Biallelic known and novel DCDC2 variants in cholestatic liver disease: Phenotype-genotype observations in four children.

Neonatal sclerosing cholangitis (NSC) is associated with progressing biliary fibrosis that often requires liver transplantation in childhood. Several recent studies have identified variants in DCDC2, encoding doublecortin domain-containing protein 2 (DCDC2), expressed in primary cilia, that accompany syndromic disease and NSC. We report four patients with hepatobiliary disease associated with two novel homozygous or compound heterozygous variants in DCDC2. Three patients with protein-truncating variants in DCDC2, expressing no DCDC2, presented with the originally described severe hepatic phenotype in infancy. One patient with a novel homozygous DCDC2 missense variant shows a markedly milder phenotype only manifest in childhood and with retained DCDC2 expression. Concomitant nephronophthisis is present in three patients and learning disability in two. This report widens the phenotypic spectrum of DCDC2-associated hepatobiliary disease. Testing for DCDC2 expression and DCDC2 variants should be included in the evaluation of cholangiopathy of unknown aetiology in childhood as well as in infancy.

Infants Requiring Maintenance Dialysis: Outcomes of Hemodialysis and Peritoneal Dialysis.

BACKGROUND: The impact of different dialysis modalities on clinical outcomes has not been explored in young infants with chronic kidney failure. STUDY DESIGN: Cohort study. SETTING & PARTICIPANTS: Data were extracted from the ESPN/ERA-EDTA Registry. This analysis included 1,063 infants 12 months or younger who initiated dialysis therapy in 1991 to 2013. FACTOR: Type of dialysis modality. OUTCOMES & MEASUREMENTS: Differences between infants treated with peritoneal dialysis (PD) or hemodialysis (HD) in patient survival, technique survival, and access to kidney transplantation were examined using Cox regression analysis while adjusting for age at dialysis therapy initiation, sex, underlying kidney disease, and country of residence. RESULTS: 917 infants initiated dialysis therapy on PD, and 146, on HD. Median age at dialysis therapy initiation was 4.5 (IQR, 0.7-7.9) months, and median body weight was 5.7 (IQR, 3.7-7.5) kg. Although the groups were homogeneous regarding age and sex, infants treated with PD more often had congenital anomalies of the kidney and urinary tract (CAKUT; 48% vs 27%), whereas those on HD therapy more frequently had metabolic disorders (12% vs 4%). Risk factors for death were younger age at dialysis therapy initiation (HR per each 1-month later initiation, 0.95; 95% CI, 0.90-0.97) and non-CAKUT cause of chronic kidney failure (HR, 1.49; 95% CI, 1.08-2.04). Mortality risk and likelihood of transplantation were equal in PD and HD patients, whereas HD patients had a higher risk for changing dialysis treatment (adjusted HR, 1.64; 95% CI, 1.17-2.31). LIMITATIONS: Inability to control for unmeasured confounders not included in the Registry database and missing data (ie, comorbid conditions). Low statistical power because of relatively small number of participants. CONCLUSIONS: Despite a widespread preconception that HD should be reserved for cases in which PD is not feasible, in Europe, we found 1 in 8 infants in need of maintenance dialysis to be initiated on HD therapy. Patient characteristics at dialysis therapy initiation, prospective survival, and time to transplantation were very similar for infants initiated on PD or HD therapy.

Multi-exon deletion in the XDH gene as a cause of classical xanthinuria.

Xanthinuria Type I is caused by mutations in the xanthine dehydrogenase gene (XDH). We report on a patient suffering from xanthinuria. Genomic DNA was screened for point mutations and imbalances in the XDH gene by sequencing and microarray typing. We could identify homozygosity of a multiexon deletion in the XDH gene; large genomic imbalances have not yet been reported in this disease. As our case and other studies on genetic alterations in kidney diseases show, large deletions (and duplications) significantly contribute to the etiology of these entities, specific assays to discover these imbalances should therefore be included in genetic testing approaches.

Withdrawn as duplicate: Expanding the phenotypic spectrum of Kenny-Caffey syndrome: a case series and systematic literature review.

This article has been withdrawn due to a publisher error that caused it to be duplicated. The definitive version of this article is published under https://doi.org/10.1210/clinem/dgad147.

Expanding the Phenotypic Spectrum of Kenny-Caffey Syndrome.

