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Objectives: We assessed the children with complex heart anomalies who undergone operative intervention of any form of Fontan intervention and analyzed them for thromboembolic complications after Fontan procedure performed at the Pediatric Clinic of Pristina.Background: Thromboembolic complications are a major cause of early and late mortality in children with single-ventricle congenital heart defects who have undergone a Fontan procedure.Thrombosis is an important and unpredictable complication, not only after Fontan operation but also associated with each stage of single-ventricle palliation. It is an important cause of morbidity, particularly when it leads to pulmonary embolism or stroke, and contributes to mortality.Methodology: The research was conducted at the Pediatric Clinic in the Cardiology and Intensive Care Service, during 2018-2021. The study includes patients who have undergone tertiary level intervention - one of the forms of the Fontan procedure, the research included 40 patients aged 0 -19 years. The children were divided into two groups: the group 29 patients using Aspirin therapy and the group of 11 patients without Aspirin therapy. In children after admission, laboratory tests were performed: hemogram, bleeding time, coagulation time, INR, PTT, and PT.Results: The mean age of children with antithrombotic therapy was 6.03 years (DS ± 5.84 years), those without therapy 3.27 years (DS ± 5.44 years). Aspirin as antithrombotic therapy was applied to 29 patients at a dose of 15 to 115 mg / 24 hours. In 6 patients the dose was less than 3-5 mg / kg body weight.Thepatients with congenital heart malformations after Fontan procedure receiving antithrombotic therapy are 1.4 times more likely to have reduced prothrombin time.Conclusions: Fontan procedure in children has been gratifying, with most survivors now leading lives of good quality into adulthood.

Most patients with congenital anomalies of the kidney and urinary tract (CAKUT) remain genetically unexplained. In search of novel genes associated with CAKUT in humans, we applied whole-exome sequencing in a patient with kidney, anorectal, spinal, and brain anomalies, and identified a rare heterozygous missense variant in the DACT1 (dishevelled binding antagonist of beta catenin 1) gene encoding a cytoplasmic WNT signaling mediator. Our patient’s features overlapped Townes–Brocks syndrome 2 (TBS2) previously described in a family carrying a DACT1 nonsense variant as well as those of Dact1-deficient mice. Therefore, we assessed the role of DACT1 in CAKUT pathogenesis. Taken together, very rare (minor allele frequency ≤ 0.0005) non-silent DACT1 variants were detected in eight of 209 (3.8%) CAKUT families, significantly more frequently than in controls (1.7%). All seven different DACT1 missense variants, predominantly likely pathogenic and exclusively maternally inherited, were located in the interaction region with DVL2 (dishevelled segment polarity protein 2), and biochemical characterization revealed reduced binding of mutant DACT1 to DVL2. Patients carrying DACT1 variants presented with kidney agenesis, duplex or (multi)cystic (hypo)dysplastic kidneys with hydronephrosis and TBS2 features. During murine development, Dact1 was expressed in organs affected by anomalies in patients with DACT1 variants, including the kidney, anal canal, vertebrae, and brain. In a branching morphogenesis assay, tubule formation was impaired in CRISPR/Cas9-induced Dact1−/− murine inner medullary collecting duct cells. In summary, we provide evidence that heterozygous hypomorphic DACT1 variants cause CAKUT and other features of TBS2, including anomalies of the skeleton, brain, distal digestive and genital tract.

Recent advances in the management of kidney tubular diseases have resulted in a significant cohort of adolescents and young adults transitioning from pediatric- to adult-focused care. Most of the patients under adult-focused care have glomerular diseases, whereas rarer tubular diseases form a considerable proportion of pediatric patients. The purpose of this review is to highlight the clinical signs and symptoms of tubular disorders, as well as their diagnostic workup, including laboratory findings and imaging, during young adulthood. We will then discuss more common disorders such as cystinosis, cystinuria, distal kidney tubular acidosis, congenital nephrogenic diabetes insipidus, Dent disease, rickets, hypercalciuria, and syndromes such as Bartter, Fanconi, Gitelman, Liddle, and Lowe. This review is a practical guide on the diagnostic and therapeutic approach of tubular conditions affecting young adults who are transitioning to adult-focused care.

