A case of A20 haploinsufficiency complicated by autoimmune hepatitis.

AIM: A20 haploinsufficiency (HA20) is a recently described autoinflammatory disease that manifests symptoms similar to those of Behçet's disease. However, little is known about the involvement of the liver in HA20. Here, we report a case of HA20 complicated by autoimmune hepatitis (AIH). CASE PRESENTATION: A 33-year-old woman was previously diagnosed with HA20 and chronic thyroiditis, and was treated with prednisolone (PSL; 7.5 mg/day) and levothyroxine sodium hydrate (125 µg/day). She experienced general malaise and jaundice, and biochemical evaluation revealed elevated liver function with an aspartate aminotransferase level of 817 U/L, an alanine aminotransferase level of 833 U/L, and a total bilirubin of 8.3 mg/dL. Pathological evaluation of the liver biopsy revealed interface hepatitis and the patient was diagnosed with acute exacerbation of AIH. Upon increasing the PSL dose to 60 mg/day, the liver enzyme levels rapidly decreased. During tapering of PSL, azathioprine 50 mg/day was added, and there was no relapse of AIH with combination therapy of PSL 7 mg/day and azathioprine 50 mg/day. CONCLUSION: This is the first report of biopsy-proven AIH in an Asian patient with HA20. This case has significant implications for the pathogenesis and treatment of AIH in patients with HA20.

Immunophenotyping of A20 haploinsufficiency by multicolor flow cytometry.

Haploinsufficiency of A20 (HA20) causes inflammatory disease resembling Behçet's disease; many cases have been reported, including some that are complicated with autoimmune diseases. This study aims to clarify the immunophenotype of patients with HA20 by analyzing lymphocyte subsets using multicolor flow cytometry. The patients with HA20 previously diagnosed in a nationwide survey were compared by their cell subpopulations. In total, 27 parameters including regulatory T cells (Tregs), double-negative T cells (DNTs), and follicular helper T cells (TFHs) were analyzed and compared with the reference values in four age groups: 0-1, 2-6, 7-19, and ≥20 years. The Tregs of patients with HA20 tended to increase in tandem with age-matched controls at all ages. In addition, patients ≥20 years had increased DNTs compared with controls, whereas TFHs significantly increased in younger patients. In HA20 patients, the increase in DNTs and TFHs may contribute to the development of autoimmune diseases.

A Heterozygous CFHR3-CFHR1 Gene Deletion in a Pediatric Patient With Transplant-associated Thrombotic Microangiopathy Who was Treated With Eculizumab.

Complement system dysregulation, such as complement Factor H (CFH) autoantibodies and deletions in CFH-related (CFHR) genes 3 and 1, might cause transplant-associated thrombotic microangiopathy (TA-TMA). The use of eculizumab, a terminal complement inhibitor, could be a targeted therapy for TA-TMA. We report a 1-year-old girl who developed TA-TMA, just after autologous peripheral blood stem cell transplantation in neuroblastoma therapy. Eculizumab improved TA-TMA. Investigation for the complement alternative pathway showed a heterozygous CFHR3-CFHR1 gene deletion, which is involved in complement activation. The patient might develop TA-TMA as a result of complement regulatory gene mutation.

Prepubertal onset of slipped capital femoral epiphysis associated with hypothyroidism: a case report and literature review.

BACKGROUND: Slipped capital femoral epiphysis (SCFE) is a common hip disorder characterized by displacement of the capital femoral epiphysis from the metaphysic through the femoral epiphyseal plate. SCFE usually occurs during puberty, with obesity a common risk factor. We experienced a rare case of SCFE associated with hypothyroidism in a prepubescent patient who was not obese. CASE PRESENTATION: The patient was an 8-year-old boy suffering from bilateral SCFE with hypothyroidism. The patient's growth had started to slow at 4 years of age, and at 8 years he was of short stature. During his evaluation for SCFE management, primary hypothyroidism was diagnosed due to the presence of anti-thyroid peroxidase and anti-thyroglobulin antibodies. After the patient was treated for hypothyroidism, which improved his thyroid function, surgery was performed for bilateral SCFE. CONCLUSIONS: Among the 42 patients with SCFE associated with hypothyroidism in the literature, most SCFE occurred during puberty or in adults with delayed epiphyseal closure. Only two patients (4.8%), including the present patient, were ≤9 years old. Although being overweight or obese is common for patients with SCFE associated with hypothyroidism (76.0%), it was not observed in the present case. Persistent hypothyroidism, however, may be a risk factor for SCFE even before puberty and without obesity.

Everolimus for Treatment of Pseudomyogenic Hemangioendothelioma.

