximab treatment. The incidence of transient and persistent hypogammaglobulinemia was examined, and risk factors were calculated by multivariate analysis using logistic regression. RESULTS: We enrolled 103 patients who received 238 single doses of rituximab. Hypogammaglobulinemia was observed in 58.4% of the patients at least once after a single dose of rituximab treatment and 22.3% developed persistent hypogammaglobulinemia. Serum IgG levels gradually increased during B-cell depletion, and patients with low serum IgG levels at rituximab treatment had persistent hypogammaglobulinemia. Repeated courses of rituximab treatment increased the incidence of hypogammaglobulinemia. A past history of steroid-resistant nephrotic syndrome (SRNS) (odds ratio [OR] = 10.02; 95% confidence interval [CI] = 2.65-37.81; P < 0.001) and low serum IgG levels at rituximab treatment (OR = 7.63; 95% CI = 2.10-27.71; P = 0.002) was significantly associated with hypogammaglobulinemia in multivariate analysis. CONCLUSIONS: Hypogammaglobulinemia is a frequent adverse event after rituximab treatment, although IgG levels slightly increase during B-cell depletion. Low serum IgG levels at rituximab treatment and a past history of SRNS are significant risk factors for the development of hypogammaglobulinemia after rituximab treatment.

Clinical characteristics of bacteremic urinary tract infection due to third-generation cephalosporin-resistant Escherichia coli in children.

Clinical characteristics of bacteremic urinary tract infection due to third-generation cephalosporin-resistant Escherichia coli in children remain unclear. We conducted a case control study comparing the clinical information of the third-generation cephalosporin-susceptible group (S-E. coli group) and the third-generation cephalosporin-resistant group (R-E. coli group). The R-E. coli group included extended-spectrum beta-lactamases (ESBLs) or AmpC-producing E. coli. We identified 52 cases of bacteremic UTI due to E. coli; 42 cases were in the S-E. coli group and 10 cases were in the R-E. coli group. Empiric antibiotics were more likely to be inappropriate for pediatric patients with bacteremic urinary tract infection due to third-generation cephalosporin-resistant E. coli than those infected by susceptible E. coli (60% vs. 0%, P < 0.001). However, duration of fever and rate of relapse were not significantly different. The outcomes of bacteremic UTI due to multidrug-resistant E. coli in children were satisfactory regardless of susceptibility to empiric antibiotics.

Type B adverse drug reactions to antibiotics and antibiotic allergy in infants and children.

BACKGROUND: Distinguishing allergic reactions from non-allergic type B adverse drug reactions (ADRs) to antibiotics is challenging, particularly in children, because we lack epidemiological information that can be used in primary care situations. This study aimed to investigate the characteristics of type B ADRs to antibiotics and antibiotic allergy (AA) in previously healthy children. METHODS: This was a retrospective cohort study of previously healthy children admitted for treating urinary tract infections over a 10 year period. The primary outcome was the frequency of type B ADRs and AAs that were assessed by pediatricians. Secondary outcomes include demographic data about patients' backgrounds, infections, treatments, ADRs, and action against ADRs. All the data were collected via patients' medical records. RESULTS: Out of 791 participants, type B ADRs were reported in 77 children (9.7%), and AA labeling was performed in six children (0.8%). Physicians assessed 30.4% of type B ADRs as severe or life-threatening symptoms. All patients were discharged without long-term complications. Physicians detected the primary cause (individual patient host factors or environmental risks) in 39 cases of type B ADRs. CONCLUSION: Type B ADRs to antibiotics were frequently reported even in previously healthy children. Physicians should use appropriate techniques (e.g., specialist consulting and skin testing) when they suspect that a type B ADR might be an AA. Labeling and de-labeling programs and tools for type B ADRs related to antibiotics should be implemented to prevent the mislabeling of AA.

Urinary tract infection caused by bacterial pathogens of the respiratory tract in children.

BACKGROUND: Urinary tract infections (UTIs) caused by bacterial pathogens of the respiratory tract such as Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis are rare and little is known about their clinical features and potential host risk factors. The aim of this study is to reveal their clinical characteristics. METHODS: We conducted a retrospective descriptive study on pediatric UTI due to S. pneumoniae, Haemophilus spp., or M. catarrhalis at a tertiary-care pediatric hospital. Pediatric patients diagnosed with UTI between 2002 and 2020 were included. Patient demographics, laboratory data, and microbiological findings were extracted from their electronic medical records and the infectious disease surveillance system. RESULTS: Among 46,332 urine samples, 76 bacteriuria (0.16%) and 22 UTI (0.05%) events due to the targeted species were identified (S. pneumoniae, n = 7, and Haemophilus spp., n = 15). Of the patients, 17 (85%) had underlying urinary tract abnormalities and 13 (60%) had vesicocutaneous fistula. All the UTI episodes caused by S. pneumoniae and Haemophilus spp. occurred after cystostomy. All the patients had satisfactory clinical outcomes. CONCLUSIONS: Although S. pneumoniae and Haemophilus spp. are rare causes of UTIs in children, they could be the true causative bacteria of UTI, particularly in the patients with urinary tract abnormalities and vesicocutaneous fistulas. Thus, clinicians should not ignore these pathogens as contaminations in special populations.

Utility of emergent plain X-ray for childhood acute leukemia with bone pain.

