Genome-wide association study in patients with posterior urethral valves

Congenital lower urinary tract obstructions (LUTO) are most often caused by posterior urethral valves (PUV), a male limited anatomical obstruction of the urethra affecting 1 in 4,000 male live births. Little is known about the genetic background of PUV. Here, we report the largest genome-wide association study (GWAS) for PUV in 4 cohorts of patients and controls. The final meta-analysis included 756 patients and 4,823 ethnicity matched controls and comprised 5,754,208 variants that were genotyped or imputed and passed quality control in all 4 cohorts. No genome-wide significant locus was identified, but 33 variants showed suggestive significance (P < 1 × 10−5). When considering only loci with multiple variants residing within < 10 kB of each other showing suggestive significance and with the same effect direction in all 4 cohorts, 3 loci comprising a total of 9 variants remained. These loci resided on chromosomes 13, 16, and 20. The present GWAS and meta-analysis is the largest genetic study on PUV performed to date. The fact that no genome-wide significant locus was identified, can be explained by lack of power or may indicate that common variants do not play a major role in the etiology of PUV. Nevertheless, future studies are warranted to replicate and validate the 3 loci that yielded suggestive associations

Genetic Drivers of Kidney Defects in the DiGeorge Syndrome

Background The DiGeorge syndrome, the most common of the microdeletion syndromes, affects multiple organs, including the heart, the nervous system, and the kidney. It is caused by deletions on chromosome 22q11.2; the genetic driver of the kidney defects is unknown. Methods We conducted a genomewide search for structural variants in two cohorts: 2080 patients with congenital kidney and urinary tract anomalies and 22,094 controls. We performed exome and targeted resequencing in samples obtained from 586 additional patients with congenital kidney anomalies. We also carried out functional studies using zebrafish and mice. Results We identified heterozygous deletions of 22q11.2 in 1.1% of the patients with congenital kidney anomalies and in 0.01% of population controls (odds ratio, 81.5; P=4.5×10(-14)). We localized the main drivers of renal disease in the DiGeorge syndrome to a 370-kb region containing nine genes. In zebrafish embryos, an induced loss of function in snap29, aifm3, and crkl resulted in renal defects; the loss of crkl alone was sufficient to induce defects. Five of 586 patients with congenital urinary anomalies had newly identified, heterozygous protein-altering variants, including a premature termination codon, in CRKL. The inactivation of Crkl in the mouse model induced developmental defects similar to those observed in patients with congenital urinary anomalies. Conclusions We identified a recurrent 370-kb deletion at the 22q11.2 locus as a driver of kidney defects in the DiGeorge syndrome and in sporadic congenital kidney and urinary tract anomalies. Of the nine genes at this locus, SNAP29, AIFM3, and CRKL appear to be critical to the phenotype, with haploinsufficiency of CRKL emerging as the main genetic driver. (Funded by the National Institutes of Health and others.)

The oculocerebrorenal syndrome of Lowe – diagnostic and therapeutic problems in Polish health care system

