The first case of hemorrhagic shock and encephalopathy syndrome with fulminant hypercytokinemia associated with pediatric COVID-19.

BACKGROUND: Infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can lead not only to respiratory symptoms but also to neurologic symptoms with various levels of severity. After the worldwide prevalence of Omicron variant, severe neurological manifestations of coronavirus disease 2019 (COVID-19) such as febrile seizure, demyelinating disease, and cerebrovascular disease, have been reported. However, reports of acute encephalopathy in patients with COVID-19 are quite limited. Especially in terms of cytokine storm-inducing hemorrhagic shock and encephalopathy syndrome (HSES), there is no case reported related to COVID-19. CASE PRESENTATION: We describe the case of an 8-year-old girl who presented with fatal HSES associated with pediatric SARS-CoV-2 infection. Status epilepticus occurs after the onset of fever and diarrhea and lasted for at least an hour. Unconsciousness was followed by circulatory failure and ultimately leading to death within 2 days after the fever onset. Analysis of forty-eight cytokines and chemokines measured in three consecutive serum samples revealed that interferon (IFN)-γ, interleukin (IL)-6, IL-10, IL-17A, tumor necrosis factor (TNF)-a, IL-8, Interferon gamma inducible protein (IP)-10, and Monocyte chemoattractant protein (MCP)-1, were increased within an hour after the onset of impaired consciousness. CONCLUSION: Here, we describe a case of fatal fulminant encephalopathy with rapid progression because of HSES associated with COVID-19. High levels of cytokines and chemokines observed in this case may be because of the SARS-CoV-2-associated cytokine storm. This study is the first COVID-19-associated case of HSES.

Neonatal onset of Niemann-Pick disease type C in a patient with cholesterol re-accumulation in the transplanted liver and inflammatory bowel disease.

BACKGROUND: Niemann-Pick disease type C (NPC) is an autosomal recessive inherited and neurodegenerative disorder. Approximately 10% of NPC patients have acute liver failure and sometimes need liver transplantation (LT), and 7% reportedly develop inflammatory bowel disease (IBD). We report the case of a girl with NPC who had a re- accumulation of cholesterol in the transplanted liver and NPC-related IBD. CASE REPORT: The patient underwent living donor liver transplantation (LDLT) due to severe acute liver failure caused by an unknown etiology inherited from her father. At 1 year and 6 months (1Y6M), she developed neurological delay, catalepsy, and vertical supranuclear gaze palsy. The foam cells were found in her skin, and fibroblast Filipin staining was positive; hence, she was diagnosed with NPC. It was identified that her father had NPC heterozygous pathogenic variant. At 2 years, she had anal fissure, skin tag and diarrhea. She was diagnosed with NPC-related IBD, using a gastrointestinal endoscopy. Three years after LT, liver biopsy revealed foam cells and numerous fatty droplets. At 8 years, broken hepatocytes and substantial fibrosis were observed. She died from circulation failure due to hypoalbuminemia at 8Y2M. CONCLUSIONS: In NPC, load of cholesterol metabolism is suggested to persist even after LT. LDLT from NPC heterozygous variant donor was insufficient to metabolize cholesterol overload. In NPC patients, the possibility of cholesterol re-accumulation should be considered when LT is performed. NPC-related IBD should be considered when NPC patients have anorectal lesions or diarrhea.

Neonatal respiratory support related to lung function abnormalities in school-age children with bronchopulmonary dysplasia.

OBJECTIVE: To elucidate the relationship between abnormal lung function (LF) at school age and neonatal respiratory support in very low birth weight children with bronchopulmonary dysplasia (BPD). STUDY DESIGN: We retrospectively examined 78 BPD children whose LF was evaluated at 8-9 years. LF abnormalities were defined by reduced values of spirometric parameters. Adjusted odds ratios (aORs) for abnormal LF by the type and postmenstrual age (PMA) of respiratory support were calculated using logistic regression analysis after controlling perinatal factors. RESULTS: Overall, 24 (31%) patients had LF abnormalities. Antenatal steroid use was associated with a decreased risk of abnormal LF [aOR, 0.31; 95% CI, 0.09-0.92]. Requiring positive-pressure support at 37 weeks' PMA correlated with abnormal LF [aOR, 4.58; 95% CI, 1.15-21.90]; whereas only low-flow oxygen at any PMA did not. CONCLUSION: Requiring positive-pressure support at 37 weeks' PMA could be an indicator of abnormal LF at school age.

