A thyroid adenoma in a pubertal male with thyroxine-binding globulin deficiency.

Complete deficiency of thyroxin-binding globulin (TBG-CD) is not commonly associated with clinical symptoms, and little is known about thyroid tumors associated with TBG-CD. We present a case report of an asymptomatic follicular adenoma that spontaneously shrank in a patient with TBG-CD. A previously healthy 13-yr-old male presented with a diffusely swollen thyroid gland. Thyroid function tests revealed low total thyroxin and TBG concentrations, indicating a TBG deficiency. Ultrasonography revealed a mildly swollen thyroid gland with a nodule (14 × 12 × 19 mm) in the left lobe. Genetic analysis of peripheral blood revealed a previously reported SERPINA7 variant, which resulted in complete loss of TBG function. The nodule was identified as a follicular adenoma using fine-needle aspiration. Subsequently, the adenoma shrank without treatment. This pubertal case suggests that careful observation with ultrasonography is warranted for follicular adenoma in patients with TBG deficiency and that treatment may not be required.

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.

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.

A Case of Axillary Fibroadenoma That Grew Rapidly from Axillary Accessory Breast Tissue over 40 Days.

Axillary accessory breast (AAB) occurs in 2%-6% of women. Like normal breast tissue, ABB can undergo changes, including periodic enlargement that can result in a palpable axillary mass. Fibroadenoma is the most common benign subcutaneous tumor of the breast: it occurs in approximately 25% of women and accounts for 50% of all breast biopsies. However, fibroadenoma in AAB is rare (2.6%). Here, we describe the case of a patient who was diagnosed first with left AAB on the basis of clinical and magnetic imaging resonance findings, and then 40 days later with fibroadenoma in left AAB by histopathology of the resected mass. The tumor, which had been undetectable at the initial visit, had transformed into a clinically obvious, hard, protruding mass at surgery. Thus, fibroadenomas originating from AAB can grow quickly, and imaging-based diagnosis should be confirmed with histology. Treatment should involve complete excision of the fibroadenoma and surrounding AAB.

No Additional Risk of Ampicillin Rash Among Pediatric Liver Transplant Recipients With Concurrent Epstein-Barr Virus Infection.

BACKGROUND: Epstein-Barr virus (EBV) infection frequently develops in children undergoing liver transplantation (LT) because of mandated immunosuppressive therapy. There is a risk of ampicillin rash when penicillin derivatives are used in patients with EBV-associated infectious mononucleosis. Hence, the administration of penicillin derivatives may raise concerns about ampicillin rash in patients with high EBV loads. However, no studies confirmed the risk of administering penicillin derivatives to EBV-infected children after LT. METHODS: This retrospective study was conducted at the largest pediatric transplantation center in Japan. We investigated all pediatric liver transplant recipients who received penicillin derivatives within 2 years of LT between 2014 and 2020. We separated the cohort into EBV-positive and EBV-negative groups to assess the frequency of ampicillin and antibiotic-associated rash. RESULTS: Two hundred eighty-six liver transplant recipients were enrolled. There were 111 recipients in the EBV-positive group and 175 recipients in the EBV-negative group. In the EBV-positive group, 49 patients had high EBV DNA loads (≥1000 copies/µg DNA). None of the patients in either group developed ampicillin rash, and the frequency of antibiotic-associated rash did not differ [8/111 (7.2%) vs. 10/175 (5.7%), P = 0.797]. Additional subgroup analysis revealed no difference in the frequency of antibiotic-associated rashes regardless of the presence or absence of high EBV loads. CONCLUSIONS: In this study, ampicillin rash was not observed, and antibiotic-associated rash was not associated with concurrent EBV infection. Penicillin derivatives can be used safely, even in liver transplant recipients with persistent asymptomatic EBV infection.

FUS regulates RAN translation through modulating the G-quadruplex structure of GGGGCC repeat RNA in C9orf72-linked ALS/FTD.

Abnormal expansions of GGGGCC repeat sequence in the noncoding region of the C9orf72 gene is the most common cause of familial amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD). The expanded repeat sequence is translated into dipeptide repeat proteins (DPRs) by noncanonical repeat-associated non-AUG (RAN) translation. Since DPRs play central roles in the pathogenesis of C9-ALS/FTD, we here investigate the regulatory mechanisms of RAN translation, focusing on the effects of RNA-binding proteins (RBPs) targeting GGGGCC repeat RNAs. Using C9-ALS/FTD model flies, we demonstrated that the ALS/FTD-linked RBP FUS suppresses RAN translation and neurodegeneration in an RNA-binding activity-dependent manner. Moreover, we found that FUS directly binds to and modulates the G-quadruplex structure of GGGGCC repeat RNA as an RNA chaperone, resulting in the suppression of RAN translation in vitro. These results reveal a previously unrecognized regulatory mechanism of RAN translation by G-quadruplex-targeting RBPs, providing therapeutic insights for C9-ALS/FTD and other repeat expansion diseases.

