Genotype-phenotype correlations in children with Gitelman syndrome.

BACKGROUND: This study aimed to analyze genotype-phenotype correlations in children with Gitelman syndrome (GS). METHODS: This multicenter retrospective study included 50 Korean children diagnosed with SLC12A3 variants in one or both alleles and the typical laboratory findings of GS. Genetic testing was performed using the Sanger sequencing except for one patient. RESULTS: The median age at the diagnosis was 10.5 years (interquartile range, 6.8;14.1), and 41 patients were followed up for a median duration of 5.4 years (interquartile range, 4.1;9.6). A total of 30 different SLC12A3 variants were identified. Of the patients, 34 (68%) had biallelic variants, and 16 (32%) had monoallelic variants on examination. Among the patients with biallelic variants, those (n = 12) with the truncating variants in one or both alleles had lower serum chloride levels (92.2 ± 3.2 vs. 96.5 ± 3.8 mMol/L, P = 0.002) at onset, as well as lower serum potassium levels (3.0 ± 0.4 vs. 3.4 ± 0.3 mMol/L, P = 0.016), and lower serum chloride levels (96.1 ± 1.9 vs. 98.3 ± 3.0 mMol/L, P = 0.049) during follow-up than those without truncating variants (n = 22). Patients with monoallelic variants on examination showed similar phenotypes and treatment responsiveness to those with biallelic variants. CONCLUSIONS: Patients with GS who had truncating variants in one or both alleles had more severe electrolyte abnormalities than those without truncating variants. Patients with GS who had monoallelic SLC12A3 variants on examination had almost the same phenotypes, response to treatment, and long-term prognosis as those with biallelic variants.

Glomerular Diseases Across Lifespan: Key Differences in Diagnostic and Therapeutic Approaches.

Glomerular diseases are common causes of chronic kidney disease in childhood, adolescence, and adulthood. The epidemiology of glomerular diseases differs between different age groups, with minimal change disease being the leading cause of nephrotic syndrome in childhood, while membranous nephropathy and focal segmental glomerulosclerosis are more common in adulthood. IgA vasculitis is also more common in childhood. Moreover, there is a difference in disease severity with more children presenting with a relapsing form of nephrotic syndrome and a more acute presentation of antineutrophil cytoplasmic antibody-associated vasculitis and concomitant glomerulonephritis, as highlighted by the higher percentage of cellular crescents on kidney biopsy specimens in comparison with older patients. There is also a female preponderance in antineutrophil cytoplasmic antibody-associated vasculitis and more children present with tracheobroncholaryngeal disease. This article aims to summarize differences in the presentation of different glomerular diseases that are encountered commonly by pediatric and adult nephrologists and potential differences in the management.

Induction and maintenance of remission with mycophenolate mofetil in ANCA-associated vasculitis: a systematic review and meta-analysis.

BACKGROUND: Uncertainties exist about the use of mycophenolate mofetil (MMF) in anti-neutrophil cytoplasmatic antibody (ANCA)-associated vasculitis (AAV), particularly for remission maintenance. METHODS: Systematic review and meta-analysis of phase II and III trials assessing the use of MMF in AAV, granulomatosis with polyangiitis and microscopic polyangiitis (MPA). A comprehensive search of several databases (Medline, EMBASE, Cochrane, Web of Science, Scopus) from inception to 5 May 2020 has been conducted. Trial data were extracted to estimate odds ratios (ORs) and estimates (ES) for MMF efficacy (remission-induction and maintenance). Severe adverse effects (SAEs) were collected. RESULTS: From 565 articles captured, 10 met the predefined criteria, 5 phase II and 5 III trials; 4 assessed remission-induction, 3 remission maintenance and 3 both. The pooled OR for remission-induction at 6 months was 1.06 (95% confidence interval 0.74, 1.52), with no significant difference by subgroup meta-analysis of trials stratified by different study-level features (i.e. kidney disease, MPA, myeloperoxidase-ANCA positivity, newly diagnosed disease) (P > 0.05). The overall ES for remission maintenance at the end of follow-up ranged between 51% and 91% (I2 = 74.8%). Subgroup meta-analysis identified kidney involvement as a possible source of heterogeneity, yielding a significantly higher rate of sustained remission in trials enrolling only patients with kidney involvement (92%, 76-100%) versus those enrolling patients with and without kidney involvement (56%, 45-66%). Results were similar in multiple sensitivity analyses. During follow-up, the frequency of SAEs in MMF-based treatment arms was 31.8%. CONCLUSIONS: In AAV, MMF use was significantly associated with higher sustained remission rates in trials enrolling only patients with kidney involvement. These findings might influence clinical practice.