BACKGROUND: Spina bifida (SB) is the second most common nonlethal congenital malformation. The existence of monogenic SB mouse models and human monogenic syndromes with SB features indicate that human SB may be caused by monogenic genes. We hypothesized that whole exome sequencing (WES) allows identification of potential candidate genes by i) generating a list of 136 candidate genes for SB, and ii) by unbiased exome-wide analysis. METHODS: We generated a list of 136 potential candidate genes from three categories: and evaluated WES data of 50 unrelated SB cases for likely deleterious variants in 136 potential candidate genes, and for potential SB candidate genes exome-wide. RESULTS: We identified 6 likely deleterious variants in 6 of the 136 potential SB candidate genes in 6 of the 50 SB cases, whereof 4 genes were derived from mouse models, 1 gene was derived from human non-syndromic SB, and 1 gene was derived from candidate genes known to cause human syndromic SB. In addition, by unbiased exome-wide analysis, we identified 12 genes as potential candidates for SB. CONCLUSIONS: Identification of these 18 potential candidate genes in larger SB cohorts will help decide which ones can be considered as novel monogenic causes of human SB.

Os sistemas nacionais de cuidados de saúde infantil são caracterizados por sua diversidade e complexidade. Os serviços de atenção à saúde primários, secundários, terciários e quaternários criam redes complexas que abrangem subespecialidades pediátricas, psicologia, sociologia, econômicas e políticas. A pediatria pode existir sem filosofia? (Pediatras poderiam existir sem filosofia?) A ausência de perspectivas filosóficas integradoras na conceituação da assistência pediátrica contribui para deficiências nos sistemas de atendimento que estruturam a atenção ao cuidado da saúde da criança? A filosofia oferece novos modos de um sistema complexo de pensamento na pediatria científica e clínica. A filosofia pode melhorar as estratégias de enfrentamento em diferentes níveis quando se está lidando com ética em projetos de pesquisa, assistência ao cuidado de saúde individual da criança e crises dos sistemas de serviços de saúde. Situações limites e finais experenciadas por crianças severamente doentes requerem ajuda, esperança e resiliência. Pacientes e familiares, assim como pediatras e outros cuidadores, devem agir em conjunto. Todos podem se beneficiar com a consulta de um filósofo. O objetivo desse artigo é apontar o risco de uma separação estrita entre o discernimento científico e a experiencia sensorial, o que afeta o cuidado à saúde da criança na nossa sociedade moderna, que é dominada pela tecnologia, competição e falta de equidade e tempo.

Introduction: Atypical hemolytic uremic syndrome (aHUS) is a rare form of thrombotic microangiopathy, caused by dysregulation of the complement alternative pathway. Deletion of the complement factor H–related genes, CFHR1 and CFHR3, together with the presence of CFH autoantibodies are reported in aHUS patients, representing 10% of cases of patients with aHUS. Case presentation: We report here on a case of 4-year-old girl with anti-CFH antibody-associated aHUS. The measurement of complement factors and anti-factor H antibodies, was the main guideline for making an accurate diagnosis and providing the appropriate therapy, with the patient responding positively to plasma exchanges (PEs) and cyclophosphamide pulses. We then, one year after disease onset, continued with glucocorticoids and mycophenolate mofetil (MMF), as maintenance therapy. There were no complications during the therapy other than neutropenia. Now, one year after the cessation of the immune suppression therapy, she is in remission with normal kidney function, no signs of hemolysis, normal C3 levels, and normal range proteinuria. The anti-factor H autoantibody titer decreased but still remained positive, the factor H antigen values remained low all throughout. Close follow-up is applied with frequent urine testing and complete blood count with an intention for early detection of relapse of the disease. Conclusion: The purpose of this case report is to emphasize the value of complement factor measurements and also to separate anti-CFH antibody-associated aHUS as an entity, because immunosuppressive therapy provides an excellent response..

