Skeletal Muscle Mass Assessment in Pediatric Patients: Development of a Normative Equation and Assessment of Factors Associated With a Low Skeletal Muscle Mass in PICU Patients.

OBJECTIVES: To develop an equation for defining a low skeletal muscle mass (SMM) in children and to investigate risk factors and outcomes associated with low SMM in critically ill pediatric patients. DESIGN: Single-center retrospective pediatric cohorts, 2011-2018. SETTING: Tertiary Emergency and Critical Care Center of Kyushu University Hospital in Japan. PATIENTS: We studied two cohorts of pediatric patients 1-15 years old who underwent abdominal CT at the level of the third lumbar vertebra (L3). First a cohort of trauma patients presented to the emergency department in whom we developed an SMM regression equation. Second, a cohort of patients who had undergone abdominal CT within 3 days of PICU admission. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The equation for estimating normal SMM used sex, age, and weight. Low SMM was defined as less than 80% of normal. In the 112 patients in the PICU cohort, median (range) age was 68 (13-191) months, and 83 (74.1%) had underlying disease. There was low SMM in 54 patients (48.2%). Regarding associations, using odds ratio (OR) and 95% CI, we found that low dietary intake (OR 4.33 [95% CI, 1.37-13.70]; p = 0.013) and the presence of underlying disease (OR 7.44 [95% CI, 2.10-26.30]; p = 0.002) were independently associated with greater odds of low SMM. Low SMM, compared with normal SMM, was also associated with longer hospital stays (42.5 d vs. 20.5 d; p = 0.007; ß, 1.59; 95% CI, 1.09-2.33; p = 0.016). CONCLUSIONS: In this retrospective PICU cohort from a single center in Japan, we found that low SMM at PICU admission was present in almost half the cases. Low SMM, as defined by being less than 80% of the normal, was associated with greater odds of low dietary intake and underlying chronic disease. Furthermore, low SMM was associated with longer hospital stays.

Successful mapping and ablation of a pediatric-onset non-reentrant fascicular tachycardia.

Non-reentrant fascicular tachycardia (NRFT) developed in a 6-year-old Japanese boy. Because of drug-resistant recurrences, he received catheter mapping and ablation at age 10 years. An electrocardiogram exhibited a superior left-axis deviation, a right bundle branch block-type configuration, and relatively narrow QRS with sharp R wave. It suggested verapamil-sensitive ventricular tachycardia (VT), but showed no sensitivity to verapamil or reentrant characteristics in the electrophysiological study. Detailed VT mapping determined the earliest presystolic Purkinje potential on the left posterior fascicle at the mid-ventricular septum. Radiofrequency current applications to the lesion led to his NRFT-free life without restriction. Learning objectives: Purkinje-related idiopathic ventricular tachycardias (VTs) are commonly due to reentrant mechanisms, and non-reentrant fascicular tachycardia (NRFT) is a rare form of idiopathic VT in adults. Although it is crucial to distinguish NRFT from reentrant VTs, there is no information about the electrophysiological studies and the treatment effect in pediatric-onset NRFT.

Early hematopoietic cell transplantation for familial hemophagocytic lymphohistiocytosis in a regional treatment network in Japan.

Familial hemophagocytic lymphohistiocytosis (FHLH) is a fatal hyperinflammation syndrome arising from the genetic defect of perforin-mediated cytolysis. Curative hematopoietic cell transplantation (HCT) is needed before development of central nervous system (CNS) disease. We studied treatment outcomes of 13 patients (FHLH2 n = 11, FHLH3 n = 2) consecutively diagnosed from 2011 to 2022 by flow cytometric screening for non-myeloablative HCT in a regional treatment network in Kyushu, Japan. One patient with a novel PRF1 variant escaped screening, but all patients with FHLH2 reached diagnosis and 8 of them received HCT until 3 and 9 months of age, respectively. The earliest HCT was conducted 65 days after birth. Three pretransplant deaths occurred in newborns with liver failure at diagnosis. Ten posttransplant patients have remained disease-free, 7 of whom had no neurological involvement. Time from first etoposide infusion to HCT was shorter in patients without CNS disease or bleeding than in patients with those factors (median [range] days: 62 [50-81] vs. 122 [89-209], p = 0.016). Six of 9 unrelated patients had a PRF1 c.1090_1091delCT variant. These results suggest that the critical times to start etoposide and HCT are within 3 months after birth and during etoposide control, respectively. Newborn screening may increase the percentage of disease-free survivors without complications.