Early distribution of18 F-labeled AAV9 vectors in the cerebrospinal fluid after intracerebroventricular or intracisternal magna infusion in non-human primates.

BACKGROUND: The delivery of adeno-associated virus (AAV) vectors via the cerebrospinal fluid (CSF) has emerged as a valuable method for widespread transduction in the central nervous system. Although infusion into the cerebral ventricles is a common protocol in preclinical studies of small animals, the cisterna magna has been recognized as an alternative target for clinical studies because it can be reached in a less invasive manner using an intrathecal catheter via the subarachnoid space from a lumbar puncture. METHODS: We evaluated the early distribution of fluorine-18-labeled AAV9 vectors infused into the lateral ventricle or cisterna magna of four non-human primates using positron emission tomography. The expression of the green fluorescent protein was immunohistochemically determined. RESULTS: In both approaches, the labeled vectors diffused into the broad arachnoid space around the brain stem and cervical spinal cord within 30 min. Both infusion routes efficiently transduced neurons in the cervical spinal cord. CONCLUSIONS: For gene therapy that primarily targets the cervical spinal cord and brainstem, such as amyotrophic lateral sclerosis, cisterna magna infusion would be a feasible and effective administration method.

Successful Management in an Infant Patient of PHACE Syndrome with a Complicated Aortic Arch Anomaly.

PHACE syndrome is a congenital disorder often associated with a cervicofacial infantile hemangioma and complicated cardiovascular malformations. Patients with PHACE syndrome often have complex aortic arch anomalies, longer aortic stenosis or agenesis segments, and increased vascular tortuosity; therefore, perioperative management and surgical repair are challenging. We report a case of a female infant with PHACE syndrome and complex cardiovascular anomalies such as a double aortic arch associated with interruption of the left aortic arch, coarctation of the right aortic arch, patent ductus arteriosus, ventricular septal defect, and atrial septal defect. She was born at 36 weeks of gestation (birth weight, 2,150 g) and the diagnosis was confirmed by three-dimensional computed tomography. Because her patent ductus arteriosus did not close at first, her heart failure was managed preoperatively without prostaglandin E 1. We initially attempted to promote weight gain. Surgical planning and simulation were performed using the patient-specific three-dimensional cardiovascular model created from computed tomography data. She underwent a successful aortic arch reconstruction by an end-to-side anastomosis with anterior patch augmentation at the age of 56 days. Detailed planning and simulation before surgery were vital in achieving favorable outcomes. Careful management and surgical planning using a patient-specific three-dimensional model are vital, especially in patients with complex malformations, such as in our case.

Membranous nephropathy without vacuolated podocytes in Fabry disease treated with agalsidase-ß and carbamazepine: A case report.

RATIONALE: Vacuolated podocytes are the most common form of renal damage in Fabry disease, but other types of renal damage have been reported, such as membranous nephropathy (MN) or IgM nephropathy. Enzyme replacement therapy (ERT) is effective at preventing renal damage, but the nephropathies require appropriate treatment to prevent renal damage. PATIENT CONCERNS: A 22-year-old male with Fabry disease presented with proteinuria during ERT with agalsidase-ß and carbamazepine. He had received the treatment for 10 years and maintained normal plasma globotryaosylceramide levels. DIAGNOSIS: Renal biopsy revealed MN without vacuolated podocytes. Immunofluorescent staining of the IgG subclass revealed granular patterns of IgG1, G2, G4, and C3 deposition in the glomerular basement membrane. INTERVENTIONS: The carbamazepine dose was reduced from 600 mg/day to 200 mg/day (serum concentration 10.0-11.0-4.0-5.0 µg/mL). OUTCOMES: After reducing the carbamazepine dose, proteinuria was negative, and the patient has had a normal urinalysis for 17 months. Plasma globotryaosylceramide levels have also remained normal. LESSONS: This report is a reminder of the co-existence of MN without vacuolated podocytes in Fabry disease during ERT with agalsidase-ß and carbamazepine.Physicians should be aware of this form of renal damage in Fabry disease, even during treatment.

Reduction of acute gastric volvulus in a 3-year-old using a balloon-attached endoscope combined with gel immersion endoscopy.

