Is influenza vaccination associated with nephrotic syndrome relapse in children? A multicenter prospective study.

BACKGROUND: Prospective research of children receiving heterogeneous vaccines has shown that immunization is not associated with pediatric idiopathic nephrotic syndrome (NS) relapses. However, prospective data concentrating only on influenza (flu) virus vaccines are not available. METHODS: This multicenter prospective study was conducted in children with NS who received inactivated flu vaccines from June 2017 to July 2018. The day of flu vaccination was defined as day 0, and the period between prevaccination and postvaccination days was defined as - X to + Y (period from day - 180 to 0 as the precontrolled period). The primary outcome was the NS relapse rate from day 0 to + 30 as a direct association with vaccination compared with those in the precontrolled period. Exacerbation was defined as children experiencing more NS relapses after vaccination compared with those in the precontrolled period, or children starting any new immunosuppressants due to NS relapse after vaccination. RESULTS: Sixty-three children were included. Relapse rates were not significantly different between the precontrolled period and 0 to + 30 periods (0.38 vs. 0.19 times/person-year, p = 0.95). Although the exacerbation rate during the 0 to + 180 period in children without NS relapse in the precontrolled period was very low (4/54 [7.4 %]), children with at least one NS relapse in the precontrolled period showed a remarkable increase in the rate (4/9 [44.4%]; p = 0.01). CONCLUSIONS: Flu vaccination did not significantly precipitate the direct relapse of NS in children. However, it might increase the disease activity in children with at least one NS relapse within a half year before vaccination. A higher resolution version of the Graphical abstract is available as Supplementary information.

Molecular mechanisms determining severity in patients with Pierson syndrome.

Null variants in LAMB2 cause Pierson syndrome (PS), a severe congenital nephrotic syndrome with ocular and neurological defects. Patients' kidney specimens show complete negativity for laminin ß2 expression on glomerular basement membrane (GBM). In contrast, missense variants outside the laminin N-terminal (LN) domain in LAMB2 lead to milder phenotypes. However, we experienced cases not showing these typical genotype-phenotype correlations. In this paper, we report six PS patients: four with mild phenotypes and two with severe phenotypes. We conducted molecular studies including protein expression and transcript analyses. The results revealed that three of the four cases with milder phenotypes had missense variants located outside the LN domain and one of the two severe PS cases had a homozygous missense variant located in the LN domain; these variant positions could explain their phenotypes. However, one mild case possessed a splicing site variant (c.3797 + 5G>A) that should be associated with a severe phenotype. Upon transcript analysis, this variant generated some differently sized transcripts, including completely normal transcript, which could have conferred the milder phenotype. In one severe case, we detected the single-nucleotide substitution of c.4616G>A located outside the LN domain, which should be associated with a milder phenotype. However, we detected aberrant splicing caused by the creation of a novel splice site by this single-base substitution. These are novel mechanisms leading to an atypical genotype-phenotype correlation. In addition, all four cases with milder phenotypes showed laminin ß2 expression on GBM. We identified novel mechanisms leading to atypical genotype-phenotype correlation in PS.

Congenital chloride diarrhea needs to be distinguished from Bartter and Gitelman syndrome.

Pseudo-Bartter/Gitelman syndrome (p-BS/GS) encompasses a clinically heterogeneous group of inherited or acquired disorders similar to Bartter syndrome (BS) or Gitelman syndrome (GS), both renal salt-losing tubulopathies. Phenotypic overlap frequently occurs between p-BS/GS and BS/GS, which are difficult to diagnose based on their clinical presentation and require genetic tests for accurate diagnosis. In addition, p-BS/GS can occur as a result of other inherited diseases such as cystic fibrosis, autosomal dominant hypocalcemia, Dent disease, or congenital chloride diarrhea (CCD). However, the detection of the variants in genes other than known BS/GS-causing genes by conventional Sanger sequencing requires substantial time and resources. We studied 27 cases clinically diagnosed with BS/GS, but with negative genetic tests for known BS/GS genes. We conducted targeted sequencing for 22 genes including genes responsible for tubulopathies and other inherited diseases manifesting with p-BS/GS symptoms. We detected the SLC26A3 gene variants responsible for CCD in two patients. In Patient 1, we found the SLC26A3 compound heterozygous variants: c.354delC and c.1008insT. In Patient 2, we identified the compound heterozygous variants: c.877G > A, p.(Glu293Lys), and c.1008insT. Our results suggest that a comprehensive genetic screening system using targeted sequencing is useful for the diagnosis of patients with p-BS/GS with alternative genetic origins.