CONTEXT: Kenny-Caffey syndrome (KCS) is a rare hereditary disorder characterized by short stature, hypoparathyroidism, and electrolyte disturbances. KCS1 and KCS2 are caused by pathogenic variants in TBCE and FAM111A, respectively. Clinically the phenotypes are difficult to distinguish. OBJECTIVE: The objective was to determine and expand the phenotypic spectrum of KCS1 and KCS2 in order to anticipate complications that may arise in these disorders. METHODS: We clinically and genetically analyzed 10 KCS2 patients from 7 families. Because we found unusual phenotypes in our cohort, we performed a systematic review of genetically confirmed KCS cases using PubMed and Scopus. Evaluation by 3 researchers led to the inclusion of 26 papers for KCS1 and 16 for KCS2, totaling 205 patients. Data were extracted following the Cochrane guidelines and assessed by 2 independent researchers. RESULTS: Several patients in our KCS2 cohort presented with intellectual disability (3/10) and chronic kidney disease (6/10), which are not considered common findings in KCS2. Systematic review of all reported KCS cases showed that the phenotypes of KCS1 and KCS2 overlap for postnatal growth retardation (KCS1: 52/52, KCS2: 23/23), low parathyroid hormone levels (121/121, 16/20), electrolyte disturbances (139/139, 24/27), dental abnormalities (47/50, 15/16), ocular abnormalities (57/60, 22/23), and seizures/spasms (103/115, 13/16). Symptoms more prevalent in KCS1 included intellectual disability (74/80, 5/24), whereas in KCS2 bone cortical thickening (1/18, 16/20) and medullary stenosis (7/46, 27/28) were more common. CONCLUSION: Our case series established chronic kidney disease as a new feature of KCS2. In the literature, we found substantial overlap in the phenotypic spectra of KCS1 and KCS2, but identified intellectual disability and the abnormal bone phenotype as the most distinguishing features.

Hemodiafiltration in infants with complications during peritoneal dialysis.

End-stage renal disease (ESRD) in neonates still has a high mortality, particularly in the first year of life. We present the combination of peritoneal dialysis (PD) with intermittent hemodiafiltration (iHDF) in neonates with ESRD. Four infants younger than 28 days were treated with PD and iHDF. Renal diagnoses leading to ESRD were cortical necrosis, prune belly syndrome, neonatal hemolytic uremic syndrome, and autosomal recessive polycystic kidney disease. Initially, three patients were on iHDF until PD was started. At the time when complications occurred during PD, patients were switched back to iHDF. iHDF was used five times as a bridge to PD in case of abdominal surgery. Two of the four patients were switched to iHDF because of peritoneal ultrafiltration failure due to recurrent peritoneal leaks. Once, iHDF became necessary due to refractory peritonitis. All four patients survived the first year of life. Two patients were transplanted successfully at an age of 35 and 22 months, respectively. The others are on renal replacement therapy, one on PD at the age of 28 months and one on iHDF at the age of 25 months, respectively. In case of PD complications, iHDF may be an appropriate bridge to achieve long-term survival until kidney transplantation.

Functional analyses indicate a pathogenic role of factor H autoantibodies in atypical haemolytic uraemic syndrome.

BACKGROUND: Atypical haemolytic uraemic syndrome (aHUS) is associated with defective complement regulation. Recently, an autoimmune aHUS form has been described that is associated with complement factor H (CFH) autoantibodies. The aim of this study was to address the pathologic relevance of CFH autoantibodies in aHUS. METHODS: CFH autoantibodies were identified and antibody levels were analysed in three aHUS patients during the disease course by the ELISA method. Epitope mapping was performed using recombinant factor H fragments and domain-mapped monoclonal antibodies. The effect of the antibodies on cell-protective activity of CFH was measured by haemolytic assays. CFH:autoantibody complexes were analysed by ELISA. RESULTS: All three autoantibodies bound to the C-terminal domain of CFH, which is essential for CFH binding to cell surfaces. In patient 1, plasma exchanges and immune adsorption temporarily reduced the autoantibody titre and led to temporary clinical improvement. In patient 2, plasma exchanges and long-term immunosuppression strongly reduced the CFH autoantibody level, and induced a stable remission of aHUS. Patient 3 had lower autoantibody levels that decreased during the follow-up and is in good clinical condition. The patients' plasma samples caused enhanced lysis of sheep erythrocytes, and the degree of lysis correlated with the CFH autoantibody titre and the amount of CFH:autoantibody complexes. An addition of purified CFH to aHUS plasma or removal of IgG inhibited the haemolytic activity. CONCLUSION: These results support a direct role of the autoantibodies in aHUS pathology by inhibiting the regulatory function of CFH at cell surfaces and suggest that reduction of the autoantibody titre is beneficial for the patients.