When performing endoscopic reduction in patients with gastric volvulus, it is important to maintain a low level of intragastric pressure and to fix the endoscope in the duodenum. Gel immersion endoscopy is a new method for securing the visual field by injecting clear gel. The balloon-attached endoscope makes it easier to fix the tip in the duodenum without mucosal damage. We report successful reduction of a mesenteroaxial gastric volvulus using an endoscope with a balloon in combination with gel immersion endoscopy. A 3-year-old Japanese male developed gastric volvulus. Since gastric decompression using a nasogastric tube failed to reduce the volvulus, endoscopic reduction was performed under general anesthesia. After aspiration of intragastric gas, clear gel was injected through the accessory channel which secured the visual field in the stomach even with residue while maintaining low intragastric pressure. After reaching the descending portion of the duodenum, the balloon attached to the tip of the endoscope was inflated and fixed in the duodenum. The volvulus was successfully reduced by pulling back the endoscope with clockwise torque. Acute mesenteroaxial gastric volvulus has the potential to cause ischemia and perforation which can be life-threatening, so most patients are treated with surgical intervention. Gel immersion endoscopy is safe and effective to secure the visual field, even in children. Endoscopic reduction may be a viable treatment option for reducing gastric volvulus in non-emergent patients.

Low donor chimerism may be sufficient to prevent demyelination in adrenoleukodystrophy.

Adrenoleukodystrophy (ALD) is a peroxisomal disorder characterized by white matter degeneration caused by adenosine triphosphate-binding cassette subfamily D member 1 (ABCD1) gene mutations, which lead to an accumulation of very-long-chain fatty acids (VLCFA). Hematopoietic stem cell transplantation (HSCT) is the most effective treatment; however, the ratio of donor-to-recipient cells required to prevent the progression of demyelination is unclear. The proband was diagnosed with the childhood cerebral form of ALD at 5 years of age based on the clinical phenotype, elevated plasma VLCFA levels, and pathogenic ABCD1 mutation c.293C>T (p.Ser98Leu). Soon after the diagnosis, he became bedridden. At 1 year of age, his younger brother was found to carry the same ABCD1 mutation; despite being asymptomatic, at 1 year and 9 months, head magnetic resonance imaging (MRI) showed high-signal-intensity lesions in the cerebral white matter. The patient underwent unrelated cord blood transplantation (UCBT) with a reduced conditioning regimen, which resulted in mixed chimerism. For 7 years after UCBT, the donor chimerism remained low (<10%) in peripheral blood and cerebrospinal fluid. However, even though a second HSCT was not performed, his neurological symptoms and brain MRI findings did not deteriorate. Our case suggests that even a small number of donor cells may prevent demyelination in ALD. This is an important case when considering the timing of a second HSCT.

WDR45 variants cause ferrous iron loss due to impaired ferritinophagy associated with nuclear receptor coactivator 4 and WD repeat domain phosphoinositide interacting protein 4 reduction.

Static encephalopathy of childhood with neurodegeneration in adulthood/ß-propeller protein-associated neurodegeneration is a neurodegenerative disorder with brain iron accumulation caused by the variants of WDR45, a core autophagy-related gene that encodes WD repeat domain phosphoinositide interacting protein 4. However, the pathophysiology of the disease, particularly the function of WDR45/WD repeat domain phosphoinositide interacting protein 4 in iron metabolism, is largely unknown. As no other variants of core autophagy-related genes show abnormalities in iron metabolism, the relation between autophagy and iron metabolism remains to be elucidated. Since iron deposition in the brain is the hallmark of static encephalopathy of childhood with neurodegeneration in adulthood/ß-propeller protein-associated neurodegeneration, iron chelation therapy has been attempted, but it was found to worsen the symptoms; thus, the establishment of a curative treatment is essential. Here, we evaluated autophagy and iron metabolism in patient-derived cells. The expression of ferritin and ferric iron increased and that of ferrous iron decreased in the patient cells with WDR45 variants. In addition, the expression of nuclear receptor coactivator 4 was markedly reduced in patient-derived cells. Furthermore, divalent metal transporter 1, which takes in ferrous iron, was upregulated, while ferroportin, which exports ferrous iron, was downregulated in patient-derived cells. The transfer of WDR45 via an adeno-associated virus vector restored WD repeat domain phosphoinositide interacting protein 4 and nuclear receptor coactivator 4 expression, reduced ferritin levels, and improved other phenotypes observed in patient-derived cells. As nuclear receptor coactivator 4 mediates the ferritin-specific autophagy, i.e. ferritinophagy, its deficiency impaired ferritinophagy, leading to the accumulation of ferric iron-containing ferritin and insufficiency of ferrous iron. Because ferrous iron is required for various essential biochemical reactions, the changes in divalent metal transporter 1 and ferroportin levels may indicate a compensatory response for maintaining the intracellular levels of ferrous iron. Our study revealed that the pathophysiology of static encephalopathy of childhood with neurodegeneration in adulthood/ß-propeller protein-associated neurodegeneration involves ferrous iron insufficiency via impaired ferritinophagy through nuclear receptor coactivator 4 expression reduction. Our findings could aid in developing a treatment strategy involving WDR45 manipulation, which may have clinical applications.