BACKGROUND: We aimed to evaluate the utility of plain X-ray radiograph (PXR) findings in suggesting a diagnosis of acute leukemia in children presenting with bone pain in the emergency department (ED) of a children's hospital. METHODS: Using our radiology reporting system and registered data for childhood acute leukemia, we collected data regarding patients who underwent musculoskeletal PXR examinations in the ED due to bone pain in their extremities, from March 1, 2002 to June 30, 2015. We retrospectively reviewed their PXR findings and clinical information from the electronic medical records. RESULTS: A total of 1,331 patients underwent PXR examinations and in 12 PXR findings showed suspected acute leukemia. From the registered data we found 12 acute leukemia patients who underwent emergency extremity PXR. Ten patients were finally confirmed to have acute leukemia by bone marrow examinations. The most common finding was lucent metaphyseal bands, demonstrated in seven cases, whereas six patients did not show any abnormalities in their peripheral blood cell counts. Sensitivity and specificity values of PXR for acute leukemia diagnosis were 90.0% and 99.8%, respectively. Positive predictive value and negative predictive values were 75.0% and 99.9%, respectively. CONCLUSIONS: Plain X-ray radiograph is a useful diagnostic tool to detect possible acute leukemia in patients presenting with bone pain, earlier than abnormalities of their peripheral blood cell counts. Our results implied the possibility of re-examining PXRs in acute leukemia more carefully, even when there are no abnormalities in blood cell counts.

Intestinal outcome of bone marrow transplantation for monogenic inflammatory bowel disease.

BACKGROUND: Some monogenic inflammatory bowel diseases (IBDs) are known to be refractory to conventional treatments. Although allogeneic hematopoietic stem-cell transplantation (allo-HSCT) has become a curative therapeutic option for certain monogenic IBDs, its effectiveness regarding endoscopic improvements has not been clarified. METHODS: The clinical course and endoscopic findings of patients with monogenic IBDs who were treated with allo-HSCT between December 2017 and November 2018 at the National Center for Child Health and Development, were retrospectively reviewed. The clinical disease activity was assessed using the weighted Pediatric Crohn's Disease Activity Index (wPCDAI) and the endoscopic finding was evaluated using the Simple Endoscopic Score for Crohn's Disease (SES-CD). Clinical remission was defined as a wPCDAI <10 and endoscopic remission was defined as an SES-CD of 2 or less. RESULTS: Four patients with severe monogenic IBDs, including three with X-linked inhibitors of apoptosis protein (XIAP) deficiency and one with interleukin-10 signaling defect, were treated with allo-HSCT with reduced-intensity conditioning. In four patients, the maximum scores of wPCDAI and SES-CD before allo-HSCT ranged from 67.5 to 120 and 20 to 34, respectively. After allo-HSCT, all four patients showed a significant improvement in intestinal inflammation and achieved both clinical and endoscopic remission. Although patients with XIAP deficiency presented with post-transplant hemophagocytic lymphohistiocytosis and a relatively late engraftment, all patients achieved prolonged clinical remission, and IBD medications were successfully discontinued in all patients. CONCLUSION: Allo-HSCT for monogenic IBD resulted in complete clinical resolution with endoscopically confirmed mucosal healing.

[ANAPHYLACTIC REACTION TO LYSOZYME CHLORIDE-INCLUDING DEODORANT SPRAY IN A CHILD WITH EGG ALLERGY].

BACKGROUND: Lysozyme chloride is a bactericidal substance that is included as an active ingredient in many medicines and quasi-drugs. We experienced a case of anaphylactic reaction caused by deodorant spray-containing lysozyme chloride. CASE: The patient was a 10-year-old girl who had an egg allergy. She visited an emergency department because of urticaria, wheezing, dyspnea, and pallor after she used deodorant spray that contained lysozyme chloride derived from hen's egg white. Results for deodorant spray and lysozyme chloride were positive in both skin prick tests and basophil activation tests. According to the medical history and the results, her condition was diagnosed as an anaphylactic reaction to lysozyme chloride in the deodorant spray. DISCUSSION: Although ingredient labelling is obligatory for lysozyme chloride in quasi-drugs, lysozyme chloride is not often described to be derived from egg white. It is important to alert patients with egg allergy to avoid lysozyme chloride-containing products.

De Novo Mutations Activating Germline TP53 in an Inherited Bone-Marrow-Failure Syndrome.

Inherited bone-marrow-failure syndromes (IBMFSs) include heterogeneous genetic disorders characterized by bone-marrow failure, congenital anomalies, and an increased risk of malignancy. Many lines of evidence have suggested that p53 activation might be central to the pathogenesis of IBMFSs, including Diamond-Blackfan anemia (DBA) and dyskeratosis congenita (DC). However, the exact role of p53 activation in each clinical feature remains unknown. Here, we report unique de novo TP53 germline variants found in two individuals with an IBMFS accompanied by hypogammaglobulinemia, growth retardation, and microcephaly mimicking DBA and DC. TP53 is a tumor-suppressor gene most frequently mutated in human cancers, and occasional germline variants occur in Li-Fraumeni cancer-predisposition syndrome. Most of these mutations affect the core DNA-binding domain, leading to compromised transcriptional activities. In contrast, the variants found in the two individuals studied here caused the same truncation of the protein, resulting in the loss of 32 residues from the C-terminal domain (CTD). Unexpectedly, the p53 mutant had augmented transcriptional activities, an observation not previously described in humans. When we expressed this mutant in zebrafish and human-induced pluripotent stem cells, we observed impaired erythrocyte production. These findings together with close similarities to published knock-in mouse models of TP53 lacking the CTD demonstrate that the CTD-truncation mutations of TP53 cause IBMFS, providing important insights into the previously postulated connection between p53 and IBMFSs.