Individuals with congenital anomalies of the kidney and urinary tract (CAKUT) show a broad spectrum of malformations. CAKUT can occur in an isolated fashion or as part of a syndromic disorder and can lead to end-stage kidney failure. A monogenic cause can be identified in approximately 12% of affected individuals. This study investigated a single-center CAKUT cohort analyzed by exome sequencing (ES). Emphasis was placed on the question whether diagnostic yield differs between certain CAKUT phenotypes (e.g., bilateral kidney affection, unilateral kidney affection or only urinary tract affection). 86 unrelated individuals with CAKUT were categorized according to their phenotype and analyzed by ES to identify a monogenic cause. Prioritized variants were rated according to recommendations of the American College of Medical Genetics and Genomics and the Association for Clinical Genomic Science. Diagnostic yields of different phenotypic categories were compared. Clinical data were collected using a standardized questionnaire. In the study cohort, 7/86 individuals had a (likely) pathogenic variant in the genes PAX2, PBX1, EYA1 or SALL1. Additionally, in one individual, a 17q12 deletion syndrome (including HNF1B) was detected. 62 individuals had a kidney affection, which was bilateral in 36. All solved cases (8/86, 9%) had bilateral kidney affection (diagnostic yield in subcohort: 8/36, 22%). Although the diagnostic yield in CAKUT cohorts is low, our single-center experience argues, that, in individuals with bilateral kidney affection, monogenic burden is higher than in those with unilateral kidney or only urinary tract affection.

Pediatric steroid-sensitive nephrotic syndrome (pSSNS) is the most common childhood glomerular disease. Previous genome-wide association studies (GWAS) identified a risk locus in the HLA Class II region and three additional signals. But the genetic architecture of pSSNS, and its genetically driven pathobiology, is largely unknown. We conducted a multi-population GWAS meta-analysis in 38,463 participants (2,440 cases) and population specific GWAS, discovering twelve significant associations (eight novel). Fine-mapping implicated specific amino acid haplotypes in HLA-DQA1 and HLA-DQB1 driving the HLA Class II risk signal. Non-HLA loci colocalized with eQTLs of monocytes and numerous T-cell subsets in independent datasets. Colocalization with kidney eQTLs was lacking, but overlap with kidney cell open chromatin suggests an uncharacterized disease mechanism in kidney cells. A polygenic risk score (PRS) associated with earlier disease onset in two independent cohorts. Altogether, these discoveries expand our knowledge of pSSNS genetic architecture across populations and provide cellspecific insights into its molecular drivers.

© 2021 American College of Medical Genetics and GenomicsPurpose: We aimed to investigate the molecular basis underlying a novel phenotype including hypopituitarism associated with primary ovarian insufficiency. Methods: We used next-generation sequencing to identify variants in all pedigrees. Expression of Rnpc3/RNPC3 was analyzed by in situ hybridization on murine/human embryonic sections. CRISPR/Cas9 was used to generate mice carrying the p.Leu483Phe pathogenic variant in the conserved murine Rnpc3 RRM2 domain. Results: We described 15 patients from 9 pedigrees with biallelic pathogenic variants in RNPC3, encoding a specific protein component of the minor spliceosome, which is associated with a hypopituitary phenotype, including severe growth hormone (GH) deficiency, hypoprolactinemia, variable thyrotropin (also known as thyroid-stimulating hormone) deficiency, and anterior pituitary hypoplasia. Primary ovarian insufficiency was diagnosed in 8 of 9 affected females, whereas males had normal gonadal function. In addition, 2 affected males displayed normal growth when off GH treatment despite severe biochemical GH deficiency. In both mouse and human embryos, Rnpc3/RNPC3 was expressed in the developing forebrain, including the hypothalamus and Rathke's pouch. Female Rnpc3 mutant mice displayed a reduction in pituitary GH content but with no reproductive impairment in young mice. Male mice exhibited no obvious phenotype. Conclusion: Our findings suggest novel insights into the role of RNPC3 in female-specific gonadal function and emphasize a critical role for the minor spliceosome in pituitary and ovarian development and function.