Rapid and long-lasting efficacy of high-dose ambroxol therapy for neuronopathic Gaucher disease: A case report and literature review.

Gaucher disease (GD) is a lysosomal storage disorder caused by a deficiency in the GBA1-encoded enzyme, ß-glucocerebrosidase. Enzyme replacement therapy is ineffective for neuronopathic Gaucher disease (nGD). High-dose ambroxol has been administered as an alternative treatment for a group of patients with nGD. However, little is known about the clinical indication and the long-term outcome of patients after ambroxol therapy. We herein report a case of a female patient who presented with a progressive disease of GD type 2 from 11 months of age and had the pathogenic variants of p.L483P (formerly defined as p.L444P) and p.R502H (p.R463H) in GBA1. A combined treatment of imiglucerase with ambroxol started improving the patient's motor activity in 1 week, while it kept the long-lasting effect of preventing the deteriorating phenotype for 30 months. A literature review identified 40 patients with nGD, who had received high-dose ambroxol therapy. More than 65% of these patients favorably responded to the molecular chaperone therapy, irrespective of p.L483P homozygous, heterozygous or the other genotypes. These results highlight the long-lasting effect of ambroxol-based chaperone therapy for patients with an expanding spectrum of mutations in GBA1.

High-Titer Anti-ZSCAN1 Antibodies in a Toddler Clinically Diagnosed with Apparent Rapid-Onset Obesity with Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation Syndrome.

Severe obesity in young children prompts for a differential diagnosis that includes syndromic conditions. Rapid-Onset Obesity with Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation (ROHHAD) syndrome is a potentially fatal disorder characterized by rapid-onset obesity associated with hypoventilation, neural crest tumors, and endocrine and behavioral abnormalities. The etiology of ROHHAD syndrome remains to be established, but recent research has been focusing on autoimmunity. We report on a 2-year-old girl with rapid-onset obesity during the first year of life who progressed to hypoventilation and encephalitis in less than four months since the start of accelerated weight gain. The patient had a high titer of anti-ZSCAN1 antibodies (348; reference range < 40), and the increased values did not decline after acute phase treatment. Other encephalitis-related antibodies, such as the anti-NDMA antibody, were not detected. The rapid progression from obesity onset to central hypoventilation with encephalitis warns about the severe consequences of early-onset ROHHAD syndrome. These data indicate that serial measurements of anti-ZSCAN1 antibodies might be useful for the diagnosis and estimation of disease severity. Further research is needed to determine whether it can predict the clinical course of ROHHAD syndrome and whether there is any difference in antibody production between patients with and without tumors.

Persistent intracranial hyper-inflammation in ruptured cerebral aneurysm after COVID-19: case report and review of the literature.

