Misdiagnosed Branchio-Oto-Renal syndrome presenting as proteinuria and renal insufficiency with insidious signs since early childhood: a report of three cases.

BACKGROUND: Branchio-oto-renal (BOR) syndrome is an inherited multi-systemic disorder. Auricular and branchial signs are highly suggestive of BOR syndrome but often develop insidiously, leading to a remarkable misdiagnosis rate. Unlike severe morphological abnormalities of kidneys, knowledge of glomerular involvement in BOR syndrome were limited. CASE PRESENTATION: Three cases, aged 8 ~ 9 years, visited pediatric nephrology department mainly for proteinuria and renal insufficiency, with 24-h proteinuria of 23.8 ~ 68.9 mg/kg and estimated glomerular filtration rate of 8.9 ~ 36.0 mL/min/1.73m2. Moderate-to-severe albuminuria was detected in case 1, while mixed proteinuria was detected in case 2 and 3. Insidious auricular and branchial fistulas were noticed, all developing since early childhood but being neglected previously. EYA1 variants were confirmed by genetic testing in all cases. Delay in diagnosis was 8 ~ 9 years since extra-renal appearances, and 0 ~ 6 years since renal abnormalities. In case 1, therapy of glucocorticoid and immunosuppressive agents to accompanying immune-complex mediated glomerulonephritis was unsatisfying. CONCLUSIONS: BOR syndrome is a rare cause of proteinuria and abnormal kidney function and easily missed, thus requiring more awareness. Careful medical history taking and physical examination are essential to early diagnosis. Massive proteinuria was occasionally seen in BOR syndrome, which might be related to immune complex deposits. A novel pathogenic variant (NM_000503.6 (EYA1): c.1171delT p.Ser391fs*9) was firstly reported.

Incidence of relapse and frequently relapsing/steroid-dependent nephrotic syndrome in Chinese children with steroid-sensitive nephrotic syndrome: A cohort study.

AIM: This study aimed to investigate the incidence of relapse and FR/SDNS in Chinese children with SSNS and to develop clinical prediction models for relapse and FR/SDNS. METHODS: This retrospective cohort study involved 339 newly onset SSNS patients between 2006 and 2016. The incidence of relapse and FR/SDNS were estimated using the Kaplan-Meier method. Prediction models were constructed based on Cox proportional-hazards regression. RESULTS: The median follow-up time was 8.7 years. The cumulative incidence of relapse at 1-, 2-, and 5-year was 51.0%, 62.5%, and 66.6%. The cumulative incidence of FR/SDNS at 1-, 2-, and 5-year was 18.4%, 29.0%, and 32.9%. The final prediction model for first relapse included four variables (serum albumin, triglycerides, IgM, and time to first remission). The model's discriminative ability was low (Harrell's C index = 0.62). The final prediction model for FR/SDNS included four variables (serum albumin, lipoprotein(a), time to first remission, and time to first relapse). The discrimination and calibration of the prediction model for FR/SDNS were acceptable (Harrell's C index = 0.73, Brier score at 1- and 2-year were 0.11 and 0.17). CONCLUSION: The first relapse and FR/SDNS mainly occurred in the first 2 years after initial SSNS onset. The prediction model for relapse developed using common clinical parameters performed poorly, while the prediction model for FR/SDNS might be useful.

Clinicopathologic features in childhood-onset lupus nephritis with antineutrophil cytoplasmic antibody positivity--a multi-center retrospective study.

BACKGROUND: Positive antineutrophil cytoplasmic antibody (ANCA) serology in adult-onset lupus nephritis (LN) is associated with more active disease and distinct renal pathology, but data with respect to childhood-onset LN remain scarce. Here, we aimed to determine the impact of positive ANCA serology on clinical and histopathologic features and renal outcomes in children with LN from multiple centers. METHODS: Clinical and histopathologic data of 61 ANCA-positive and 330 ANCA-negative LN children (1

Serum levels and significance of soluble B-cell maturation antigen in childhood-onset systemic lupus erythematosus with renal involvement.

OBJECTIVE: The aim of this study was to investigate serum levels of soluble B-cell maturation antigen (sBCMA) in childhood-onset systemic lupus erythematous (cSLE) patients with renal involvement, and to elucidate their association with clinical characteristics. METHODS: 116 cases of cSLE patients with renal involvement (84 females and 32 males; median age 11.6 (10.1, 12.9) years) hospitalized in Department of Pediatric Nephrology and Rheumatology, the First Affiliated Hospital, Sun Yat-sen University and 31 healthy controls (HCs) were enrolled. Serum concentrations of sBCMA were determined using enzyme-linked immunosorbent assay (ELISA). Clinical and laboratory information of cSLE patients were retrospectively analyzed. RESULTS: Serum sBCMA levels were significantly increased in primary cSLE when compared with treated cSLE patients and HCs, whereas there was no significant difference between treated cSLE patients and HCs. Patients with high disease activity displayed higher serum sBCMA levels compared with those with no or mild to moderate disease activity. Positive correlation was observed between serum sBCMA levels and systemic lupus erythematosus disease activity index-2K (SLEDAI-2K), antinuclear antibody titers, anti-double-stranded DNA titers, erythrocyte sedimentation rate, and immunoglobulin G levels, while sBCMA levels were negatively correlated with blood white blood cell count, hemoglobin, platelet count, complement C3 and C4 levels. Serum sBCMA levels decreased as disease ameliorated after treatments among 11 cases with follow-up examinations. CONCLUSIONS: In cSLE patients with renal involvement, serum sBCMA levels correlated significantly with disease activity, immunological, and hematological parameters, but not with renal parameters. Our results suggest the potential and significance of serum sBCMA as a biomarker in cSLE patients.