The Long-Term Effect of Preterm Birth on Renal Function: A Meta-Analysis.

The preterm-born adult population is ever increasing following improved survival rates of premature births. We conducted a meta-analysis to investigate long-term effects of preterm birth on renal function in preterm-born survivors. We searched PubMed and EMBASE to identify studies that compared renal function in preterm-born survivors and full-term-born controls, published until 2 February 2019. A random effects model with standardized mean difference (SMD) was used for meta-analyses. Heterogeneity of the studies was evaluated using Higgin's I2 statistics. Risk of bias was assessed using the Newcastle-Ottawa quality assessment scale. Of a total of 24,388 articles screened, 27 articles were finally included. Compared to full-term-born controls, glomerular filtration rate and effective renal plasma flow were significantly decreased in preterm survivors (SMD -0.54, 95% confidence interval (CI), -0.85 to -0.22, p = 0.0008; SMD -0.39, 95% CI, -0.74 to -0.04, p = 0.03, respectively). Length and volume of the kidneys were significantly decreased in the preterm group compared to the full-term controls (SMD -0.73, 95% CI, -1.04 to -0.41, p < 0.001; SMD -0.82, 95% CI, -1.05 to -0.60, p < 0.001, respectively). However, serum levels of blood urea nitrogen, creatinine, and cystatin C showed no significant difference. The urine microalbumin to creatinine ratio was significantly increased in the preterm group. Both systolic and diastolic blood pressures were also significantly elevated in the preterm group, although the plasma renin level did not differ. This meta-analysis demonstrates that preterm-born survivors may be subject to decreased glomerular filtration, increased albuminuria, decreased kidney size and volume, and hypertension even though their laboratory results may not yet deteriorate.

The Effect of Interleukin-4 and Dexamethasone on RNA-Seq-Based Transcriptomic Profiling of Human Podocytes: A Potential Role in Minimal Change Nephrotic Syndrome.

Interleukin-4 (IL-4) expression is implicated in the pathogenesis of nephrotic syndrome (NS). This study aimed to investigate the changes in the transcriptomes of human podocytes induced by IL-4 treatment and to analyze whether these changes could be affected by simultaneous steroid treatment. Three groups of human podocytes were treated with control, IL-4, and IL-4 plus dexamethasone (DEX), respectively. We performed whole-transcriptome sequencing to identify differentially expressed genes (DEGs) between the groups. We investigated relevant biological pathways using Gene Ontology (GO) enrichment analyses. We also attempted to compare and validate the DEGs with the genes listed in PodNet, a literature-based database on mouse podocyte genes. A total of 176 genes were differentially expressed among the three groups. GO analyses showed that pathways related to cytoskeleton organization and cell signaling were significantly enriched. Among them, 24 genes were listed in PodNet, and 12 of them were previously reported to be associated with IL-4-induced changes in human podocytes. Of the 12 genes, the expression levels of BMP4, RARB, and PLCE1 were reversed when podocytes were simultaneously treated with DEX. In conclusion, this study explored changes in the transcriptome profiles of human podocytes treated with IL-4. Few genes were reported in previous studies and were previously validated in experiments with human podocytes. We speculate that IL-4 may exert pathogenic effects on the transcriptome of human podocytes, and a few genes may be involved in the pathogenesis.

Significance of sonographically detected bladder debris in children less than 2 years old with febrile urinary tract infection.