Nephrolithiasis (NL) affects 1 in 11 individuals worldwide, leading to significant patient morbidity. NL is associated with nephrocalcinosis (NC), a risk factor for chronic kidney disease. Causative genetic variants are detected in 11-28% of NL and/or NC, suggesting additional NL/NC-associated genetic loci await discovery. Therefore, we employed genomic approaches to discover novel genetic forms of NL/NC.Exome sequencing and directed sequencing of the OXGR1 locus were performed in a worldwide NL/NC cohort. Putatively deleterious rare OXGR1 variants were functionally characterized.Exome sequencing revealed a heterozygous OXGR1 missense variant (c.371TG, p.L124R) co-segregating with calcium oxalate NL and/or NC disease in an autosomal dominant inheritance pattern within a multi-generational family with five affected individuals. OXGR1 encodes 2-oxoglutarate (α-ketoglutarate) receptor 1 in the distal nephron. In response to its ligand α-ketoglutarate (AKG), OXGR1 stimulates the chloride-bicarbonate exchanger Pendrin, which also regulates transepithelial calcium transport in cortical connecting tubules. Strong amino acid conservation in orthologues and paralogues, severe in silico prediction scores, and extreme rarity in exome population databases suggested the variant was deleterious. Interrogation of the OXGR1 locus in 1107 additional NL/NC families identified five additional deleterious dominant variants in five families with calcium oxalate NL/NC. Rare, potentially deleterious OXGR1 variants were enriched in NL/NC subjects relative to ExAC controls (ΧRare, dominant loss-of-function OXGR1 variants are associated with recurrent calcium oxalate NL/NC disease.

Aim: Multiple stakeholders are involved in achieving Universal Health Coverage (UHC) as part of the Sustainable Development Goals (SDG). The estimated over 90 million children with disabilities are among the most vulnerable members of the world’s population. Paediatricians around the world are united to promote a world where all children, regardless of their abilities or disabilities, can enjoy a healthy life and well-being. We examined: ‘What would be the least paediatricians could do to contribute to the UHC?’Methods: In cross-sectional study paediatricians, engaged in care for children with disabling and rare conditions, were questioned on eight of the UHC statements concerning child health, primary care services, availability and affordability of diagnostics and therapies and digital health; as well as country of residence and level of practice.Results: Responders from Europe and Israel, Asia and the US practice at primary-, secondary- and tertiary care level in high and middle economy countries. Promotion of paediatric primary care could reduce mortality and morbidity, according to 39/48 (81%) respondents. An active role of paediatricians in providing quality information would increase access to health services for children with disabilities, according to 40/48 (83%) responders. Improved data exchange is necessary to deliver primary care as a cornerstone, according to 38/48 (79%) responders. Respondents practising in middle economy countries reported significantly more frequently than their colleagues in high economies countries about “out of pocket” payments for diagnostics and therapies as well as reduced availability. In order to increase global awareness and international solidarity, a panel of participants in a paediatric network felt that paediatricians should undertake necessary actions to support the achievement of UHC.Conclusion: The economic gap in diagnostic and therapeutic facilities in paediatric practice should be considered in achieving UHC. An international paediatric network should support achieving the UHC by providing adequate paediatric training and quality (digital) information.

BackgroundCilia are dynamic cellular extensions that generate and sense signals to orchestrate proper development and tissue homeostasis. They rely on the underlying polarisation of cells to participate in signalling. Cilia dysfunction is a well-known cause of several diseases that affect multiple organ systems including the kidneys, brain, heart, respiratory tract, skeleton and retina.MethodsAmong individuals from four unrelated families, we identified variants in discs large 5 (DLG5) that manifested in a variety of pathologies. In our proband, we also examined patient tissues. We depleted dlg5 in Xenopus tropicalis frog embryos to generate a loss-of-function model. Finally, we tested the pathogenicity of DLG5 patient variants through rescue experiments in the frog model.ResultsPatients with variants of DLG5 were found to have a variety of phenotypes including cystic kidneys, nephrotic syndrome, hydrocephalus, limb abnormalities, congenital heart disease and craniofacial malformations. We also observed a loss of cilia in cystic kidney tissue of our proband. Knockdown of dlg5 in Xenopus embryos recapitulated many of these phenotypes and resulted in a loss of cilia in multiple tissues. Unlike introduction of wildtype DLG5 in frog embryos depleted of dlg5, introduction of DLG5 patient variants was largely ineffective in restoring proper ciliation and tissue morphology in the kidney and brain suggesting that the variants were indeed detrimental to function.ConclusionThese findings in both patient tissues and Xenopus shed light on how mutations in DLG5 may lead to tissue-specific manifestations of disease. DLG5 is essential for cilia and many of the patient phenotypes are in the ciliopathy spectrum.