Acute focal bacterial nephritis characterized by acute encephalopathy with biphasic seizures and late reduced diffusion.

Acute focal bacterial nephritis (AFBN) is a localized bacterial infection of the kidney presenting as an inflammatory mass, and some patients show deterioration of clinical condition with neurological symptoms. Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) is a syndrome that is characterized by biphasic seizures and impaired consciousness with reduced diffusion in the subcortical white matter on magnetic resonance imaging, typically observed between days 3 and 9 after clinical onset. Although AFBN sometimes causes neurological symptoms, no cases of AFBN with AESD have been reported, and no studies have presented the cytokine profiles of patients with a severe form of acute encephalopathy with AFBN. We report here a very rare case involving a 6-month-old boy who developed AFBN due to Enterococcus faecalis with both the clinical and radiological features of AESD. In our patient, serum interleukin (IL)-6, IL-10, and interferon (IFN)-γ levels markedly increased on admission, and on day 4, only IL-6 levels significantly increased in the cerebrospinal fluid (CSF). These results suggest that high serum cytokines are produced locally in response to AFBN and elevated IL-6 levels in CSF may have neuroprotective roles.

Diagnostic challenge in a patient with nephropathic juvenile cystinosis: a case report.

BACKGROUND: Cystinosis is a rare autosomal recessive lysosomal disorder characterized by the accumulation of cystine in lysosomes. Cystinosis is much rarer in Asian than Caucasian populations. There are only 14 patients have with cystinosis alive in Japan. Most cystinosis is the nephropathic infantile form, as indicated by its apparent and severe clinical manifestations, including renal and ocular symptoms. Patients with the nephropathic juvenile form account for 5% of those with cystinosis. Their diagnosis is frequently delayed and difficult because of slower progression to end-stage renal disease and fewer cystine crystals in the cornea. Molecular analysis and a cysteine-binding protein assay should be performed when patients with proximal tubulopathy of an unknown origin are encountered. CASE PRESENTATION: A 12-year-old boy had been suffering from Fanconi syndrome since he was 3 years old. He was only recently diagnosed despite repeated ophthalmological examinations. Corneal cystine crystals were found when he was 12 years old, and he was diagnosed with cystinosis by high free cystine content in granulocytes (6.36 nmol half-cystine/mg protein, normal: <0.15). Analysis of the CTNS gene showed two novel heterozygous single nucleotide substitutions of c.329G > C and c.329 + 2 T > C. Both were splicing site variants causing exon 6 skipping proven by transcript analysis, although the functional prediction site showed c.329G > C, p.(Gly110Ala) as a benign missense substitution. The patient's estimated glomerular filtration rate was 66.8 mL/min/1.73 m2. He was immediately treated with cysteamine after diagnosis. CONCLUSIONS: Even if no ophthalmological abnormalities are present, nephropathic juvenile cystinosis should be suspected in children with Fanconi syndrome. Transcript analysis was useful to detect pathogenic splicing variants in this patient.

Differential diagnosis of Bartter syndrome, Gitelman syndrome, and pseudo-Bartter/Gitelman syndrome based on clinical characteristics.