Measurement of immature platelet fraction is useful in the differential diagnosis of MYH9 disorders.

INTRODUCTION: Although the presence of large and giant platelets is important in screening for MYH9 disorders, platelet morphology evaluation is dependent on operator subjectivity. Immature platelet fraction (IPF%) is widely used in clinical practice because of its rapidity and reproducibility; however, IPF% has been rarely analyzed in MYH9 disorders. Therefore, our study aimed to clarify the usefulness of IPF% in the differential diagnosis of MYH9 disorders. METHODS: We assessed 24 patients with MYH9 disorders, 10 with chronic immune thrombocytopenia (cITP), 14 with myelodysplastic syndromes (MDS) with thrombocytopenia (<100 × 109 /L), and 20 healthy volunteers. Platelet-related data, including IPF% and platelet morphology (diameter, surface area, and staining), were retrospectively analyzed. RESULTS: Median IPF% in MYH9 disorders, 48.7%, was significantly higher than in all other groups (cITP: 13.4%, MDS: 9.4%, controls: 2.6%). IPF% in MYH9 disorders was significantly negatively correlated with platelet count and significantly positively correlated with the diameter and surface area of platelets, but a correlation was not found between IPF% and platelet staining. The area under the curve of IPF% for the differential diagnosis of MYH9 disorders was 0.987 (95% CI: 0.969-1.000), with a sensitivity of 95.8% and specificity of 93.2% when the cutoff value of IPF% was 24.3%. CONCLUSION: Our study strongly suggests that IPF% is useful in the differential diagnosis between MYH9 disorders and other types of thrombocytopenia.

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.

Essential Roles and Risks of G-Quadruplex Regulation: Recognition Targets of ALS-Linked TDP-43 and FUS.

A non-canonical DNA/RNA structure, G-quadruplex (G4), is a unique structure formed by two or more guanine quartets, which associate through Hoogsteen hydrogen bonding leading to form a square planar arrangement. A set of RNA-binding proteins specifically recognize G4 structures and play certain unique physiological roles. These G4-binding proteins form ribonucleoprotein (RNP) through a physicochemical phenomenon called liquid-liquid phase separation (LLPS). G4-containing RNP granules are identified in both prokaryotes and eukaryotes, but extensive studies have been performed in eukaryotes. We have been involved in analyses of the roles of G4-containing RNAs recognized by two G4-RNA-binding proteins, TDP-43 and FUS, which both are the amyotrophic lateral sclerosis (ALS) causative gene products. These RNA-binding proteins play the essential roles in both G4 recognition and LLPS, but they also carry the risk of agglutination. The biological significance of G4-binding proteins is controlled through unique 3D structure of G4, of which the risk of conformational stability is influenced by environmental conditions such as monovalent metals and guanine oxidation.

Early therapeutic plasma exchange may lead to complete neurological recovery in moderate to severe influenza-associated acute necrotizing encephalopathy.

BACKGROUND: Acute necrotizing encephalopathy (ANE) is a pediatric neurological disease, presumably caused by cytokine storms, with a poor prognosis. Immunomodulatory therapy, including therapeutic plasma exchange (TPE), could be an effective treatment. CASES: Two patients with influenza-associated ANE were treated. The ANE severity scores were 3 and 8 in case 1 (a 3-y-old boy) and case 2 (a 7-y-old boy), respectively. In case 1, intravenous methylprednisolone and TPE were initiated at 8 and 16 h, respectively, after the onset of impaired consciousness. In case 2, multiple organ failure and septic shock persisted even after infusion of fluids and inotropic agents. Intravenous methylprednisolone and TPE were started at 5 and 9 h, respectively, after the onset of impaired consciousness, which improved the inotrope-refractory septic shock. Patient 1 and 2 achieved complete neurological recovery within 4 weeks and after 3 months, respectively. In both patients, cytokine levels were serially measured. There were increased serum interleukin (IL)-6 and IL-10 levels in both patients; patient 1 showed increased IL-6 levels in the initial cerebrospinal fluid sample. There was a post-treatment decrease in serum IL-6 levels in both cases. DISCUSSION: Early intensive immunomodulatory therapy with TPE may improve neurological outcomes in pediatric influenza-associated ANE. Further studies are required to establish the efficacy of TPE for ANE.

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.

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.

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.