International audience; Congenital anomalies of the kidney and urinary tract (CAKUT) constitute one of the most frequent birth defects and represent the most common cause of chronic kidney disease in the first three decades of life. Despite the discovery of dozens of monogenic causes of CA-KUT, most pathogenic pathways remain elusive. We performed whole-exome sequencing (WES) in 551 individuals with CAKUT and identified a heterozygous de novo stop-gain variant in ZMYM2 in two different families with CAKUT. Through collaboration, we identified in total 14 different heterozygous loss-of-function mutations in ZMYM2 in 15 unrelated families. Most mutations occurred de novo, indicating possible interference with reproductive function. Human disease features are replicated in X. tropicalis larvae with morpho-lino knockdowns, in which expression of truncated ZMYM2 proteins, based on individual mutations, failed to rescue renal and cranio-facial defects. Moreover, heterozygous Zmym2-deficient mice recapitulated features of CAKUT with high penetrance. The ZMYM2 protein is a component of a transcriptional corepressor complex recently linked to the silencing of developmentally regulated endoge-nous retrovirus elements. Using protein-protein interaction assays, we show that ZMYM2 interacts with additional epigenetic silencing complexes, as well as confirming that it binds to FOXP1, a transcription factor that has also been linked to CAKUT. In summary, our findings establish that loss-of-function mutations of ZMYM2, and potentially that of other proteins in its interactome, as causes of human CAKUT, offering new routes for studying the pathogenesis of the disorder.

Congenital anomalies of the kidney and urinary tract (CAKUT) are the most common cause of chronic kidney disease in the first three decades of life, and in utero obstruction to urine flow is a frequent cause of secondary upper urinary tract malformations. Here, using whole-exome sequencing, we identified three different biallelic mutations in CHRNA3, which encodes the α3 subunit of the nicotinic acetylcholine receptor, in five affected individuals from three unrelated families with functional lower urinary tract obstruction and secondary CAKUT. Four individuals from two families have additional dysautonomic features, including impaired pupillary light reflexes. Functional studies in vitro demonstrated that the mutant nicotinic acetylcholine receptors were unable to generate current following stimulation with acetylcholine. Moreover, the truncating mutations p.Thr337Asnfs(∗)81 and p.Ser340(∗) led to impaired plasma membrane localization of CHRNA3. Although the importance of acetylcholine signaling in normal bladder function has been recognized, we demonstrate for the first time that mutations in CHRNA3 can cause bladder dysfunction, urinary tract malformations, and dysautonomia. These data point to a pathophysiologic sequence by which monogenic mutations in genes that regulate bladder innervation may secondarily cause CAKUT.

Renal hypouricemia (RHUC) is caused by an inherited defect in the main reabsorption system of uric acid, SLC22A12 (URAT1) and SLC2A9 (GLUT9). RHUC is characterized by a decreased serum uric acid concentration and an increase in its excreted fraction. Patients suffer from hypouricemia, hyperuricosuria, urolithiasis, and even acute kidney injury. We report clinical, biochemical, and genetic findings in a cohort recruited from the Košice region of Slovakia consisting of 27 subjects with hypouricemia and relatives from 11 families, 10 of whom were of Roma ethnicity. We amplified, directly sequenced, and analyzed all coding regions and exon–intron boundaries of the SLC22A12 and SLC2A9 genes. Sequence analysis identified dysfunctional variants c.1245_1253del and c.1400C&gt, T in the SLC22A12 gene, but no other causal allelic variants were found. One heterozygote and one homozygote for c.1245_1253del, nine heterozygotes and one homozygote for c.1400C&gt, T, and two compound heterozygotes for c.1400C&gt, T and c.1245_1253del were found in a total of 14 subjects. Our result confirms the prevalence of dysfunctional URAT1 variants in Roma subjects based on analyses in Slovak, Czech, and Spanish cohorts, and for the first time in a Macedonian Roma cohort. Although RHUC1 is a rare inherited disease, the frequency of URAT1-associated variants indicates that this disease is underdiagnosed. Our findings illustrate that there are common dysfunctional URAT1 allelic variants in the general Roma population that should be routinely considered in clinical practice as part of the diagnosis of Roma patients with hypouricemia and hyperuricosuria exhibiting clinical signs such as urolithiasis, nephrolithiasis, and acute kidney injury.