PURPOSE: Phenotypic overlap exists among type III Bartter syndrome (BS), Gitelman syndrome (GS), and pseudo-BS/GS (p-BS/GS), which are clinically difficult to distinguish. We aimed to clarify the differences between these diseases, allowing accurate diagnosis based on their clinical features. METHODS: A total of 163 patients with genetically defined type III BS (n = 30), GS (n = 90), and p-BS/GS (n = 43) were included. Age at diagnosis, sex, body mass index, estimated glomerular filtration rate, and serum and urine electrolyte concentrations were determined. RESULTS: Patients with p-BS/GS were significantly older at diagnosis than those with type III BS and GS. Patients with p-BS/GS included a significantly higher percentage of women and had a lower body mass index and estimated glomerular filtration rate than did patients with GS. Although hypomagnesemia and hypocalciuria were predominant biochemical findings in patients with GS, 17 and 23% of patients with type III BS and p-BS/GS, respectively, also showed these abnormalities. Of patients with type III BS, GS, and p-BS/GS, 40, 12, and 63%, respectively, presented with chronic kidney disease. CONCLUSIONS: This study clarified the clinical differences between BS, GS, and p-BS/GS for the first time, which will help clinicians establish differential diagnoses for these three conditions.

Pathogenesis of hypokalemia in autosomal dominant hypocalcemia type 1.

BACKGROUND: Autosomal dominant hypocalcemia type 1 (ADH1) is a relatively rare endocrine disorder characterized by hypocalcemia and inadequate parathyroid hormone secretion. ADH is caused by activating mutations in the calcium-sensing receptor (CaSR) gene, CASR. CaSR plays a crucial role in calcium and magnesium homeostasis in the kidney. ADH may be accompanied by hypokalemia and metabolic alkalosis when it is classified as type V Bartter syndrome. However, the mechanism underlying hypokalemia in this disease is unclear. METHODS: We investigated a 33-year-old woman with hypocalcemia and hypoparathyroidism since childhood, whose mother also had hypocalcemia and hypoparathyroidism, but with no clinical symptoms. Blood examinations showed hypokalemia and metabolic alkalosis in the patient, but not her mother. We conducted mutation analysis and diuretic tests to clarify the patient's and her mother's diagnosis and to investigate the onset mechanism of hypokalemia in ADH1. We also determined the localization of CaSR in the kidney by immunohistochemistry. RESULTS: We detected a known gain-of-function mutation in CASR in both the patient and her mother. Diuretic tests revealed a response to furosemide and no reaction to thiazide in the patient, although the mother responded well to both diuretics. CaSR co-localized with the Na(+)-Cl(-) cotransporter (NCCT) on distal tubular epithelial cells. CONCLUSIONS: These results indicate that the NCCT in the distal convoluted tubule was secondarily affected in this patient. We conclude that the main pathogenesis of secondary hypokalemia in ADH1 in this patient was secondary NCCT dysfunction.

Milder clinical aspects of X-linked Alport syndrome in men positive for the collagen IV α5 chain.

X-linked Alport syndrome is caused by mutations in the COL4A5 gene encoding the type IV collagen α5 chain (α5(IV)). Complete absence of α5(IV) in the renal basal membrane is considered a pathological characteristic in male patients; however, positive α5(IV) staining has been found in over 20% of patients. We retrospectively studied 52 genetically diagnosed male X-linked Alport syndrome patients to evaluate differences in clinical characteristics and renal outcomes between 15 α5(IV)-positive and 37 α5(IV)-negative patients. Thirteen patients in the α5(IV)-positive group had non-truncating mutations consisting of nine missense mutations, three in-frame deletions, and one splice-site mutation resulting in small in-frame deletions of transcripts. The remaining two showed somatic mutations with mosaicism. Missense mutations in the α5(IV)-positive group were more likely to be located before exon 25 compared with missense mutations in the α5(IV)-negative group. Furthermore, urinary protein levels were significantly lower and the age at onset of end-stage renal disease was significantly higher in the positive group than in the negative group. These results help to clarify the milder clinical manifestations and molecular characteristics of male X-linked Alport syndrome patients expressing the α5(IV) chain.

Association between Factor XIII Activity and Clinical Course in Pediatric Patients with Immunoglobulin A Vasculitis.