Valine metabolites analysis in ECHS1 deficiency.

Short-chain enoyl-CoA hydratase (ECHS1) is involved in amino acid and fatty acid catabolism in mitochondria and its deficiency causes Leigh syndrome or exercise-induced dystonia. More than 60 patients with this condition have been reported till date. The accumulation of intermediate metabolites of valine is assumed to be responsible for the cytotoxicity. Since protein restriction, including valine reportedly improves neurological symptoms, it is essential to consider the possible incidence of and diagnose ECHS1 syndrome in the earlier stages. This study reported the liquid chromatography with tandem mass spectrometry (LC-MS/MS) urine and plasma metabolite analysis in six cases, including four new cases with ECHS1 deficiency. The values of urine cysteine/cysteamine conjugates from valine metabolites, S-(2-carboxypropyl) cysteine/cysteamine from methacrylyl-CoA, and S-(2-carboxyethyl) cysteine/cysteamine from acryloyl-CoA were separated between six patients and six normal controls. The LC-MS/MS analysis revealed that these metabolites can be used for the early diagnosis and evaluation of diet therapy.

Two cases of DYNC1H1 mutations with intractable epilepsy.

BACKGROUND: The DYNC1H1 gene encodes the heavy chain of cytoplasmic dynein 1, a core structure of the cytoplasmic dynein complex. Dominant DYNC1H1 mutations are implicated in Charcot-Marie-Tooth disease, axonal, type 20, spinal muscular atrophy, lower extremity-predominant 1, and autosomal dominant mental retardation 13 with neuronal migration defects. We report two patients with DYNC1H1 mutations who had intractable epilepsy and intellectual disability (ID), one with and one without pachygyria. CASE REPORTS: Patient 1 had severe ID. At the age of 2 months, she presented myoclonic seizures and tonic seizures, and later experienced atonic seizures and focal impaired-awareness seizures (FIAS). EEG showed slow waves in right central areas during myoclonic seizures. Brain MRI revealed pachygyria, predominantly in the occipital lobe. After callosal transection her atonic seizures disappeared, but FIAS remained. Patient 2 was diagnosed with autism spectrum disorder (ASD) and severe ID. At the age of 7 years, he presented generalized tonic-clonic seizures, myoclonic seizures, and FIAS. Interictal EEG showed generalized spike-and-wave complexes, predominantly in the left frontal area. Brain MRI was unremarkable. Exome sequencing revealed novel de novo mutations in DYNC1H1: c.4691A > T, p.(Glu1564Val) in Patient 1 and c.12536 T > C, p.(Leu4179Ser) in Patient 2. CONCLUSIONS: DYNC1H1 comprises a stem, stalk, and six AAA domains. Patient 2 is the second report of an AAA6 domain mutation without malformations of cortical development. The p.(Gly4072Ser) mutation in the AAA6 domain was also reported in a patient with ASD. It may be that the AAA6 domain has little effect on neuronal movement of DYNC1H1 along microtubules.

Forced normalization of Lennox-Gastaut syndrome using lacosamide: A case report.

PURPOSE: Forced normalization (FN) indicates psychotic episodes associated with seizure remission and disappearance of epileptiform activity on EEG. FN is likely to occur when frequent seizures are abruptly terminated by anti-epileptic drugs (AEDs) or epilepsy surgery. METHODS: We describe an atypical case of a patient with FN induced by lacosamide (LCM). RESULTS: A 23-year-old female patient with Lennox-Gastaut syndrome (LGS) was administered AEDs for LGS and hospitalised with weight loss and abnormal behaviour. Her condition fulfilled the FN criteria, which was considered to be induced by LCM. After a reduction in LCM dose, her abnormal behaviour and appetite improved. During LCM use, the patient developed no seizures, and the high amplitude diffuse sharp and slow wave complexes that were frequently observed before LCM disappeared on EEG. The LCM dose was tapered to 150 mg per day, and she became calmer with socially appropriate behaviours, although a few mild focal seizures relapsed. CONCLUSION: LCM was effective for treating LGS in this patient and induced FN. Initially, it was difficult to recognise FN in cases of psychiatric disorders, especially in patients with intellectual disability. Patients with FN induced by LCM are rare, and only four patients have been previously reported who were treated by antipsychotic drug for psychosis.