Pseudomyogenic hemangioendothelioma (PMH) is a recently described vascular neoplasm that occurs most commonly in the soft tissue of the distal extremities of young adults. Metastatic PMH can be fatal and there are no effective medications. We describe a case of a 15-year-old boy with metastatic PMH, who responded to treatment with everolimus, a mammalian target of rapamycin inhibitor. Immunohistochemistry showed that mammalian target of rapamycin was expressed in PMH biopsy specimens, which may explain the reduction in PMH tumor size following treatment.

Successful Everolimus Treatment of Kaposiform Hemangioendothelioma With Kasabach-Merritt Phenomenon: Clinical Efficacy and Adverse Effects of mTOR Inhibitor Therapy.

Kasabach-Merritt phenomenon (KMP) is a life-threatening consumptive coagulopathy associated with underlying kaposiform hemangioendothelioma (KHE) in infancy. We describe the case of a 3-month-old girl with KHE complicated by KMP who responded dramatically to treatment with everolimus, a mechanistic target of rapamycin (mTOR) inhibitor. Immunohistochemical expression of mTOR was found in the KHE biopsy specimens, which may explain the improvement of KMP and reduction in KHE tumor size with mTOR inhibitor treatment. This effective use of everolimus may shed light on the emerging role of mTOR signaling in the development and pathogenesis of KHE and KMP.

Propranolol for infantile hemangioma: Effect on plasma vascular endothelial growth factor.

BACKGROUND: Propranolol has recently been shown to be highly effective for infantile hemangioma (IH), but the mechanism of action of propranolol and the usefulness of measurement of vascular endothelial growth factor (VEGF) remain poorly understood. The aim of this study was therefore to determine the efficacy of propranolol treatment and to evaluate changes in plasma VEGF in IH patients who underwent propranolol treatment. METHODS: The study group consisted of 35 children with IH. Oral propranolol was give at a dose of 2.0 mg/kg/day and was divided in three doses. Outcome was assessed using the visual analog scale (VAS) of size and color. Plasma VEGF concentration was analyzed on enzyme-linked immunoabsorbent assay, and compared between the groups. RESULTS: Improvement in VAS in patients who started propranolol before 6 months of age was superior to that in those who started propranolol after 6 months of age. VEGF concentration was significantly correlated with lesion size (P = 0.002), whereas no correlation was observed with age. VEGF concentration 4 weeks after treatment was significantly lower than that before treatment (P < 0.01). CONCLUSIONS: Measurement of VEGF may be a useful tool for predicting the course of IH and monitoring the effectiveness of treatment.

Complete bone regeneration in hemophilic pseudotumor of the mandible.

Hemophilic pseudotumor (HP) is rare, seen in 1-2% of patients with hemophilia, and is extremely uncommon in the mandible. A 6-year-old boy with moderate hemophilia A presented to our hospital with left mandibular swelling. Based on clinical and radiological findings, a tentative diagnosis of HP was made. After factor VIII administration, the lesion was curetted and HP was confirmed on histopathology. The patient was treated with twice-weekly factor VIII until the lesion had completely resolved and bone had regenerated at 1 year. The best treatment for HP is not established; however, appropriate initial treatment and postoperative prophylaxis are effective.

Inborn errors of ketone body utilization.

Succinyl-CoA:3-ketoacid CoA transferase (SCOT) deficiency and mitochondrial acetoacetyl-CoA thiolase (beta-ketothiolase or T2) deficiency are classified as autosomal recessive disorders of ketone body utilization characterized by intermittent ketoacidosis. Patients with mutations retaining no residual activity on analysis of expression of mutant cDNA are designated as severe genotype, and patients with at least one mutation retaining significant residual activity, as mild genotype. Permanent ketosis is a pathognomonic characteristic of SCOT-deficient patients with severe genotype. Patients with mild genotype, however, may not have permanent ketosis, although they may develop severe ketoacidotic episodes similar to patients with severe genotype. Permanent ketosis has not been reported in T2 deficiency. In T2-deficient patients with severe genotype, biochemical diagnosis is done on urinary organic acid analysis and blood acylcarnitine analysis to observe characteristic findings during both ketoacidosis and non-episodic conditions. In Japan, however, it was found that T2-deficient patients with mild genotype are common, and typical profiles were not identified on these analyses. Based on a clinical study of ketone body utilization disorders both in Japan and worldwide, we have developed guidelines for disease diagnosis and treatment. These diseases are treatable by avoiding fasting and by providing early infusion of glucose, which enable the patients to grow without sequelae.

The first case in Asia of 2-methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency (HSD10 disease) with atypical presentation.