PURPOSE: To investigate the relationship between bladder debris found on renal and bladder ultrasonography (RBUS) and the first febrile urinary tract infection (UTI) episode in children under 2 years old. METHODS: We retrospectively reviewed the data of children aged <2 years with the first febrile UTI. We recorded bladder debris on RBUS and other findings (blood test, urinalysis, and urine culture). Other RBUS findings (renal pelvis debris, renal parenchymal change, wall thickening, and renal collecting system [RCS] dilatation) were recorded. Patients were divided into the debris (D) and non-D groups. RESULTS: Of 128 patients (boys: girls = 81:47, mean age = 5.6 ± 4.2 months), 24 (18.8%) had bladder debris. The mean C-reactive protein (CRP) levels were higher in the D group (6.1 ± 4.0 vs 4.3 ± 3.5, P = .03). Twenty-one patients in the D group (87.5%) had hematuria (odds ratio = 3.706, 95% confidence interval = 1.035-13.267, P = .04). No significant differences were seen in the urine culture results between both groups. Significant associations were seen between bladder debris and other RBUS findings such as debris in renal pelvis, renal parenchymal change, and RCS wall thickening. CONCLUSION: Bladder debris on RBUS is a common finding in children aged <2 years during the first febrile UTI. Bladder debris was related to higher CRP levels, hematuria and sonographic findings, but not to urine culture results.

Current understandings in treating children with steroid-resistant nephrotic syndrome.

Steroid-resistant nephrotic syndrome (SRNS) remains a challenge for paediatric nephrologists. SRNS is viewed as a heterogeneous disease entity including immune-based and monogenic aetiologies. Because SRNS is rare, treatment strategies are individualized and vary among centres of expertise. Calcineurin inhibitors (CNI) have been effectively used to induce remission in patients with immune-based SRNS; however, there is still no consensus on treating children who become either CNI-dependent or CNI-resistant. Rituximab is a steroid-sparing agent for patients with steroid-sensitive nephrotic syndrome, but its efficacy in SRNS is controversial. Recently, several novel monoclonal antibodies are emerging as treatment option, but their efficacy remains to be seen. Non-immune therapies, such as angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers, have been proven efficacious in children with SRNS and are recommended as adjuvant agents. This review summarizes and discusses our current understandings in treating children with idiopathic SRNS.

An Unusual Pediatric Case of Seronegative Systemic Lupus Erythematosus Presented With Acute Abdominal Pain and Gross Hematuria.

ABSTRACT: A child with acute abdomen with gross hematuria occasionally visits the emergency department (ED). Usually, such a condition is subject to differential diagnosis for stones, injuries, or sometimes malignancies in the urinary tract. Here we introduce an unusual case of a 9-year-old girl who presented to ED with acute lower abdominal pain and gross hematuria. She had no medical history. An urgent computed tomographic image revealed a renal vein thrombosis. Laboratory tests for autoimmune diseases and coagulaopathies were performed, and the results were within normal ranges. At the time, she did not fulfil the criteria for systemic lupus erythematosus or antiphospholipid syndrome. Later at follow-up, however, she had a recurrent episode of renal vein thrombosis. A kidney biopsy was performed to reveal histology of membranous lupus nephropathy. The case emphasizes the importance for both ED physicians and pediatricians to have a clinical suspicion of autoimmune diseases in cases with major vessel thrombosis, even when the patient is seronegative.

Lower albumin level and longer disease duration are risk factors of acute kidney injury in hospitalized children with nephrotic syndrome.