BackgroundCongenital anomalies of the kidneys and urinary tract (CAKUT) constitute the most common cause of chronic kidney disease in the first three decades of life. Variants in four Forkhead box (FOX) transcription factors have been associated with CAKUT. We hypothesized that other FOX genes, if highly expressed in developing kidneys, may also represent monogenic causes of CAKUT.MethodsWe here performed whole-exome sequencing (WES) in 541 families with CAKUT and generated four lists of CAKUT candidate genes: (A) 36 FOX genes showing high expression during renal development, (B) 4 FOX genes known to cause CAKUT to validate list A, (C) 80 genes that we identified as unique potential novel CAKUT candidate genes when performing WES in 541 CAKUT families and (D) 175 genes identified from WES as multiple potential novel CAKUT candidate genes.ResultsTo prioritize potential novel CAKUT candidates in the FOX gene family, we overlapped 36 FOX genes (list A) with lists C and D of WES-derived CAKUT candidates. Intersection with list C identified a de novo FOXL2 in-frame deletion in a patient with eyelid abnormalities and ureteropelvic junction obstruction, and a homozygous FOXA2 missense variant in a patient with horseshoe kidney. Intersection with list D identified a heterozygous FOXA3 missense variant in a CAKUT family with multiple affected individuals.ConclusionsWe hereby identified FOXL2, FOXA2 and FOXA3 as novel monogenic candidate genes of CAKUT, supporting the utility of a paralog-based approach to discover mutated genes associated with human disease.

Purpose Congenital anomalies of the kidneys and urinary tract (CAKUT) constitute the leading cause of chronic kidney disease in children. In total, 174 monogenic causes of isolated or syndromic CAKUT are known. However, syndromic features may be overlooked when the initial clinical diagnosis of CAKUT is made. We hypothesized that the yield of a molecular genetic diagnosis by exome sequencing (ES) can be increased by applying reverse phenotyping, by re-examining the case for signs/symptoms of the suspected clinical syndrome that results from the genetic variant detected by ES. Methods We conducted ES in an international cohort of 731 unrelated families with CAKUT. We evaluated ES data for variants in 174 genes, in which variants are known to cause isolated or syndromic CAKUT. In cases in which ES suggested a previously unreported syndromic phenotype, we conducted reverse phenotyping. Results In 83 of 731 (11.4%) families, we detected a likely CAKUT-causing genetic variant consistent with an isolated or syndromic CAKUT phenotype. In 19 of these 83 families (22.9%), reverse phenotyping yielded syndromic clinical findings, thereby strengthening the genotype–phenotype correlation. Conclusion We conclude that employing reverse phenotyping in the evaluation of syndromic CAKUT genes by ES provides an important tool to facilitate molecular genetic diagnostics in CAKUT.

Distal renal tubular acidosis (dRTA) is characterized by an impaired ability of the distal tubule to excrete acid, leading to metabolic acidosis. Associated complications include bone disease, growth failure, urolithiasis and hypokalaemia. Due to its rarity, there is limited evidence to guide diagnosis and management; however, available data strongly suggest that metabolic control of the acidosis by alkali supplementation can halt or revert almost all complications. Despite this, cohort studies show that adequate metabolic control is present in only about half of patients, highlighting problems with treatment provision or adherence. With these clinical practice points the authors, part of the working groups tubulopathies in the European Rare Kidney Disease Reference network and inherited kidney diseases of the European Society for Paediatric Nephrology, aim to provide guidance for the management of patients with dRTA to facilitate adequate treatment and establish an initial best practice standard against which treatment of patients can be audited. ispartof: NEPHROLOGY DIALYSIS TRANSPLANTATION vol:36 issue:9 pages:1585-1596 ispartof: location:England status: published