Human C-terminal CUBN variants associate with chronic proteinuria and normal renal function.

BACKGROUNDProteinuria is considered an unfavorable clinical condition that accelerates renal and cardiovascular disease. However, it is not clear whether all forms of proteinuria are damaging. Mutations in CUBN cause Imerslund-Gräsbeck syndrome (IGS), which is characterized by intestinal malabsorption of vitamin B12 and in some cases proteinuria. CUBN encodes for cubilin, an intestinal and proximal tubular uptake receptor containing 27 CUB domains for ligand binding.METHODSWe used next-generation sequencing for renal disease genes to genotype cohorts of patients with suspected hereditary renal disease and chronic proteinuria. CUBN variants were analyzed using bioinformatics, structural modeling, and epidemiological methods.RESULTSWe identified 39 patients, in whom biallelic pathogenic variants in the CUBN gene were associated with chronic isolated proteinuria and early childhood onset. Since the proteinuria in these patients had a high proportion of albuminuria, glomerular diseases such as steroid-resistant nephrotic syndrome or Alport syndrome were often the primary clinical diagnosis, motivating renal biopsies and the use of proteinuria-lowering treatments. However, renal function was normal in all cases. By contrast, we did not found any biallelic CUBN variants in proteinuric patients with reduced renal function or focal segmental glomerulosclerosis. Unlike the more N-terminal IGS mutations, 37 of the 41 proteinuria-associated CUBN variants led to modifications or truncations after the vitamin B12-binding domain. Finally, we show that 4 C-terminal CUBN variants are associated with albuminuria and slightly increased GFR in meta-analyses of large population-based cohorts.CONCLUSIONCollectively, our data suggest an important role for the C-terminal half of cubilin in renal albumin reabsorption. Albuminuria due to reduced cubilin function could be an unexpectedly common benign condition in humans that may not require any proteinuria-lowering treatment or renal biopsy.FUNDINGATIP-Avenir program, Fondation Bettencourt-Schueller (Liliane Bettencourt Chair of Developmental Biology), Agence Nationale de la Recherche (ANR) Investissements d'avenir program (ANR-10-IAHU-01) and NEPHROFLY (ANR-14-ACHN-0013, to MS), Steno Collaborative Grant 2018 (NNF18OC0052457, to TSA and MS), Heisenberg Professorship of the German Research Foundation (KO 3598/5-1, to AK), Deutsche Forschungsgemeinschaft (DFG) Collaborative Research Centre (SFB) KIDGEM 1140 (project 246781735, to CB), and Federal Ministry of Education and Research (BMB) (01GM1515C, to CB).

A novel mutation of the RRM2B gene in an infant with early fatal encephalomyopathy, central hypomyelination, and tubulopathy.

A baby-girl with congenital deafness was admitted at the age of 8 weeks for lack of head control, truncal hypotonia and echodense kidneys. At the age of 10 weeks cranial MRI showed a normal brain structure, generalized mild hypomyelination but no lactate peak on (1)H MR spectroscopy. A combined defect of respiratory chain enzyme complexes I, III, IV and V and severe depletion of mitochondrial DNA was found in skeletal muscle tissue. Genetic analysis revealed a novel mutation c.368T>C (p.Phe123Ser) in the RRM2B gene in the expressed maternal allele. The paternal allele was present in genomic DNA, but was not expressed as mature mRNA.