BACKGROUND: Children with nephrotic syndrome (NS) are at an increased risk of acute kidney injury (AKI) and the incidence of AKI in this population is reportedly increasing. This study aimed to investigate the incidence, clinical profiles, and risk factors of AKI in hospitalized children with NS through a nationwide study. METHODS: This retrospective multicenter study included 14 pediatric nephrology centers in Korea. From 2013 to 2017, a total of 814 patients with idiopathic NS were cared for at participating centers. Among them, 363 patients were hospitalized for NS and investigated in this study. RESULTS: A total of 363 children with NS were hospitalized 574 times. AKI occurred in 93 admissions (16.2%) of 89 patients: 30 (32.3%) stage 1; 24 (25.8%) stage 2; and 39 (41.9%) stage 3. Multivariate logistic regression analysis showed that longer disease duration, lower albumin level, and methylprednisolone pulse treatment were significantly associated with AKI development in hospitalized children with NS. AKI was associated with a longer hospital stay than non-AKI (median 10 vs. 7 days, P = 0.001). Among 93 admissions, 85 (91.4%) episodes recovered from AKI without complication, whereas 6 (6.5%) progressed to advanced chronic kidney disease (CKD). CONCLUSIONS: AKI is not uncommon in hospitalized children with NS, and its incidence in this nationwide study was 16.2%. Risk factors for AKI in hospitalized children with NS include longer disease duration, lower albumin level, and methylprednisolone pulse therapy. Pediatric NS patients with these characteristics should be under more strict scrutiny for the occurrence of AKI. Graphical abstract.

First Case of Peroxisomal D-bifunctional Protein Deficiency with Novel HSD17B4 Mutations and Progressive Neuropathy in Korea.

Peroxisomal D-bifunctional protein (DBP), encoded by the HSD17B4 gene, catalyzes ß-oxidation of very long chain fatty acids (VLCFAs). The deficiency of this peroxisomal enzyme leads to the accumulation of VLCFAs, causing multisystemic manifestations including the brain, retina, adrenal gland, hearing, and skeletal system. Herein, we report the first Korean neonatal case of peroxisomal DBP deficiency and the clinical prognosis over 2 years. This patient showed craniofacial dysmorphism, club foot, and seizures with cyanosis one day after birth. Elevated VLCFAs levels were indicative of a peroxisomal disorder. Targeted exome sequencing was performed and two missense mutations p.Asp117Val and p.Phe279Ser in the HSD17B4 gene were identified. The patient had type III DBP deficiency; therefore, docosahexaenoic acid and non-soluble vitamins were administered. However, progressive nystagmus, optic nerve atrophy, and bilateral hearing defects were observed and follow-up brain imaging revealed leukodystrophy and brain atrophy. Multiple anti-epileptic drugs were required to control the seizures. Over two years, the patient achieved normal growth with home ventilation and tube feeding. Hereby, the subject's parents had support during the second pregnancy from the proven molecular information. Moreover, targeted exome sequencing is an effective diagnostic approach, considering genetic heterogeneity of Zellweger spectrum disorders.

Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome: A systematic review.

BACKGROUND: Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a monogenic disorder characterized by early onset fatal multi-system autoimmunity due to loss-of-function mutations in the gene encoding the forkhead box P3 (FOXP3) transcription factor which is crucial for the development, maturation, and maintenance of CD4+ regulatory T (T-reg) cells. Various autoimmune phenomena such as enteropathy, endocrinopathies, cytopenias, renal disease, and skin manifestations are characteristic findings in patients affected by IPEX syndrome. OBJECTIVES: In this systematic review, we focus on both clinical and demographic characteristics of IPEX patients, highlighting possible genotype-phenotype correlations and address prognostic factors for disease outcome. METHODS: We performed a literature search to systematically investigate the case reports of IPEX which were published before August 7th, 2017. RESULTS: A total of 75 articles (195 patients) were identified. All IPEX patients included had FOXP3 mutations which were most frequently located in the forkhead domain (n = 68, 34.9%) followed by the leucine-zipper domain (n = 30, 15.4%) and repressor domain (n = 36, 18.4%). Clinical manifestations were as follows: enteropathy (n = 191, 97.9%), skin manifestations (n = 121, 62.1%), endocrinopathy (n = 104, 53.3%), hematologic abnormalities (n = 75, 38.5%), infections (n = 78, 40.0%), other immune-related complications (n = 43, 22.1%), and renal involvement (n = 32, 16.4%). Enteropathic presentations (P = 0.017), eczema (P = 0.030), autoimmune hemolytic anemia (P = 0.022) and food allergy (P = 0.009) were associated with better survival, while thrombocytopenia (P = 0.034), septic shock (P = 0.045) and mutations affecting the repressor domain (P = 0.021), intron 7 (P = 0.033) or poly A sequence (P = 0.025) were associated with increased risk of death. Immunosuppressive therapy alone was significantly associated with increased cumulative survival compared to patients who received no treatment (P = 0.041). CONCLUSIONS: We report the most comprehensive summary of demographic and clinical profiles derived from a total of 195 IPEX patients with deleterious mutations in FOXP3. Analysis of our findings provides new insights into genotype/phenotype correlations, and clinical and genetic factors associated with increased risk of death and response to treatment strategies.