Classification and rising medication therapy in stiff skin syndrome: A case report and literature review.

Stiff skin syndrome (SSS) is a rare disorder characterized by skin induration and limited joint mobility in the absence of visceral, musculoskeletal, vascular, or immunologic abnormalities. Distinctive subsets of SSS could be distinguished by various manifestation and mechanism, which accounts for the high heterogeneity in SSS cases. Although rehabilitation training remains the mainstay of management, rising medications has drawn awareness in recent years, owing to the potential efficacy. Nevertheless, experience was limited, especially in widespread SSS. We report on a 5-year-old girl with widespread SSS, whose lesion stopped progressing after combination therapy by mycophenolic acid (MPA) and losartan (LST) in addition to rehabilitation exercise. Despite limited experience, a combined therapy of MPA and LST seems to be effective in retarding progression of widespread SSS.

Dyslipidemia may be a risk factor for progression in children with IgA nephropathy.

BACKGROUND: IgA nephropathy (IgAN) is often chronically progressive and commonly accompanied by dyslipidemia. However, the intrinsic relationship between dyslipidemia and IgAN remains to be elucidated. This study aimed to investigate the impact of different types of dyslipidemia on clinical and pathological characteristics in children with IgAN. METHODS: In our retrospective cohort study from January 2006 to January 2021, 276 children with IgAN were ultimately included in the baseline analysis, and 169 were included in the follow-up analysis. The clinical and pathological features of different types of dyslipidemia and their effect on kidney prognosis were analyzed. RESULTS: Children in the dyslipidemia group had more severe clinical characteristics (higher blood urea nitrogen, serum uric acid, and 24-h proteinuria; higher proportion of hypertension; and lower serum albumin and estimated glomerular filtration rate) and pathological changes (higher proportion of Lee grades IV-V and E1, S1, and C2 in MEST-C). Furthermore, the clinical and pathological characteristics were worse in the mixed hyperlipidemia group. Multivariate logistic analysis showed that hypertension, steroid treatment, lower serum albumin, severe proteinuria, and segmental glomerulosclerosis were independent risk factors for dyslipidemia in children with IgAN. The Kaplan-Meier analysis revealed that the probability of kidney survival in children with dyslipidemia was lower than that in those without dyslipidemia, with a median follow-up of 5.9 years. CONCLUSIONS: Children with IgAN and dyslipidemia, especially mixed hyperlipidemia, are prone to more severe clinical and pathological changes. Our study provides further insight into dyslipidemia as a potential risk factor in children with IgAN. A higher resolution version of the Graphical abstract is available as Supplementary information.

Long-Term Outcome of Secondary Steroid-Resistant Nephrotic Syndrome in Chinese Children.

INTRODUCTION: Secondary steroid-resistant nephrotic syndrome (SRNS) refers to the condition when patients with initial steroid-sensitive nephrotic syndrome develop steroid resistance in subsequent relapses. Long-term outcomes of secondary SRNS in children are uncertain. METHODS: This was a single-center retrospective study of 56 children with secondary SRNS between 2006 and 2016. The survival curve was estimated using the Kaplan-Meier method. Independent risk factors for end-stage renal disease (ESRD) were determined using Cox proportional hazards model. RESULTS: The median time from nephrotic syndrome onset to secondary SRNS was 7.8 months. Biopsy results at diagnosis secondary SRNS showed that 64.3% of cases were minimal change disease (MCD). No remission was observed in seven (12.5%) patients within the first year. The mean follow-up time was 7.8 ± 3.2 years. Eight patients were clinically cured, one died before ESRD, 10 reached ESRD, and 75.0% (3 of 4) of patients recurred post-transplantation. The 10-year ESRD-free survival rate was 85.8%. No response to intensified immunosuppression (IIS) in the first year was the independent predictor for ESRD. Repeat biopsies were performed in 20 cases, revealing that the reclassification from MCD to mesangial hypercellularity and focal segmental glomerulosclerosis (FSGS) in two when secondary steroid resistance appeared, from MCD and mesangial hypercellularity to FSGS in seven who developed multidrug resistance, and from FSGS to MCD and mesangial hypercellularity in two with favorable outcomes. CONCLUSIONS: The long-term outcome in children with secondary SRNS was heterogeneous, and no response to IIS in the first year was the independent predictor for ESRD. In patients with repeat biopsy, changes in histological appearance to FSGS were associated with multidrug resistance.