BACKGROUND: Immunoglobulin A vasculitis is a systemic form of vasculitis that predominantly affects children. Factor XIII activity is decreased in some cases, and several reports have shown an association between abdominal pain and decreased factor XIII activity. However, the clinical significance of decreased factor XIII activity in pediatric immunoglobulin A vasculitis has not been fully elucidated. This study aimed to identify the association between factor XIII activity and the clinical course of pediatric patients with immunoglobulin A vasculitis. METHODS: Forty-four pediatric patients, admitted to Kita-Harima Medical Center with a clinical diagnosis of immunoglobulin A vasculitis between October 1, 2013 and September 30, 2022, were retrospectively reviewed, and 22 patients were analyzed. The patients' background characteristics and clinical course were compared between the normal and decreased factor XIII activity (<70%) groups. RESULTS: The group with decreased factor XIII activity showed a significantly increased duration of hospitalization (14 [6-36] vs. 7 [5-13] days, p = 0.01), total glucocorticoid dose (prednisolone 22.7 [4.9-55.5] vs. 10.1 [3.4-19.6] mg/kg, p = 0.02), and duration of glucocorticoid administration (19 [4-85] vs. 10 [3-15] days, p = 0.03). Correlational analyses showed that these three parameters were negatively correlated with factor XIII activity. CONCLUSIONS: Factor XIII activity was negatively correlated with the duration of hospitalization, total glucocorticoid dose, and duration of glucocorticoid administration. Factor XIII activity is not only associated with abdominal symptoms but also may be a marker to predict the overall trajectory of acute-phase treatment in pediatric patients with immunoglobulin A vasculitis.

Kawasaki Disease with an Initial Manifestation Mimicking Bacterial Inguinal Cellulitis.

BACKGROUND: Kawasaki disease (KD) is typically characterized by fever, oral cavity erythematous changes, bilateral bulbar conjunctival injection, skin rash, erythema and edema of the hands and feet, and cervical lymphadenopathy. Some atypical patients with KD initially develop cervical and pharyngeal cellulitis; however, an initial presentation with inguinal cellulitis is extremely rare. In addition, to our knowledge, no report has documented the cytokine profile in a KD patient with cellulitis. Case presentation. A previously healthy 8-year-old Japanese girl was hospitalized following a 2-day history of fever and a 5-day history of pain and erythema in the left inguinal region. She was diagnosed with bacterial inguinal cellulitis and was administered antibiotics. The next day, a polymorphous rash emerged on her trunk. After 3 days of antibiotics, however, her fever continued and the cellulitis had spread over the entire lower abdomen. Simultaneously, the bilateral bulbar conjunctival injection without exudate became more prominent and her lips became erythematous. In addition, erythematous changes on her palms appeared a few hours later, which led to the diagnosis of KD. Since she had a high risk score that predicted no response to initial intravenous immunoglobulin (IVIG) at the initiation of treatment, she was treated with IVIG, intravenous prednisolone (PSL), and oral aspirin. The KD symptoms improved the next day, but the cellulitis did not completely resolve until 2 months after discharge. The patient's serum cytokine profile at admission had an IL-6 dominant pattern which was consistent with that of patients with KD despite her initial lack of KD symptoms, and the pattern observed at admission was sustained until IVIG and PSL administration. CONCLUSION: KD should be included in the differential diagnosis for patients presenting with inguinal cellulitis who are unresponsive to initial empiric antibiotics.

Somatic mosaicism and variant frequency detected by next-generation sequencing in X-linked Alport syndrome.

X-linked Alport syndrome (XLAS) is a progressive, hereditary nephropathy. Although men with XLAS usually develop end-stage renal disease before 30 years of age, some men show a milder phenotype and develop end-stage renal disease later in life. However, the molecular mechanisms associated with this milder phenotype have not been fully identified. We genetically diagnosed 186 patients with suspected XLAS between January 2006 and August 2014. Genetic examination involved: (1) extraction and analysis of genomic DNA using PCR and direct sequencing using Sanger's method and (2) next-generation sequencing to detect variant allele frequencies. We identified somatic mosaic variants in the type VI collagen, α5 gene (COL4A5) in four patients. Interestingly, two of these four patients with variant frequencies in kidney biopsies or urinary sediment cells of ≥50% showed hematuria and moderate proteinuria, whereas the other two with variant frequencies of <50% were asymptomatic or only had hematuria. De novo variants can occur even in asymptomatic male cases of XLAS resulting in mosaicism, with important implications for genetic counseling. This is the first study to show a tendency between the variant allele frequency and disease severity in male XLAS patients with somatic mosaic variants in COL4A5. Although this is a very rare status of somatic mosaicism, further analysis is needed to show this correlation in a larger population.