BACKGROUND: The systemic manifestations of coronavirus disease 2019 (COVID-19) include hyperinflammatory reactions in various organs. Recent studies showed evidence for the frequent involvement of central nervous system in affected patients; however, little is known about clinical features of cerebrovascular diseases in childhood-onset COVID-19. CASE PRESENTATION: A 10-year-old boy recovered from SARS-CoV-2 infection without complication. On 14 days after infection, he presented with loss of consciousness. A head computed tomography detected a ruptured cerebral aneurysm at the left posterior cerebral artery accompanying subarachnoid hemorrhage (SAH). Immediate surgical intervention did not rescue the patient, resulting in the demise 7 days after admission. Serological and genetic tests excluded the diagnosis of vasculitis and connective tissue disorders. Retrospective analysis showed markedly higher levels of interleukin (IL)-1ß, IL-6 and IL-8 in the cerebrospinal fluid than the serum sample concurrently obtained. A review of literature indicated that adult patients with COVID-19 have a risk for the later development of SAH during the convalescent phase of COVID-19. CONCLUSIONS: SAH is a severe complication of COVID-19 in children and adults who have asymptomatic cerebrovascular aneurysms. The markedly high levels of cytokines detected in the cerebrospinal fluid suggested that intracranial hyperinflammatory condition might be one of the possible mechanisms involved in the rupture of a preexisting cerebrovascular aneurysms.

CD14 down-modulation as a real-time biomarker in Kawasaki disease.

Objectives: The objectives of this study were to investigate the pathophysiology of Kawasaki disease (KD) from immunological and oxidative stress perspectives, and to identify real-time biomarkers linked to innate immunity and oxidative stress in KD. Methods: We prospectively enrolled 85 patients with KD and 135 patients with diverse conditions including immune, infectious and non-infectious diseases for this investigation. Flow cytometry was used to analyse the surface expression of CD14, CD38 and CD62L on monocytes, along with a quantitative assessment of CD14 down-modulation. Additionally, oxidative stress levels were evaluated using derivatives of reactive oxygen metabolites (d-ROMs) and antioxidant capacity measured by a free radical elective evaluator system. Results: During the acute phase of KD, we observed a prominent CD14 down-modulation on monocytes, reflecting the indirect detection of circulating innate immune molecular patterns. Moreover, patients with KD showed a significantly higher CD14 down-modulation compared with infectious and non-infectious disease controls. Notably, the surface expression of CD14 on monocytes was restored concurrently with responses to intravenous immunoglobulin and infliximab treatment in KD. Furthermore, d-ROM levels in patients with KD were significantly elevated compared with patients with infectious and non-infectious diseases. Following intravenous immunoglobulin treatment, oxidative stress levels decreased in patients with KD. Conclusion: Monitoring CD14 down-modulation on monocytes in real-time is a valuable strategy for assessing treatment response, distinguishing KD relapse from concomitant infections and selecting second-line therapy after IVIG treatment in KD patients. The interplay between inflammation and oxidative stress likely plays a crucial role in the development of KD.

The Etiology and Outcome of Area Postrema Syndrome in Childhood: Two Cases and a Literature Review.

BACKGROUND: Area postrema syndrome (APS), a rare childhood condition, manifests as intractable nausea and hiccups. APS has high diagnostic significance in neuromyelitis optica syndrome spectrum disorders (NMOSD) and can be the initial presentation of other critical diseases, including brainstem glioma. METHODS: We described two representative cases of unrelated Japanese patients with APS. An etiologic evaluation, including a detailed intracranial neuroradiological examination and autoantibodies assessment, was performed. We also reviewed the literature focusing on the prognosis of pediatric APS symptoms. RESULTS: A 14-year-old girl with aquaporin-4 antibody-positive NMOSD showed a good prognosis with immunotherapy, whereas another nine-year-old girl with irresectable medullary low-grade glioma had persistent symptoms for more than 10 years. All reported children aged >12 years were diagnosed with NMOSD, and patients aged <13 years showed heterogeneous etiologies. CONCLUSIONS: Distinctive time courses and neuroimaging features were key clinical findings for the diagnostic and therapeutic processes in these patients. This literature review highlights the wide spectrum and prognosis of pediatric-onset APS.

Long-Term Renal Involvement in Association with Fontan Circulation.