Intra-cisterna magna delivery of an AAV vector with the GLUT1 promoter in a pig recapitulates the physiological expression of SLC2A1.

Glucose transporter 1 deficiency syndrome (GLUT1DS) is caused by haplo-insufficiency of SLC2A1, which encodes GLUT1, resulting in impaired hexose transport into the brain. Previously, we generated a tyrosine-mutant AAV9/3 vector in which SLC2A1 was expressed under the control of the endogenous GLUT1 promoter (AAV-GLUT1), and confirmed the improved motor function and cerebrospinal fluid glucose levels of Glut1-deficient mice after cerebroventricular injection of AAV-GLUT1. In preparation for clinical application, we examined the expression of transgenes after intra-cisterna magna injection of AAV-GFP (tyrosine-mutant AAV9/3-GFP with the CMV promoter) and AAV-GLUT1. We injected AAV-GFP or AAV-GLUT1 (1.63 × 1012 vector genomes/kg) into the cisterna magna of pigs to compare differential promoter activity. After AAV-GFP injection, exogenous GFP was expressed in broad areas of the brain and peripheral organs. After AAV-GLUT1 injection, exogenous GLUT1 was expressed predominantly in the brain. At the cellular level, exogenous GLUT1 was mainly expressed in the endothelium, followed by glia and neurons, which was contrasted with the neuronal-predominant expression of GFP by the CMV promotor. We consider intra-cisterna magna injection of AAV-GLUT1 to be a feasible approach for gene therapy of GLUT1DS.

Gallbladder cancer with ascites in a child with metachromatic leukodystrophy.

INTRODUCTION: Metachromatic leukodystrophy (MLD) refers to leukodystrophy caused by the accumulation of sulfatide from arylsulfatase A (ARSA) gene mutations. Sulfatide also accumulates in various organs, including the peripheral nerves, kidney, and gallbladder. Proliferative changes in the gallbladder have been reported in several patients, while gallbladder cancer is reported in only two adult MLD cases. We report what is likely the first pediatric case of MLD with gallbladder cancer. CASE REPORT: The patient was a 5-year-old girl diagnosed with MLD using head magnetic resonance imaging and detecting a homozygous mutation of c.302G>A (p.Gly101Asp) in ARSA. Abdominal bloating was observed at the age of 4 years; CT revealed a giant tumor in the gallbladder and massive ascites. Cholecystectomy was performed and pathological examination revealed adenocarcinoma. Measurement of serum sulfatide revealed increased levels compared to the average healthy range. DISCUSSION: Rapidly increased ascites and large polyps which are reported as risk factors for cancer were characteristic in our MLD case. When such lesions are detected, they should be removed immediately because of the possibility of cancer, even in a pediatric patient.

Gene Therapy in a Mouse Model of Niemann-Pick Disease Type C1.

Niemann-Pick disease type C1 (NPC1) is a fatal congenital neurodegenerative disorder caused by mutations in the NPC1 gene, which is involved in cholesterol transport in lysosomes. Broad clinical manifestations of NPC1 include liver failure, pulmonary disorder, neurological deficits, and psychiatric symptoms. The main cause of death in NPC1 patients involves central nervous system (CNS) dysfunction; there is no essential treatment. We generated a tyrosine-mutant adeno-associated virus (AAV) 9/3 vector that expresses human NPC1 under a cytomegalovirus (CMV) promoter (AAV-CMV-hNPC1) and injected it into the left lateral ventricle (5 µL) and cisterna magna (10 µL) of Npc1 homo-knockout (Npc1-/-) mice. Each mouse received total 1.35 × 1011 vector genome on days 4 or 5 of life. AAV-treated Npc1-/- mice (n = 11) had an average survival of >28 weeks, while all saline-treated Npc1-/- mice (n = 11) and untreated Npc1-/- mice (n = 6) died within 16 weeks. Saline-treated and untreated Npc1-/- mice lost body weight from 7 weeks until death. However, the average body weight of AAV-treated Npc1-/- mice increased until 15 weeks. AAV-treated Npc1-/- mice also showed a significant improvement in the rotarod test performance. A pathological analysis at 11 weeks showed that cerebellar Purkinje cells were preserved in AAV-treated Npc1-/- mice. In contrast, untreated Npc1-/- mice showed an almost total loss of cerebellar Purkinje cells. Combined injection into both the lateral ventricle and cisterna magna achieved broader delivery of the vector to the CNS, leading to better outcomes than noted in previous reports, with injection into the lateral ventricles or veins alone. In AAV-treated Npc1-/- mice, vector genome DNA was detected widely in the CNS and liver. Human NPC1 RNA was detected in the brain, liver, lung, and heart. Accumulated unesterified cholesterol in the liver was reduced in the AAV-treated Npc1-/- mice. Our results suggest the feasibility of gene therapy for patients with NPC1.