Multicystic dysplastic kidney is a rare congenital anomaly of the kidney and urinary tract. The association with the posterior urethral valve is also very rare. Here we present a patient with both entities and prenatal resolution of the cysts. A 10-week old baby was referred for nephrourological work up due to prenatal diagnosis of the left multicystic kidney. He had serial US scans during the pregnancy. Immediately before delivery the cysts were not seen (prenatal resolution). There were no extrarenal anomalies. The first postnatal ultrasound scan revealed normal sized right kidney without dilatation of the pelvicalyceal system. The bladder had normal thickness of the wall. Technetium-99m dimercaptosuccinic acid scan showed no activity on the left side, and the right kidney appeared normal. At two months of age, a poor urinary steam was observed and additional urologic work up was indicated on clinical suspicion of PUV. Voiding urethrocystography revealed posterior urethral valve and the baby underwent cytoscopic valve resection. Conclusion: We present a rare association of two congenital anomalies of the kidney and urinary tract with prenatal involution of the multicystic dysplastic kidney that is extremely rare event as seen in our case. Presence of posterior urethral valve must be suspected in a male baby with a poor urinary stream even when his ultrasound scan of urinary system appears normal.

INTRODUCTION: Congenital anomalies of the kidney and urinary tract (CAKUT) are the most common cause of chronic kidney disease (~45%) that manifests before 30 years of age. The genetic locus containing COL4A1 (13q33–34) has been implicated in vesicoureteral reflux (VUR), but mutations in COL4A1 have not been reported in CAKUT. We hypothesized that COL4A1 mutations cause CAKUT in humans. METHODS: We performed whole exome sequencing (WES) in 550 families with CAKUT. As negative control cohorts we used WES sequencing data from patients with nephronophthisis (NPHP) with no genetic cause identified (n=257) and with nephrotic syndrome (NS) due to monogenic causes (n=100). RESULTS: We identified a not previously reported heterozygous missense variant in COL4A1 in three siblings with isolated VUR. When examining 549 families with CAKUT, we identified nine additional different heterozygous missense mutations in COL4A1 in 11 individuals from 11 unrelated families with CAKUT, while no COL4A1 mutations were identified in a control cohort with NPHP and only one in the cohort with NS. Most individuals (12/14) had isolated CAKUT with no extrarenal features. The predominant phenotype was VUR (9/14). There were no clinical features of the COL4A1-related disorders (e.g., HANAC syndrome, porencephaly, tortuosity of retinal arteries). Whereas COL4A1-related disorders are typically caused by glycine substitutions in the collagenous domain (84.4% of variants), only one variant in our cohort is a glycine substitution within the collagenous domain (1/10). CONCLUSION: We identified heterozygous COL4A1 mutations as a potential novel autosomal dominant cause of CAKUT that is allelic to the established COL4A1-related disorders and predominantly caused by non-glycine substitutions.

Objectives: Molecular characterization of a patient with BWS. Clinical presentation and intervention: A 4-year-old boy with overgrowth (weight above 99th and height at 99th percentile) had longitudinal hemihypertrophy of the tongue and left cheek. In addition, there was a difference of one centimeter in the circumference of the left and right leg. Molecular genetic analysis revealed hypomethylation of KvDRM1 (LIT1) in the imprinting control region-2 (ICR2) on chromosome 11p15.5 and a normal methylation pattern of the H19-differentially methylated region (H19-DMR) in the ICR1. The estimated tumor risk was 1-5%. Conclusion: This patient with clinical characteristics of BWS has an imprinting defect associated with a low risk of embryonal tumors.

Escherichia coli infections are becoming increasingly difficult to treat because of emerging antimicrobial resistance, mostly to expanded-spectrum cephalosporins, due to the production of extended-spectrum β-lactamases (ESBLs).Despite extensive studies of ESBL- producing E.coli in adult patients, there is a lack of information about the epidemiology and spread of ESBL organisms in pediatric population. The aim of this study was to examine the gastrointestinal tract as an endogenous reservoir for the respiratory tract colonization with ESBL- E. coli in children, hospitalized because of the severity of the respiratory illness. The study group consists of 40 children with ESBL-producing E. coli strains isolated from the sputum and from the rectal samples. A control group of 15 E. coli isolated from rectal swabs of healthy children were included in the analysis. The comparison of the strains was done by using antimicrobial susceptibility patterns of the stains, and pulsed field gel electrophoresis was performed for molecular typing, using XbaI digestion. 90% of the compared pairs of strains in the study group were with identical antimicrobial susceptibility patterns and indistinguishable in 79.2% by the obtained PFGE – profiles.33.3% (5/15) of confirmed E. coli strains from the control group were found to be ESBL – producers. Resulting band profiles of all isolates demonstrated presence of 12 pulsotypes, with 100% similarity within the pulsotypes. Although, some isolates obtained from different patients were genetically indistinguishable, these strains were not hospital acquired, as none of the patients satisfied the criteria for hospital acquired pneumonia, and there was a lack of an obvious transmission chain. All ESBL –E. coli isolated from sputum in clinical cases were obtained from patients under the age of one. According to the resistance profile of the compared pairs and the PFGE comparison of all isolates, it can be concluded that the gastrointestinal tract is the main reservoir of ESBL-E. coli. Small age in infants is a risk factor for translocation of bacteria, enabling the colonization of the respiratory tract.