Transforming growth factor-beta receptor mutations and pulmonary arterial hypertension in childhood.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a potentially fatal vasculopathy that can develop at any age. Adult-onset disease has previously been associated with mutations in BMPR2 and ALK-1. Presentation in early life may be associated with congenital heart disease but frequently is idiopathic. METHODS AND RESULTS: We performed mutation analysis in genes encoding receptor members of the transforming growth factor-beta cell-signaling pathway in 18 children (age at presentation <6 years) with PAH. Sixteen children were initially diagnosed with idiopathic PAH and 2 with PAH in association with congenital heart defects. Germ-line mutations were observed in 4 patients (22%) (age at disease onset, 1 month to 6 years), all of whom presented with idiopathic PAH. The BMPR2 mutations (n=2, 11%) included a partial gene deletion and a nonsense mutation, both arising de novo in the proband. Importantly, a missense mutation of ALK-1 and a branch-site mutation of endoglin were also detected. Presenting clinical features or progression of pulmonary hypertension did not distinguish between patients with mutations in the different genes or between those without mutations. CONCLUSIONS: The cause of PAH presenting in childhood is heterogeneous in nature, with genetic defects of transforming growth factor-beta receptors playing a critical role.

Future expectations--what paediatric nephrologists and urologists await from paediatric uroradiology.

Cooperation between paediatric nephrology/urology and paediatric radiology is essential for timely and correct diagnosis and therapy of kidney and urinary tract disorders. We need the direct contact between doctors before or after investigations, interdisciplinary discussions, and rapid access to the images. This should lead to optimal settings for investigations, a reduction of radiation burden and the number of investigations, and further improvement in the management of patients. Modern sonography including colour Doppler sonography, amplitude-coded Doppler sonography, and eventually 3D-ultrasound is and will be the method of choice as the basic, non-invasive investigation. These investigations should become the routine in all institutions. Refinement and standardisation of already established investigations are needed. Recently introduced investigations, like MRI, will have to show their impact on future diagnostic imaging. Future introduction of new non-invasive methods is welcome, e.g. to correctly diagnose vesicoureteral reflux without catheterisation/puncture of the bladder.

Continuous renal replacement therapy with Prismaflex HF20 disposable set in children from 4 to 15 kg.

Continuous venovenous hemodiafiltration (CVVHDF) in infants is challenging due to a lack of specific and widely available technology. There is need for high precision of fluid balance and hemodynamic stability. The aim of this study is to report the first experience with the newly developed Prismaflex HF20 disposable set (HF20 set) in infants with CVVHDF. We provided safe treatment in four infants (4-14 kg) suffering from acute renal failure with the HF20 set. Treatment monitoring included patients' blood pressure, patients' weight change, and fluid balance. The anticoagulation was performed with unfractionated heparin. We used commercially available bicarbonate-buffered solutions as dialysate fluid and substitution fluid. At start and during the treatment, the patients showed hemodynamic stability. Desired fluid balance was achieved in all patients during the treatment periods of 49-102 hours. No complications occurred. This report presents CVVHDF experience on the feasibility and safety of the HF20 set in infants. It can be used in CVVHDF or hemodialysis mode. Treatments were well tolerated in all patients, and flow rate adaptability to infants' needs was very acceptable, and the usage of this device was easy and safe.

First experience with the Prismaflex HF 20 set in four infants.

PURPOSE: Renal replacement therapy (RRT) in infants is challenging due to a lack of widely available technology that is specific to this patient population. We present our initial experience with the newly developed Prismaflex HF20 disposable set used on the Prismaflex device in infants with renal failure. PATIENTS: Four infants, age 5 to 24 months, were enrolled. Overall 120 treatment sessions were performed over 300 patient-days. Treatment monitoring included patient weight change and fluid balance, treatment efficacy, number of interventions, and alarms. RESULTS: Desired fluid balance according to the prescribed weight loss was achieved in all patients (R²=0.86, p<0.0001). Treatment efficacy was monitored by blood urea nitrogen (BUN) and serum creatinine values at the start of RRT (59 ± 17 mg/dL and 5.1 ± 1.1 mg/dL) and their decrease after 4 hours of RRT (23 ± 7 mg/dL and 2.2 ± 0.6 mg/dL). Measured urea and creatinine clearances for the HF20 filter were 23 ± 7 ml/min and 19 ± 4 ml/min, respectively. No complications occurred. CONCLUSION: This is the first report on the use of the Prismaflex HF20 set in infants. No adverse events were observed, treatments were well tolerated in all patients, and flow rate adaptability to infants' needs was good.

Nephropathia epidemica (puumala virus infection) in Austrian children.