2-Methyl-3-hydroxybutyryl-CoA dehydrogenase (2M3HBD) deficiency (HSD10 disease) is a rare inborn error of metabolism, and <30 cases have been reported worldwide. This disorder is typically characterized by progressive neurodegenerative disease from 6 to 18 months of age. Here, we report the first patient with this disorder in Asia, with atypical clinical presentation. A 6-year-old boy, who had been well, presented with severe ketoacidosis following a 5-day history of gastroenteritis. Urinary organic acid analysis showed elevated excretion of 2-methyl-3-hydroxybutyrate and tiglylglycine. He was tentatively diagnosed with ß-ketothiolase (T2) deficiency. However, repeated enzyme assays using lymphocytes showed normal T2 activity and no T2 mutation was found. Instead, a hemizygous c.460G>A (p.A154T) mutation was identified in the HSD17B10 gene. This mutation was not found in 258 alleles from Japanese subjects (controls). A normal level of the HSD17B10 protein was found by immunoblot analysis but no 2M3HBD enzyme activity was detected in enzyme assays using the patient's fibroblasts. These data confirmed that this patient was affected with HSD10 disease. He has had no neurological regression until now. His fibroblasts showed punctate and fragmented mitochondrial organization by MitoTracker staining and had relatively low respiratory chain complex IV activity to those of other complexes.

Ketone body metabolism and its defects.

Acetoacetate (AcAc) and 3-hydroxybutyrate (3HB), the two main ketone bodies of humans, are important vectors of energy transport from the liver to extrahepatic tissues, especially during fasting, when glucose supply is low. Blood total ketone body (TKB) levels should be evaluated in the context of clinical history, such as fasting time and ketogenic stresses. Blood TKB should also be evaluated in parallel with blood glucose and free fatty acids (FFA). The FFA/TKB ratio is especially useful for evaluation of ketone body metabolism. Defects in ketogenesis include mitochondrial HMG-CoA synthase (mHS) deficiency and HMG-CoA lyase (HL) deficiency. mHS deficiency should be considered in non-ketotic hypoglycemia if a fatty acid beta-oxidation defect is suspected, but cannot be confirmed. Patients with HL deficiency can develop hypoglycemic crises and neurological symptoms even in adolescents and adults. Succinyl-CoA-3-oxoacid CoA transferase (SCOT) deficiency and beta-ketothiolase (T2) deficiency are two defects in ketolysis. Permanent ketosis is pathognomonic for SCOT deficiency. However, patients with "mild" SCOT mutations may have nonketotic periods. T2-deficient patients with "mild" mutations may have normal blood acylcarnitine profiles even in ketoacidotic crises. T2 deficient patients cannot be detected in a reliable manner by newborn screening using acylcarnitines. We review recent data on clinical presentation, metabolite profiles and the course of these diseases in adults, including in pregnancy.

Facial palsy as an unusual presenting symptom associated with acute myeloid leukemia.

Extramedullary infiltration is common in acute myeloid leukemia (AML) patients. Although AML can cause neurological symptoms, especially when associated with extramedullary infiltration, a presenting manifestation of facial palsy is rare. We report on a 1-year-old boy who developed right facial palsy. Detailed examination led to a diagnosis of AML (French-American-British classification M1). Magnetic resonance imaging enhanced with gadolinium-diethylenetriamine penta-acetic acid showed abnormal enhancement of the right facial nerve, which disappeared after chemotherapy. AML should be considered as a differential diagnosis of facial palsy. Enhanced magnetic resonance imaging may be useful for diagnosing facial palsy associated with AML and for evaluating treatment outcome.

Molecular basis of two-exon skipping (exons 12 and 13) by c.1248+5g>a in OXCT1 gene: study on intermediates of OXCT1 transcripts in fibroblasts.

The molecular basis of simultaneous two-exon skipping induced by a splice-site mutation has yet to be completely explained. The splice donor site mutation c.1248+5g>a (IVS13) of the OXCT1 gene resulted predominantly in skipping of exons 12 and 13 in fibroblasts from a patient (GS23) with succinyl-CoA:3-ketoacid CoA transferase (SCOT) deficiency. We compared heteronuclear RNA (hnRNA) intermediates between controls' and GS23's fibroblasts. Our strategy was to use RT-PCR of hnRNA to detect the presence or absence of spliced exon clusters in RNA intermediates (SECRIs) comprising sequential exons. Our initial hypothesis was that a SECRI comprising exons 12 and 13 was formed first followed by skipping of this SECRI in GS23 cells. However, such a pathway was revealed to be not a major one. Hence, we compared the intron removal of SCOT transcript between controls and GS23. In controls, intron 11 was the last intron to be spliced and the removal of intron 12 was also rather slow and occurred after the removal of intron 13 in a major pathway. However, the mutation in GS23 cells resulted in retention of intron 13, thus causing the retention of introns 12 and 11. This "splicing paralysis" may be solved by skipping the whole intron 11-exon 12-intron 12-exon 13-mutated intron 13, resulting in skipping of exons 12 and 13.

Development of MLPA for human ACAT1 gene and identification of a heterozygous Alu-mediated deletion of exons 3 and 4 in a patient with mitochondrial acetoacetyl-CoA thiolase (T2) deficiency.