Multiorgan dysfunction is a concern of Fontan patients. To clarify the pathophysiology of Fontan nephropathy, we characterize renal disease in the long-term observational study. Medical records of 128 consecutive Fontan patients [median age: 22 (range 15-37) years old] treated between 2009 and 2018 were reviewed to investigate the incidence of nephropathy and its association with other clinical variables. Thirty-seven patients (29%) showed proteinuria (n = 34) or < 90 mL/min/1.73 m2 of estimated glomerular filtration rate (eGFR) (n = 7), including 4 overlapping cases. Ninety-six patients (75%) had liver dysfunction (Forns index > 4.21). Patients with proteinuria received the Fontan procedure at an older age [78 (26-194) vs. 56 (8-292) months old, p = 0.02] and had a higher cardiac index [3.11 (1.49-6.35) vs. 2.71 (1.40-4.95) L/min/m2, p = 0.02], central venous pressure [12 (7-19) vs. 9 (5-19) mmHg, p < 0.001], and proportion with > 4.21 of Forns index (88% vs. 70%, p = 0.04) than those without proteinuria. The mean renal perfusion pressure was lower in patients with a reduced eGFR than those without it [55 (44-65) vs. 65 (45-102) mmHg, p = 0.03], but no other variables differed significantly. A multivariable analysis revealed that proteinuria was associated with an increased cardiac index (unit odds ratio 2.02, 95% confidence interval 1.12-3.65, p = 0.02). Seven patients with severe proteinuria had a lower oxygen saturation than those with no or mild proteinuria (p = 0.01, 0.03). Proteinuria or a decreased eGFR differentially occurred in approximately 30% of Fontan patients. Suboptimal Fontan circulation may contribute to the development of proteinuria and reduced eGFR.

Pretransplant ribavirin and interferon-α therapy for rhinovirus interstitial pneumonia in a RAG1-deficient infant.

Severe combined immunodeficiency (SCID) is one of the most serious inborn errors of immunity leading to a fatal infection in early infancy. Allogeneic hematopoietic cell transplantation (HCT) or elective gene therapy prior to infection or live-attenuated vaccination is the current standard of curative treatment. Even in the era of newborn screening for SCID, pretransplant control of severe infection is challenging for SCID. Multiple pathogens are often isolated from immunocompromised patients, and limited information is available regarding antiviral strategies to facilitate curative HCT. We herein present a case of successfully controlled pretransplant pneumonia after ribavirin and interferon-α therapy in an infant with RAG1-deficiency. A four-month-old infant presented with severe interstitial pneumonia due to a co-infection of rhinovirus and Pneumocystis jirovecii. The tentative diagnosis of SCID prompted to start antibiotics and trimethoprim-sulfamethoxazole on ventilatory support. Because of the progressive respiratory failure four days after treatment, ribavirin and then pegylated interferon-α were started. He showed a drastic response to the treatment that led to a curative HCT 32 days after admission. This patient received the genetic diagnosis of RAG1-deficiency. Currently, he is an active 3-year-old boy with normal growth and development. The review of literature indicated that rhinovirus had a comparable or rather greater impact on the mortality of pediatric patients than respiratory syncytial virus. Considered the turn-around time to the genetic diagnosis of SCID, prompt ribavirin plus interferon-α therapy may help to control severe rhinovirus pneumonia and led to the early curative HCT for the affected infants.

Divergent neurodevelopmental profiles of very-low-birth-weight infants.