From 2000 to 2007, 19 Austrian children (aged 6-18 years) had serologically verified nephropathia epidemica. Common clinical features were abdominal/flank/back pain, fever, nausea, vomiting, headache, and transient visual disturbances. Acute renal failure was present in 18 (95%) patients. All patients recovered completely. Childhood nephropathia epidemica in Austria takes a similar course to those reported for Northern European Puumala virus strains.

Complement inhibitor eculizumab in atypical hemolytic uremic syndrome.

BACKGROUND AND OBJECTIVES: Atypical hemolytic uremic syndrome (aHUS) is associated with a congenital or acquired dysregulation of the complement alternative pathway that leads to continuous complement activation on host cells causing inflammation and damage. Eculizumab, a humanized mAb against complement protein C5, inhibits activation of the terminal complement pathway. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We report an adolescent with relapsing unclassified aHUS. On admission, a high plasma creatinine level indicated a poor prognosis, and hemodialysis had to be started. Plasma exchanges were initially effective against the microangiopathic hemolytic activity and allowed a temporary improvement of renal function with termination of hemodialysis after 7 wk. Subsequently, plasma exchanges (three times per week) failed to prevent ongoing aHUS activity and progressive renal failure. After 12 wk, aHUS treatment was switched to eculizumab. RESULTS: Eculizumab was effective in terminating the microangiopathic hemolytic process in two aHUS relapses; however, after normalization of complement activity, aHUS recurred and ultimately led to anuric end-stage renal failure. CONCLUSIONS: In this patient, complement inhibition by eculizumab temporarily terminated the microangiopathic hemolytic activity. Nevertheless, renal damage as a result of preceding and subsequent aHUS activity resulted in end-stage renal failure; therefore, therapeutic success may depend on early administration of eculizumab. The optimal duration of treatment may be variable and remains to be determined.

Functional characterization of GATA3 mutations causing the hypoparathyroidism-deafness-renal (HDR) dysplasia syndrome: insight into mechanisms of DNA binding by the GATA3 transcription factor.

The hypoparathyroidism-deafness-renal (HDR) dysplasia syndrome is an autosomal dominant disorder caused by mutations of the dual zinc finger transcription factor, GATA3. We investigated 21 HDR probands and 14 patients with isolated hypoparathyroidism for GATA3 abnormalities. Thirteen different heterozygous germline mutations were identified in patients with HDR. These consisted of three nonsense mutations, six frameshifting deletions, two frameshifting insertions, one missense (Leu348Arg) mutation and one acceptor splice site mutation. The splice site mutation was demonstrated to cause a pre-mRNA processing abnormality leading to the use of an alternative acceptor site 8 bp downstream of the normal site, resulting in a frameshift and prematurely terminated protein. Electrophoretic mobility shift assays (EMSAs) revealed three classes of GATA3 mutations: those that lead to a loss of DNA binding which represent over 90% of all mutations, and involved a loss of the carboxy-terminal zinc finger; those that resulted in a reduced DNA-binding affinity; and those (e.g. Leu348Arg) that did not alter DNA binding or the affinity but likely altered the conformational change that occurs during binding in the DNA major groove as predicted by a three-dimensional modeling. These results elucidate further the molecular mechanisms underlying the altered functions of mutants of this zinc finger transcription factor and their role in causing this developmental anomaly. No mutations were identified in patients with isolated hypoparathyroidism, thereby indicating that GATA3 abnormalities are more likely to result in two or more of the phenotypic features of the HDR syndrome and not in one, such as isolated hypoparathyroidism.

Skin transplantation to monitor clinical donor-related tolerance in mixed hematopoietic chimerism.

Mixed hematopoietic chimerism usually carries with it the tolerance to any other tissue from the same donor. Consequently, the establishment of a sustained chimerism may allow long-term acceptance of transplanted organs without immunosuppression. We report a girl with refractory severe aplastic anemia who developed low recipient level hematopoietic chimerism following transplantation of maternal highly purified CD34+ cells without prophylactic immunosuppression. Renal thrombotic microangiopathy led to chronic renal failure and she received skin allografts from her mother in view of a future kidney donation. The maternal skin grafts were accepted without immunosuppression and the hematopoietic chimerism remained stable. Skin transplantation may be a helpful and easily applicable tool to monitor donor-related tolerance in hematopoietic chimerism clinically. It should contribute to minimize the risks of subsequent solid organ transplantation from the same donor without immunosuppression.