Corrigendum to "Association between Serum Matrix Metalloproteinase- (MMP-) 3 Levels and Systemic Lupus Erythematosus: A Meta-Analysis".

[This corrects the article DOI: 10.1155/2019/9796735.].

Review on long-term non-renal complications of childhood nephrotic syndrome.

BACKGROUND: Nephrotic syndrome (NS) is the most common glomerular childhood disease. A body of literature has described the long-term renal prognosis of childhood-onset idiopathic NS. However, the nonrenal outcomes have not been studied as much. AIM: We aimed to discuss the long-term non-renal outcomes of childhood NS, highlighting studies with a follow-up period of more than 10 years. RESULTS: We reviewed the literature and found that a number of immunosuppressive agents have stopped inflammation, stabilised the podocyte cytoskeleton and reduce proteinuria. However, prolonged treatment has frequently been associated with a high risk of renal and non-renal complications in patients with a complicated disease course, defined as frequent relapses or steroid dependency. Non-renal complications may include impaired longitudinal growth and pubertal development, undesirable fertility outcomes, ocular complications, bone mineral diseases and potential malignancies. CONCLUSION: This review discusses and summarises the non-renal outcomes of idiopathic childhood NS.

Association between Serum Matrix Metalloproteinase- (MMP-) 3 Levels and Systemic Lupus Erythematosus: A Meta-analysis.

INTRODUCTION: Matrix metalloproteinase (MMP) is an emerging disease marker in rheumatic diseases. This is a meta-analysis aimed at systematically reviewing association between serum MMP-3 levels and systematic lupus erythematosus (SLE) activity, which sought to raise interest in MMP-3 as a putative biomarker. METHODS: We conducted a meta-analysis of serum MMP-3 levels in patients with SLE and controls. We performed a PubMed search, EMBASE search, and forward search of the retrieved articles published until Oct. 1, 2018. In addition to this, we included data from a case-control study on a national pediatric SLE cohort, in which serum MMP-3 levels were measured in 11 SLE patients and 9 controls (unpublished). Subgroup analyses based on gender and disease activity were performed. RESULTS: A total of 662 cases and 771 controls including 651 patients and 762 controls from 11 publications were studied. We observed significantly higher MMP-3 levels in SLE patients compared to healthy controls (P < 0.001, Hedges' g: 2.104, 95% CI 1.426-2.782). In subgroup analyses, we found a significant elevation of MMP-3 in the patients with nephritis compared to those without (P = 0.006, Hedges' g: 0.611, 95% CI 0.611-1.704). This finding was consistent between patients with persistent proteinuria and those without (P = 0.023, Hedges' g: 1.535, 95% CI 0.207-2.862). Meta-analysis showed no association between MMP-3 levels and gender or anti-double strand DNA antibody titer. CONCLUSIONS: Our meta-analysis demonstrated significantly higher MMP-3 levels in SLE patients than in controls and in patients with renal involvement than in those without.

Inflammasomes and autoimmune and rheumatic diseases: A comprehensive review.

Inflammasomes are a multi-protein platform forming a part of the innate immune system. Inflammasomes are at standby status and can be activated when needed. Inflammasome activation is an important mechanism for the production of active interleukin (IL)-1ß and IL-18, which have important roles to instruct adaptive immunity. Active forms of inflammasomes trigger a series of inflammatory cascades and lead to the differentiation and polarization of naïve T cells and secretion of various cytokines, which can induce various kinds of autoimmune and rheumatic diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), gout, Sjögren's syndrome, Behçet's disease, anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis and IgA vasculitis (former Henoch-Schönlein purpura ). In this review, we summarize studies published on inflammasomes and review their roles in various autoimmune diseases. Understanding of the role of inflammasomes may facilitate the diagnosis of autoimmune diseases and the development of tailored therapies in the future.