BACKGROUND: Advanced perinatal medicine has decreased the mortality rate of preterm infants. Long-term neurodevelopmental outcomes of very-low-birth-weight infants (VLBWIs) remain to be investigated. METHODS: Participants were 124 VLBWIs who had in-hospital birth from 2007 to 2015. Perinatal information, developmental or intelligence quotient (DQ/IQ), and neurological comorbidities at ages 3 and 6 years were analyzed. RESULTS: Fifty-eight (47%) VLBWIs received neurodevelopmental assessments at ages 3 and 6 years. Among them, 15 (26%) showed DQ/IQ <75 at age 6 years. From age 3 to 6 years, 21 (36%) patients showed a decrease (≤-10), while 5 (9%) showed an increase (≥+10) in DQ/IQ scores. Eight (17%) with autism spectrum disorder or attention-deficit hyperactivity disorder (ASD/ADHD) showed split courses of DQ/IQ, including two with ≤-10 and one with +31 to their scores. On the other hand, all 7 VLBWIs with cerebral palsy showed DQ ≤35 at these ages. Magnetic resonance imaging detected severe brain lesions in 7 (47%) of those with DQ <75 and 1 (18%) with ASD/ADHD. CONCLUSIONS: VLBWIs show a broad spectrum of neurodevelopmental outcomes after 6 years. These divergent profiles also indicate that different risks contribute to the development of ASD/ADHD from those of cerebral palsy and epilepsy in VLBWIs. IMPACT: Very-low-birth-weight infants (VLBWIs) show divergent neurodevelopmental outcomes from age 3 to 6 years. A deep longitudinal study depicts the dynamic change in neurodevelopmental profiles of VLBWIs from age 3 to 6 years. Perinatal brain injury is associated with developmental delay, cerebral palsy and epilepsy, but not with ASD or ADHD at age 6 years.

Non-conditioned cord blood transplantation for infection control in athymic CHARGE syndrome.

OBJECTIVE: CHARGE syndrome is a congenital malformation syndrome caused by heterozygous mutations in the CHD7 gene. Severe combined immunodeficiency (SCID) arises from congenital athymia called CHARGE/complete DiGeorge syndrome. While cultured thymus tissue implantation (CTTI) provides an immunological cure, hematopoietic cell transplantation (HCT) is an alternative option for immuno-reconstitution of affected infants. We aimed to clarify the clinical outcomes of patients with athymic CHARGE syndrome after HCT. METHODS: We studied the immunological reconstitution and outcomes of four patients who received non-conditioned unrelated donor cord blood transplantation (CBT) at Kyushu University Hospital from 2007 to 2022. The posttransplant outcomes were compared with the outcomes of eight reported patients. RESULTS: Four index cases received CBT 70-144 days after birth and had no higher than grade II acute graft-versus-host disease. One infant was the first newborn-screened athymic case in Japan. They achieved more than 500/µL naïve T cells with balanced repertoire 1 month post transplant, and survived more than 12 months with home care. Twelve patients including the index cases received HCT at a median 106 days after birth (range: 70-195 days). One-year overall survival rate was significantly higher in patients who underwent non-conditioned HCT than in those who received conditioned HCT (100% vs. 37.5%, p = .02). Nine patients died, and the major cause of death was cardiopulmonary failure. CONCLUSIONS: Athymic infants achieved a prompt reconstitution of non-skewing naïve T cells after non-conditioned CBT that led to home care in infancy without significant infections. Non-conditioned CBT is a useful bridging therapy for newborn-screened cases toward an immunological cure by CTTI.

Pediatric leukemia and maternal occupational exposure to anticancer drugs: the Japan Environment and Children's Study.

ABSTRACT: Occupational exposure to medical agents and ionizing radiation has been suggested as a possible risk factor for childhood cancer. However, the relationship between such exposure and pediatric malignant neoplasms has not yet been comprehensively studied. This cohort study aimed to investigate the association between parental occupational exposure to hazardous medical agents or ionizing radiation and the risk of childhood cancer in offspring. Data from a large birth cohort in Japan, which included 104 062 fetuses, were analyzed. The primary outcome was the development of leukemia or brain tumors diagnosed by community physicians during the first 3 years after birth. Exposure factors were medical agents, including anticancer agents, ionizing radiation, and anesthetics, handled by mothers during pregnancy or by fathers for 3 months before conception. The incidence of leukemia, but not of brain tumors, was higher in mothers exposed to anticancer drugs. Multivariable regression analysis showed that maternal exposure to anticancer drugs was associated with an increased risk of leukemia in offspring older than 1 year (adjusted relative risk, 7.99 [95% confidence interval, 1.98-32.3]). Detailed information obtained from medical certificates of patients with identified leukemia revealed no infant leukemia but acute lymphoblastic leukemias in the exposed group. Our findings suggest that maternal occupational exposure to anticancer drugs may be a potential risk factor for acute lymphoblastic leukemia in offspring older than 1 year. Effective prevention methods may be necessary to prevent maternal exposure to anticancer drugs and to reduce the risk of childhood malignant neoplasms.