Zespół oczno-mózgowo-nerkowy, opisany po raz pierwszy przez Lowe’a w 1952 roku, jest rzadkim defektem genetycznym (częstość 1 : 500 000), wywołanym mutacją w genie OCRL kodującym enzym 5-fosfatazę 4,5-dwufosfo-fosfatydyloinozytolu. Jest on zlokalizowany na chromosomie X (Xq25-26), a choroba dziedziczy się w sposób recesywny sprzężony z płcią. Typowymi objawami są: wrodzona zaćma, upośledzenie rozwoju umysłowego i tubulopatia proksymalna (wtórny zespół Fanconiego bez glukozurii) z wolno postępującym upośledzeniem czynności nerek, aż do schyłkowej ich niewydolności w 2–4 dekadzie życia. Inne objawy to: zaburzenia wzrastania, jaskra, woloocze, hipotonia mięśniowa, opóźnienie rozwoju motorycznego, dziwne zachowania (napady agresji i złości, ruchy mimowolne), wentrykulomegalia, przykurcze, artropatie, osteopenia, wnętrostwo, dysplazja zębów, torbiele skórne i skaza krwotoczna. Rozpoznanie wstępne można postawić na podstawie obrazu klinicznego z typową sekwencją pojawiania się objawów, z których początkowymi są zaćma, hipotonia z brakiem odruchów głębokich i białkomocz cewkowy. Potwierdzenie diagnozy stanowi badanie genetyczne, w którym stwierdza się jeden z ponad 200 znanych wariantów genu OCRL lub mutację de novo. Przedstawiono przypadek 2-letniego chłopca z obrazem klinicznym zespołu Lowe’a (wrodzona zaćma, hipotonia, opóźnienie rozwoju psychofizycznego i tubulopatia), diagnozowanego i leczonego w wielu ośrodkach. Po przekazaniu chorego pod opiekę powiatowego oddziału pediatrycznego w Międzyrzeczu rozpoznanie potwierdzono badaniem genetycznym, w którym wykazano hemizygotyczną punktową mutację w eksonie 13 OCRL (c.1351G > A); badanie wykonano dzięki uprzejmości prof. Michaela Ludwiga w Laboratorium Biologii Molekularnej Uniwersytetu w Bonn. Zwrócono uwagę na celowość wczesnego zgłaszania chorych z podejrzeniem zespołu Lowe’a do krajowego rejestru POLtube, co ułatwia dostęp do diagnostyki molekularnej.The oculocerebrorenal syndrome described by C.U. Lowe in 1952 is a rare genetic defect (prevalence 1:500 000) caused by mutation of the OCRL gene which encodes phosphatidylinositol 4,5-bisphosphate 5-phosphatase. Its location on chromosome X (Xq25-26) leads to an X-linked recessive mode of inheritance. A typical clinical triad characterizing the disease consists of congenital cataract, mental retardation and proximal tubulopathy (secondary Fanconi syndrome without glycosuria) with slow progression to end stage kidney disease in the 2nd–4th decade. There are many other symptoms reported like: growth retardation, glaucoma, buphthalmos, muscle hypotonia, neuromotor retardation, behavioral abnormalities (aggression, temper tantrums, repetitive purposeless movements), ventriculomegaly, contractures, arthropathy, osteopenia, cryptorchidism, dental anomalies, skin cysts and bleeding disorders. Preliminary diagnosis may be based on the clinical picture with a typical sequence of symptoms starting from cataracts, hypotonia with a lack of deep tendon reflexes and tubular proteinuria. Final identification of the disease is confirmed by molecular testing with one out of more than 200 known mutations (or de novo variant) found. Here we reported a 2-year-old boy with the clinical picture of Lowe syndrome (congenital cataract, hypotonia, psychomotor development retardation and tubulopathy), examined and treated in many medical centers. The final diagnosis was confirmed by genetic testing planned in the regional hospital in Międzyrzecz and performed by prof. Michael Ludwig from the Laboratory of Molecular Biology at University of Bonn, Germany. A single hemizygous deviation in exon 13 (c.1351G > A) was found. Attention was paid to the purpose of early notification of such patients to the national registry POLtube which facilitates molecular diagnosis

Characterization of 28 novel patients expands the mutational and phenotypic spectrum of Lowe syndrome

BACKGROUND The oculocerebrorenal syndrome of Lowe (OCRL) is a rare X-linked multi-systemic disorder, almost always characterized by the triad of congenital cataract, cognitive and behavioral impairment and a proximal tubulopathy. METHODS Twenty-eight novel patients with suspected Lowe syndrome were studied. RESULTS All patients carried OCRL gene defects with mutational hot spots at CpG dinucleotides. Mutations previously unknown in Lowe syndrome were observed in ten of the 28 patients, and carriership was identified in 30.4 % of the mothers investigated. Mapping the exact breakpoints of a complete OCRL gene deletion revealed involvement of several flanking repeat elements. We noted a similar pattern of documented clinically relevant symptoms, and even though the patient cohort comprised relatively young patients, 32 % of these patients already showed advanced chronic kidney disease. Thrombocytopenia was seen in several patients, and hyperosmia and/or hyperacusis were reported recurrently. A p.Asp523Asn mutation in a Polish patient, associated with the typical cerebrorenal spectrum but with late cataract (10 year), was also evident in two milder affected Italian brothers with ocular involvement of similar progression. CONCLUSIONS We have identified clinical features in 28 patients with suspected Lowe syndrome that had not been recognized in Lowe syndrome prior to our study. We also provide further evidence that OCRL mutations cause a phenotypic continuum with selective and/or time-dependent organ involvement. At least some of these mutants might exhibit a genotype-phenotype correlation

Four Cases of Maturity Onset Diabetes of the Young (MODY) Type 5 Associated with Mutations in the Hepatocyte Nuclear Factor 1 Beta (HNF1B) Gene Presenting in a 13-Year-Old Boy and in Adult Men Aged 33, 34, and 35 Years in Poland

Objective: Congenital defects/diseases Background: Maturity onset diabetes of the young (MODY) usually presents in patients under the age of 25 years and is an autosomal dominant condition associated with mutations in the hepatocyte nuclear factor 1 alpha gene, glucokinase gene, or hepatocyte nuclear factor 4 alpha gene. This report is of a series of 4 cases from Poland of MODY type 5 associated with mutations in the hepatocyte nuclear factor 1 beta (HNF1B) gene, including a 13-year-old boy and adult men aged 33, 34, and 35 years. Case Reports: Three cases were diagnosed late, in patients in their mid-thirties. In two patients, the initial presentation was symptomatic diabetes complicated by ketoacidosis and hyperglycemic hyperosmolar state. Renal cysts were found in all patients, and pancreatic hypoplasia in 3 patients. All patients except 1 were negative for autoantibodies; 1 presented with hypomagnesemia. Insulin therapy was instituted in all cases. The combination of family history, imaging study results, and biochemical characteristics led to the decision to perform genetic analysis, which was conducted in 2 cases at diagnosis, and in the 2 remaining patients at 1 month and 2 years after diagnosis, respectively. Follow-up data revealed hypomagnesemia and/or hypermagnesuria in all patients. Conclusions: We present 3 young men over 25 years and 1 boy with HNF1B-MODY. Although rare, autosomal dominant gene associations should be considered in young patients with diabetes who present with renal/pancreatic anomalies and low serum magnesium. Unusual presentation and the presence of autoantibodies should not eliminate the possibility of a HNF1B defect

Interest of URS-L in the Treatment of Ureterolithiasis in Preschool Children.