Levamisole in Children with Idiopathic Nephrotic Syndrome: Clinical Efficacy and Pathophysiological Aspects.

Steroid sensitive nephrotic syndrome is one of the most common pediatric glomerular diseases. Unfortunately, it follows a relapsing and remitting course in the majority of cases, with 50% of all cases relapsing once or even more often. Most children with idiopathic nephrotic syndrome respond initially to steroid therapy, nevertheless repeated courses for patients with relapses induce significant steroid toxicity. Patients with frequent relapses or steroid dependency thus require alternative treatment, such as cyclophosphamide, cyclosporine, tacrolimus, mycophenolate mofetil, levamisole, or rituximab. To reduce the relapse rate, several drugs have been used. Among these, levamisole has been considered the least toxic and least expensive therapy. Several randomized controlled trials (RCT) showed that levamisole is effective in reducing the relapse risk in steroid sensitive forms of nephrotic syndrome with a low frequency of side effects. Levamisole is a synthetic imidazothiazole derivative with immune-modulatory properties. In this article, we review recent data from randomized trials and observational studies to assess the efficacy of levamisole in frequently relapsing nephrotic syndrome and steroid-dependent nephrotic syndrome.

Increased Serum Soluble Urokinase-Type Plasminogen Activator Receptor (suPAR) Levels in FSGS: A Meta-Analysis.

INTRODUCTION: The soluble urokinase-type plasminogen activator receptor (suPAR) has been found to be elevated in primary focal segmental glomerulosclerosis (pFSGS). However, its usefulness as a biomarker for FSGS remains controversial. We conducted a meta-analysis aiming at investigating the significance of suPAR in diagnosing pFSGS. METHODS: Electronic databases (PubMed and EMBASE) were searched to identify studies comparing suPAR levels in FSGS patients and controls, from the earliest available date to May 1, 2018. A random-effects model with standardized mean difference (SMD) was used for meta-analyses. Risk of bias was assessed using the Newcastle-Ottawa quality assessment scale. RESULTS: A total of 187 articles were screened, and the final analysis included 13 articles. In comparison to healthy controls, serum suPAR levels were significantly increased in pFSGS patients (SMD, 1.07, 95% confidence interval (CI) 0.65 to 1.48; participants = 814; studies = 9, I 2 = 85%). Higher suPAR levels were also found in patients with pFSGS compared to those with minimal change disease (SMD 0.53, 95% CI 0.22 to 0.84). Of note, such a difference was not found in pediatric groups (SMD 0.42, 95% CI -0.13 to 0.96) while it was more evidently noted in adult patients (SMD 1.32, 95% CI 0.90 to 1.74). Serum suPAR levels did not differ between pFSGS patients in remission compared to those in active proteinuric state (SMD 0.29, 95% CI -0.30 to 0.88). Comparison with membranous nephropathy and IgA nephropathy showed no significant difference. CONCLUSIONS: Our meta-analysis demonstrated that, in comparison to both healthy controls and controls with minimal change disease, suPAR levels were significantly higher in adult patients with pFSGS. suPAR levels did not differ between pFSGS patients during the initial period of diagnosis and those in remission.

Features of Autosomal Recessive Alport Syndrome: A Systematic Review.

Alport syndrome (AS) is one of the most frequent hereditary nephritis leading to end-stage renal disease (ESRD). Although X-linked (XLAS) inheritance is the most common form, cases with autosomal recessive inheritance with mutations in COL4A3 or COL4A4 are being increasingly recognized. A systematic review was conducted on autosomal recessive Alport syndrome (ARAS). Electronic databases were searched using related terms (until Oct 10th, 2018). From 1601 articles searched, there were 26 eligible studies with 148 patients. Female and male patients were equally affected. About 62% of patients had ESRD, 64% had sensorineural hearing loss (SNHL) and 17% had ocular manifestation. The median at onset was 2.5 years for hematuria (HU), 21 years for ESRD, and 13 years for SNHL. Patients without missense mutations had more severe outcomes at earlier ages, while those who had one or two missense mutations had delayed onset and lower prevalence of extrarenal manifestations. Of 49 patients with kidney biopsy available for electron microscopy (EM) pathology, 42 (86%) had typical glomerular basement membrane (GBM) changes, while 5 (10%) patients showed GBM thinning only. SNHL developed earlier than previously reported. There was a genotype phenotype correlation according to the number of missense mutations. Patients with missense mutations had delayed onset of hematuria, ESRD, and SNHL and lower prevalence of extrarenal manifestations.