Primary pediatric endobronchial Ewing sarcoma family of tumors.

BACKGROUND: Ewing sarcoma family of tumors is the second most common primary bone tumor of childhood. Extraosseous Ewing sarcoma family of tumors is rare. We present a pediatric case of primary endobronchial Ewing sarcoma family of tumors. CASE REPORT: A 12-year-old boy presented with dyspnea and chest radiography showed right pulmonary atelectasis. Chest computed tomography demonstrated tumor in the right main bronchus. Histopathological examination of the resected tumor demonstrated Ewing sarcoma family of tumors. No other lesions were detected throughout the body and the right main bronchus was thought to be the primary site. As of 1 year and 6 months after further resection of residual tumor followed by chemotherapy and radiotherapy, the patient remains disease-free. CONCLUSIONS: Extraosseous Ewing sarcoma family of tumors arises in soft tissues of the trunk or extremities, but primary endobronchial Ewing sarcoma family of tumors has rarely been reported. Although quite rare, Ewing sarcoma family of tumors should be considered among the differential diagnoses for pediatric bronchial tumor.

SLC26A3 gene analysis in patients with Bartter and Gitelman syndromes and the clinical characteristics of patients with unidentified mutations.

We analyzed the SLC26A3 gene in patients with a clinical diagnosis of Bartter and Gitelman syndromes in whom genetic diagnoses could not be determined. We also examined the genetic and clinical characteristics of patients for whom genetic proof could not be obtained. The present study included 10 patients. With regard to genetic characteristics, 1 patient harbored a heterozygous mutation in the SLC12A3 gene (c.2573T>A, p.L858H), which was also reported in a previous report. With regard to clinical characteristics, 3 patients had abnormalities that were identified incidentally during medical examinations and other illnesses and 1 patient had polyhydramnios. One case of nephrocalcinosis was also noted. Eight patients were of below average height. Although we analyzed the SLC26A3 gene in these 10 patients, none were found to have pathological mutations. Investigation of the outcomes of these cases showed that examination findings had normalized and medication was no longer necessary for 3 patients, whereas hypokalemia and metabolic alkalosis were observed in another patient only in the presence of acute disease. We concluded that few patients develop illnesses because of SLC26A3 mutations. Other disease-related genes may also be involved. Although hypokalemia and metabolic alkalosis are clinical characteristics of Bartter and Gitelman syndromes, many other conditions also present such symptoms, and thus, differential diagnosis is of paramount importance.

Place of death of pediatric cancer patients in a single institute during 7 years.

Place of death is an important issue at the end-of-life. It is poorly understood in pediatric cancer patients in Japan. This study aimed to clarify place of death of children with cancer as well as variables associated with place of death. Study population was pediatric cancer patients who died in the Department of Pediatrics at Kobe University Hospital during the last 7 years. The medical records were retrospectively reviewed regardless of cause of death to derive data relating to patients' characteristics and disease. 18 patients were included. Median age at death was 12.2 years old. 6 patients including 5 children in complete remission had hematological disease and 12 patients suffered from solid tumors. 4 patients (22.2%) died at home, whereas 14 patients (77.8%) died in the hospital including 6 ICU deaths. No one died in hospices. Preference of patients was unavailable due to the lack of inquiry. Factors influencing place of death (home, ICU, non-ICU) were disease (hematological disease vs. solid tumor, p=0.010, brain tumor vs. non-brain tumor, p=0.023), disease status (complete remission vs. non-complete remission, p=0.0014) and preference of families (p=0.029). Among 6 families who expressed preference, no disparity was observed between actual and preferred place of death. This is the first English publication of place of death of pediatric cancer patients in Japan. The low percentage of home death, factors influencing place of death and the lack of disparity between actual and preferred place of death were indicated. Further studies are required to better understand place of death.