Mitochondrial acetoacetyl-CoA thiolase deficiency is an autosomal recessive disorder, characterized by intermittent ketoacidosis. We developed a multiplex ligation-dependent probe amplification method for mutation detection in the ACAT1 gene, which encodes this enzyme, and validated it using DNAs from two previously reported patients having partial deletion and duplication in this gene. Using this method, we identified a heterozygous deletion including exons 3-4 in a third patient, likely due to Alu-mediated non-equal homologous recombination between Alu sequences.

Effectiveness of Double-J Metallic Mesh Ureteral Stents for Malignant Ureteral Obstruction: A Retrospective Study.

BACKGROUND/AIM: Malignant ureteral obstruction is associated with high rates of failure with traditional ureteral stents. Double-J metallic mesh ureteral stent is one of the latest options for treating malignant ureteral obstruction. However, data regarding the efficacy of using this stent in this context are limited. Thus, we retrospectively investigated the efficacy of this stent. PATIENTS AND METHODS: We retrospectively analyzed the records of all patients who required double-J metallic mesh ureteral stent placement for malignant ureteral obstruction at Ishikawa Prefectural Central Hospital (Kanazawa, Japan) between October 2018 and April 2022. Primary stent patency was defined as complete or partial resolution of hydronephrosis as shown by imaging studies or successful removal of a preexisting nephrostomy tube. Stent failure was defined as unplanned stent exchange or nephrostomy tube placement for signs or symptoms of recurrent ureteral obstruction. A competing risk model was used to estimate the cumulative incidence of stent failure. RESULTS: Double-J metallic mesh ureteral stents were placed in 63 ureters of 44 patients (13 males, 31 females). The median age of patients was 67 years (range=37-92 years). There was no grade 3 or higher complications. The overall primary patency rate was 95% (60 ureters). Stent failure occurred in seven patients (11%) during follow-up. The cumulative incidence of stent failure at 12 months after placement was 17.3%. CONCLUSION: Double-J metallic mesh ureteral stent is a safe, simple, and promising treatment option for malignant ureteral obstruction.

A Noble-Metal-Free Spintronic System with Proximity-Enhanced Ferromagnetic Topological Surface State of FeSi above Room Temperature.

Strongly spin-orbit coupled states at metal interfaces, topological insulators, and 2D materials enable efficient electric control of spin states, offering great potential for spintronics. However, there are still materials challenges to overcome, including the integration into advanced silicon electronics and the scarce resources of constituent heavy elements of those materials. Through magneto-transport measurements and first-principles calculations, here robust spin-orbit coupling (SOC)-induced properties of a ferromagnetic topological surface state in FeSi and their controllability via hybridization with adjacent materials are demonstrated. In comparison to the case of its naturally oxidized surface, the ferromagnetic transition temperature is greatly increased beyond room temperature and the effective SOC strength is almost doubled at the surface in proximity to a wide-bandgap fluoride insulator. Those enhanced magnetic properties enable room-temperature magnetization switching, being applicable to spin-orbit torque based spintronic devices. Realization of strong SOC in the noble-metal-free silicon-based compound will accelerate spintronic applications.

Ureteral Metastasis of Colonic Adenocarcinoma with Enteroblastic Differentiation: A Rare Case to be Distinguished from Clear Cell Adenocarcinoma of the Urinary Tract.

Adenocarcinomas with enteroblastic differentiation are rare clear cell tumors that are positive for enteroblastic markers. Enteroblastic differentiation is particularly uncommon in colorectal adenocarcinomas. Herein, we report a case of clear cell adenocarcinoma with enteroblastic differentiation in the sigmoid colon of a 38-year-old Japanese woman that metastasized to the lower left ureter. After neoadjuvant chemotherapy, the patient underwent low anterior resection. The tumor consisted of tubular, cribriform, and focal micropapillary proliferation of clear cells immunopositive for spalt-like transcription factor 4 (SALL4), glypican 3, and alpha-fetoprotein. Six months after the colonic resection, a tumor was found in the left lower ureter, which was resected. The ureteral tumor revealed clear cell adenocarcinoma, which was identical to the colonic tumor proliferating in the ureteral mucosa. Metastatic ureteral tumors are rare. We performed a literature search and found only 50 reported cases of ureteral metastases from colorectal cancer. Of these, only 10 metastatic tumors were identified in the ureteral mucosa. No case of ureteral metastasis of clear cell colorectal adenocarcinoma or colorectal adenocarcinoma with enteroblastic differentiation has been reported. Hence, it can be challenging to distinguish them from clear cell adenocarcinoma of the urinary tract and/or clear cell urothelial carcinoma. This paper discussed the differential diagnosis of these tumors and reviewed the clinicopathological features of colorectal carcinomas metastasizing to the ureter.