Progressive myoclonic epilepsy as an expanding phenotype of NGLY1-associated congenital deglycosylation disorder: A case report and review of the literature.

INTRODUCTION: NGLY1-associated congenital disorder of deglycosylation (CDDG1: OMIM #615273) is a rare autosomal recessive disorder caused by a functional impairment of endoplasmic reticulum in degradation of glycoproteins. Neurocognitive dysfunctions have been documented in patients with CDDG1; however, deteriorating phenotypes of affected individuals remain elusive. CASE PRESENTATION: A Japanese boy with delayed psychomotor development showed ataxic movements from age 5 years and myoclonic seizures from age 12 years. Appetite loss, motor and cognitive decline became evident at age 12 years. Electrophysiological studies identified paroxysmal discharges on myoclonic seizure and a giant somatosensory evoked potential. Perampanel was effective for controlling myoclonic seizures. Exome sequencing revealed that the patient carried compound heterozygous variants in NGLY1, NM_018297.4: c.857G > A and c.-17_12del, which were inherited from mother and father, respectively. A literature review confirmed that myoclonic seizures were observed in 28.5% of patients with epilepsy. No other patients had progressive myoclonic epilepsy or cognitive decline in association with loss-of-function variations in NGLY1. CONCLUSION: Our data provides evidence that a group of patients with CDDG1 manifest slowly progressive myoclonic epilepsy and cognitive decline during the long-term clinical course.

The Effectiveness of Deflux® Treatment for Vesicoureteral Reflux Following Pediatric Renal Transplantation: A Single-Institution Challenging Experience.

PURPOSE: To validate the effectiveness of Deflux® treatment for vesicoureteral reflux (VUR) following pediatric renal transplantation (RT), based on our single-institution experience. METHOD: A retrospective study was conducted using the medical records of pediatric patients who underwent Deflux® treatment for VUR after RT from April 2008 to March 2022. RESULTS: Sixty-eight pediatric patients underwent RT. VUR was subsequently detected in 22 (32 %) of these patients. Seven of the 22 patients (32 %) underwent Deflux® treatment to avoid renal dysfunction due to urinary infection (UTI). The median age at the time of RT was 4 years (range:2-12). All 7 patients had urinary UTIs before Deflux® treatment. The median estimated glomerular filtration rate (eGFR) before Deflux® treatment was 67 ml/min/1.73 m2 (range:42-138 ml/min/1.73 m2). After Deflux® treatment, VUR was downgraded in three cases (43 %). Four patients (57 %) experienced postoperative UTI, two of who underwent a second Deflux® treatment, one underwent submuscular tunnel reconstruction, and the other one experienced UTI without VUR after 1st Deflux® treatment but did not reoccur. All seven patients continued prophylactic medication after Deflux® treatment, without any history of recurrent UTIs during the observation period after treatment (median 37 months [range 7-86 months]). Furthermore, the eGFRs did not significantly decrease after Deflux® treatment (median eGFR 58 ml/min/1.73 m2 [range:33-99 ml/min/1.73 m2], p > 0.1). CONCLUSION: Deflux® treatment for VUR after RT is technically challenging because the new ureteral orifice is ventrally anastomosed at the bladder. We believe our results indicate the possibility of reducing the frequency of UTIs and contributing to preservation of the renal function after RT. TYPE OF STUDY: Retrospective Study. LEVEL OF EVIDENCE: Level III.

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.