BackgroundChildren are recognised as at lower risk of severe COVID-19 compared with adults, but the impact of immunosuppression is yet to be determined. This study aims to describe the clinical course of COVID-19 in children with kidney disease taking immunosuppressive medication and to assess disease severity.MethodsCross-sectional study hosted by the European Rare Kidney Disease Reference Network and supported by the European, Asian and International paediatric nephrology societies. Anonymised data were submitted online for any child (age Results113 children were reported in this study from 30 different countries. Median age: 13 years (49% male). Main underlying reasons for immunosuppressive therapy: kidney transplant (47%), nephrotic syndrome (27%), systemic lupus erythematosus (10%). Immunosuppressive medications used include: glucocorticoids (76%), mycophenolate mofetil (MMF) (54%), tacrolimus/ciclosporine A (58%), rituximab/ofatumumab (11%). 78% required no respiratory support during COVID-19 illness, 5% required bi-level positive airway pressure or ventilation. Four children died; all deaths reported were from low-income countries with associated comorbidities. There was no significant difference in severity of COVID-19 based on gender, dialysis status, underlying kidney condition, and type or number of immunosuppressive medications.ConclusionsThis global study shows most children with a kidney disease taking immunosuppressive medication have mild disease with SARS-CoV-2 infection. We therefore suggest that children on immunosuppressive therapy should not be more strictly isolated than children who are not on immunosuppressive therapy.

Purpose: Multiple stakeholders are involved in achieving Universal Health Coverage (UHC) as part of the Sustainable Development Goals (SDG). The estimated over 90 million children with disabilities are among the most vulnerable members of the world’s population. We questioned :‘What would be the least paediatricians could do to contribute to the UHC?’Methods: In a cross sectional study an international network of paediatricians engaged in children with disabling and rare conditions was questioned on eight of the UHC statements regarding child health in relation to primary care services, availability and affordability of diagnostics and therapies as well as digital health.Results: Promotion of paediatric primary care could reduce mortality and morbidity according to 39/48 (81%) respondents. Pediatricians could play an active role providing quality information to increase access to health services for children with disabilities stated 40/48 (83%) responders. Improved data exchange is necessary to deliver primary care as a cornerstone according to 38/48 (79%) responders. Respondents practising in middle economy countries reported significant more frequently than their colleagues in high economies countries about “out of pocket” payments for diagnostics and therapies as well as reduced availability. All respondents agreed that taking no action to support the achievement of UHC, is not an option.Conclusion: The economic gap in diagnostic and therapeutic facilities in paediatric practice should be considered in achieving UHC. An international paediatric network should support achieving the UHC by providing adequate paediatric training and quality (digital) information.

Genetic studies of population isolates have great potential to provide a unique insight into genetic differentiation and phenotypic expressions. Galičnik village is a population isolate located in the northwest region of the Republic of North Macedonia, established around the 10th century. Alport syndrome-linked nephropathy with a complex inheritance pattern has been described historically among individuals in the village. In order to determine the genetic basis of the nephropathies and to characterize the genetic structure of the population, 23 samples were genotyped using a custom-made next generation sequencing panel and 111 samples using population genetic markers. We compared the newly obtained population data with fifteen European population data sets. NGS analysis revealed four different mutations in three different collagen genes in twelve individuals within the Galičnik population. The genetic isolation and small effective population size of Galičnik village have resulted in a high level of genomic homogeneity, with domination of R1a-M458 and R1b-U106* haplogroups. The study explains complex autosomal in cis digenic and X-linked inheritance patterns of nephropathy in the isolated population of Galičnik and describes the first case of Alport syndrome family with three different collagen gene mutations.