A cDNA analysis disclosed the discordance of genotype-phenotype correlation in a patient with attenuated MPS II and a 76-base deletion in the gene for iduronate-2-sulfatase.

We previously showed that the genotype-phenotype correlation in MPS II is well-conserved in Japan (Kosuga et al., 2016). Almost all of our patients with attenuated MPS II have missense variants, which is expected to result in residual activity of iduronate-2-sulfatase. In contrast, our patients with severe MPS II have so-called null-type disease-associated variants, such as nonsense variants, frame-shifts, gene insertions, gene deletions and rearrangement with pseudogene (IDS2), none of which are expected to result in residual activity. However, we recently encountered a patient with attenuated MPS II who had a presumable null-type disease-associated variant and 76-base deletion located in exon 1 that extended into intron 1. To investigate this discordance, we extracted RNA from the leukocytes of the patient and performed reverse transcription polymerase chain reaction. One of the bands of the cDNA analysis was found to include a nucleotide sequence whose transcript was expected to generate an almost full-length IDS mature peptide lacking only part of its signal peptide as well as only one amino acid at the end of the N-terminus. This suggests that an alternative splicing donor site is generated in exon 1 upstream of the deleted region. Based on these observations, we concluded that the phenotype-genotype discordance in this patient with MPS II was due to the decreased amount of IDS protein induced by the low level of the alternatively spliced mRNA, lacking part of the region coding for the signal peptide but including the region coding almost the full mature IDS protein. The first 25 amino acids at the N-terminus of IDS protein are a signal peptide. The alternative splice transcript has only 13 (1 M-13 L) of those 25 amino acids; 14G-25G are missing, suggesting that the exclusively hydrophobic 1 M-13 L of the signal peptide of IDS might have a crucial role in the signal peptide.

Juvenile polyposis syndrome-hereditary hemorrhagic telangiectasia associated with a SMAD4 mutation in a girl.

Juvenile polyposis syndrome (JPS) and hereditary hemorrhagic telangiectasia (HHT) are both relatively rare hereditary disorders. Some patients with the SMAD4 gene mutation develop both JPS and HHT, a condition termed JPS-HHT. We herein report a case of childhood-onset JPS-HHT. At nine years old, the patient underwent colonoscopy under suspicion of Crohn's disease, which revealed multiple polyps. A genetic analysis for familial adenomatous polyposis and Peutz-Jeghers syndrome found no mutations. After several years, extraintestinal manifestations, such as repeated epistaxis and several telangiectasias in the upper palate and stomach, were identified, which led to the performance of gene mutation analysis for SMAD4. As a result, a missense mutation in exon 8, codon 361 from arginine to cysteine (c.1081 C>T) was found. Based on this finding, the patient underwent cerebral magnetic resonance angiography, pulmonary perfusion scintigraphy and thoracoabdominal contrast computed tomography. The examination revealed that she had pulmonary arteriovenous fistulas and arteriovenous malformations in both the liver and right mammary gland. Thus, continuous surveillance for vascular lesions and gastrointestinal cancer is scheduled. Making a precise diagnosis of JPS-HHT can lead to the detection of asymptomatic complications and enable appropriate future disease management.

Percutaneous Atrial Septal Defect Closure in Adult Ebstein's Anomaly with Exertional Hypoxemia.

In Ebstein's anomaly, percutaneous atrial septal defect (ASD) closure for the treatment of hypoxemia due to a right-to-left interatrial shunt remains controversial. We report the case of a 40-year-old woman with Ebstein's anomaly who developed cyanosis and shortness of breath on exercise. Her symptoms improved after percutaneous ASD closure and her clinical course has been good during follow-up. The balloon ASD occlusion test, combined with dobutamine stimulation before the procedure, is useful to confirm treatment indication. A prior electrophysiological evaluation is also important because Ebstein's anomaly is often complicated by atrioventricular recurrent tachycardia.