[Clinicopathological features of children with lupus nephritis with positive antineutrophil cytoplasmic antibody].

OBJECTIVE: To study the clinicopathological features of children with lupus nephritis (LN) with positive anti-neutrophil cytoplasmic antibody (ANCA). METHODS: A retrospective analysis was performed for the children who were diagnosed with LN in the First Affiliated Hospital of Sun Yat-sen University from January 2003 to December 2019. According to the results of serum ANCA, they were divided into two groups: ANCA-positive group (n=59) and ANCAnegative group (n=454). The two groups were compared in terms of clinical manifestations, histopathological features, remission rate, and prognosis. RESULTS: Compared with the ANCA-negative group, the ANCA-positive group had a significant reduction in leukocytes and a significant increase in erythrocyte sedimentation rate (P < 0.05). There were no significant differences between the two groups in serum creatinine, urine protein, and urine red blood cell count (P > 0.05). A total of 308 children underwent kidney biopsy. The results on light microscopy showed that compared with the ANCAnegative group, the ANCA-positive group had a significantly higher proportion of children with cellular fibrous crescents (P < 0.05) and a significantly lower proportion of children with immune complex deposition (P < 0.05). There were no significant differences between the two groups in the remission rate and survival rate (P > 0.05). CONCLUSIONS: Children with ANCA-positive LN tend to have more severe renal pathological injury, which is not exactly parallel with clinical manifestations, suggesting that timely renal biopsy is of great importance.

Case Report: Denys-Drash Syndrome With WT1 Causative Variant Presenting as Atypical Hemolytic Uremic Syndrome.

The WT1 variant is confirmed to be pathogenic for Denys-Drash syndrome (DDS), a rare disorder characterized by early-onset nephrotic syndrome and renal failure, pseudo-hermaphroditism, and a high risk of Wilms' tumor. Several cases of DDS presenting with atypical hemolytic uremic syndrome (aHUS) have been reported. Here we report the case of a 2-year-old child who was diagnosed with WT1 missense variant, associated with DDS and initial presentation of aHUS. Complement factor H autoantibodies were negative. Complement regulatory system-related gene variants were not found, but a de novo heterozygous c.754G>A missense variant in exon 9 of WT1 gene was detected, resulting in a p. Asp252Asn substitution, by next-generation sequencing. The patient was a female morphologically but proved to be a genetic male because of karyotype 46, XY with normally developed female external genitalia. Bilateral nephrectomy and renal transplantation were performed 1 year later, and there was no recurrence of aHUS at 10 months after transplantation.

Analysis of 10 Pediatric Nephrotic Syndrome Cases With Complications of Cerebral Sinovenous Thrombosis.

Background: To analyze the clinical characteristics of nephrotic syndrome (NS) with complications of cerebral sinovenous thrombosis (CSVT) in children. Method: Clinical, radiographic, laboratory, and treatment data obtained from 10 confirmed cases of NS with complications of CSVT were analyzed. All patients were followed up for at least 18 months. CSVT was diagnosed by cerebral computed tomography (CT) and/or magnetic resonance imaging (MRI) with or without magnetic resonance venography (MRV) of the cerebral vessels. Results: Among 10 cases reported, 4 were steroid-sensitive NS with frequent relapse, 5 were steroid-resistant (three of them had renal biopsies showing two minimal change disease and one IgA nephropathy), and 1 was steroid-sensitive with one relapse. Common clinical manifestations were headache or ophthalmodynia complicated by vomiting, dizziness, convulsion, and coma. Neuropathologic signs were positive in some cases. Papilledema appeared in only one case with winding of vein. Cerebrospinal fluid was examined in three cases with elevated pressure but normal cytological and biochemical results. D dimer and fibrinogen levels were elevated while prothrombin time and activated partial thromboplastin time were shortened. Five out of seven cases who had performed cranial CT were suspicious for cerebral thrombosis. Nine cases had cranial MRI with abnormal signs in seven cases. All of the cases received MRV, confirming the diagnosis of CVST. Conclusion: Clinical manifestations of NS with CSVT are not specific but varied. Therefore, CSVT should be considered once nervous manifestations present. MRV is a better method in the diagnosis of CSVT.

Monolithic beam splitter in silicon-on-insulator.

Inductively coupled plasma reactive ion etching is used to fabricate the monolithic beam splitter in silicon-on-insulator wafer. The near-field image shows that the symmetric 1x2 T-branch works well. The rms roughness of the corner mirror surfaces is measured by atomic force microscope, and the sidewall surface roughness of rib waveguide is evaluated by the corner mirror rms roughness. The scattering losses from the rough sidewall surfaces and the rough mirror surfaces are evaluated to be 0.5 dB/cm and 0.2 dB/mirror, respectively. And the fiber-waveguide insertion loss is measured approximately 5.0 dB.