Rapid-Onset Obesity with Hypoventilation, Hypothalamic, Autonomic Dysregulation, and Neuroendocrine Tumors (ROHHADNET) Syndrome: A Systematic Review.

BACKGROUND AND AIM: ROHHADNET (rapid-onset obesity with hypoventilation, hypothalamic, autonomic dysregulation, neuroendocrine tumor) syndrome is a rare disease with grave outcome. Although early recognition is essential, prompt diagnosis may be challenging due to its extreme rarity. This study aimed to systematically review its clinical manifestation and to identify genetic causes. MATERIALS AND METHODS: We firstly conducted a systematic review on ROHHAD/NET. Electronic databases were searched using related terms. We secondly performed whole exome sequencing (WES) and examined copy number variation (CNV) in two patients to identify genetic causes. RESULTS: In total, 46 eligible studies including 158 patients were included. There were 36 case reports available for individual patient data (IPD; 48 patients, 23 ROHHAD, and 25 ROHHADNET) and 10 case series available for aggregate patient data (APD; 110 patients, 71 ROHHAD, and 39 ROHHADNET). The median age at onset calculated from IPD was 4 years. Gender information was available in 100 patients (40 from IPD and 60 from APD) in which 65 females and 35 males were showing female preponderance. Earliest manifestation was rapid obesity, followed by hypothalamic symptoms. Most common types of neuroendocrine tumors were ganglioneuromas. Patients frequently had dysnatremia and hyperprolactinemia. Two patients were available for WES. Rare variants were identified in PIK3R3, SPTBN5, and PCF11 in one patient and SRMS, ZNF83, and KMT2B in another patient, respectively. However, there was no surviving variant shared by the two patients after filtering. CONCLUSIONS: This study systematically reviewed the phenotype of ROHHAD/NET aiming to help early recognition and reducing morbidity. The link of variants identified in the present WES requires further investigation.

Delayed transplantation may affect intellectual ability in children.

BACKGROUND: Decline in neurocognitive function is a reported complication in children with chronic illness. Concerns have been increasing that exposure to a major surgery or trauma may negatively affect cognitive performance in children. This study evaluated cognitive function in 43 Korean children who received organ transplantation (Tx), and sought to identify associated clinical factors. METHODS: Pediatric recipients of kidney (KT) or liver Tx (LT) from 1999 to 2011 were recruited for cognitive tests. Cognitive function was evaluated using intelligence quotient (IQ), social quotient (SQ), and Continuous Performance Test using Advanced Test for Attention scores, which reflect attention ability. Intellectual delay was graded as intellectual disability (ID; IQ <70) or low intelligence (LI; IQ<85). Diagnosis for attention-deficit-hyperactivity disorder (ADHD) was made by pediatric psychiatrists. RESULTS: The subjects consisted of 43 pediatric recipients of 28 LT and 15 KT. There were 20 boys (46.5%). Median age was 3.1 years (range, 0.5-15.3 years) at Tx. Median age at cognitive evaluation was 12.9 years (range, 3.4-18.4 years). Median pre-Tx duration of illness was 1.6 years (range, 0-13.5 years). The prevalence of ID, LI, and ADHD was 11.6%, 32.5%, and 32.5%, respectively. On multivariate analysis, longer pre-Tx duration of illness was a significant factor for LI (OR, 1.263; 95%CI: 1.033-1.544, P = 0.023). CONCLUSION: Longer pre-Tx duration may negatively affect intellectual ability in Korean children. Pre-Tx duration was more significant than the age at Tx or total disease duration per se. Early Tx may be beneficial for cognitive function in children.