Urolithiasis can affect all children even preschool ones. Diagnostic difficulties in the youngest children are due to the problems in locating pain and determining its character and severity. In keeping with the ALARA (As Low As Reasonably Achievable) protocol, the number of imaging tests possible to perform is very limited. Ultrasound is the first line exam of choice. After diagnosis of the presence of a stone, ESWL (Extracorporeal Shock Wave Lithotrypsy) should always be considered and offered to parents due to its high effectiveness and minimal invasiveness. If ESWL is contraindicated or not well-accepted by parents, authors suggest another minimal invasive approach: URS-L (Uretherorenoscopy-Lithotrypsy). Our study clinically analyzes 87 children, which were treated between 2009 and 2017 using the URS-L procedure. URS-L treatments were performed using Lithoclast until 2009, and after that time, using the holmium laser Ho:YAG. The overall effectiveness of treatments was 93.3%. There was no failure in the access to the stones. A macroscopic hematuria (Clavien-Dindo I grade) was observed through the second post-operative day in 9.2% of treated patients. No urosepsis was observed. Full metabolic evaluation was performed on all patients. Children remained under constant urological and nephrological observation. A recurrence of urolithiasis was observed in 35.6% of the cases. Treating ureteral lithiasis in young infants remains a big challenge. Our series shows that modern minimal invasive techniques used by very experienced pediatric urologists in high volume centers gives excellent results. In most cases, surgery should no longer need to be an option.info:eu-repo/semantics/publishe

Hypomagnesemia is underestimated in children with HNF1B mutations

Background Hypomagnesemia in patients with congenital anomalies of the kidneys and urinary tract or autosomal dominant tubulointerstitial kidney disease is highly suggestive of HNF1B-associated disease. Intriguingly, the frequency of low serum Mg2+ (sMg) level varies and is lower in children than in adults with HNF1B mutations that could be partially due to application of inaccurate normal limit of sMg, irrespective of age and gender. We aimed to re-assess cross-sectionally and longitudinally the frequency of hypomagnesemia in HNF1B disease by using locally derived reference values of sMg. Methods Fourteen children with HNF1B-associated kidney disease were included. Control group comprising 110 subjects served to generate 2.5th percentiles of sMg as the lower limits of normal. Results In both controls and patients, sMg correlated with age, gender, and fractional excretion of Mg2+. In girls, sMg concentration was higher than in boys when analyzed in the entire age spectrum (p < 0.05). In HNF1B patients, mean sMg was lower than in controls as compared with respective gender- and age-specific interval (p < 0.001). Low sMg levels (< 0.7 mmol/l) were found in 21.4% of patients at diagnosis and 36.4% at last visit, which rose to 85.7% and 72.7% respectively when using the age- and gender-adjusted reference data. Similarly, in the longitudinal observation, 23% of sMg measurements were < 0.7 mmol/l versus 79.7% when applying respective references. Conclusions Hypomagnesemia is underdiagnosed in children with HNF1B disease. sMg levels are age- and gender-dependent; thus, the use of appropriate reference data is crucial to hypomagnesemia in children

Hyperuricemia Is an Early and Relatively Common Feature in Children with HNF1B Nephropathy but Its Utility as a Predictor of the Disease Is Limited

Background: Hyperuricemia is recognized as an important feature of nephropathy, associated with a mutation in the hepatocyte nuclear factor-1B (HNF1B) gene, and could serve as a useful marker of the disease. However, neither a causal relationship nor its predictive value have been proven. The purpose of this study was to assess this in children with renal malformations, both with (mut+) and without HNF1B mutations (mut-). Methods: We performed a retrospective analysis of clinical characteristics of pediatric patients tested for HNF1B mutations, collected in a national registry. Results: 108 children were included in the study, comprising 43 mut+ patients and 65 mut- subjects. Mean sUA was higher and hyperuricemia more prevalent (42.5% vs. 15.4%) in HNF1B carriers. The two groups were similar with respect to respect to age, sex, anthropometric parameters, hypertension, and renal function. Renal function, fractional excretion of uric acid and parathyroid hormone level were independent predictors of sUA. The potential of hyperuricemia to predict mutation was low, and addition of hyperuricemia to a multivariate logistic regression model did not increase its accuracy. Conclusions: Hyperuricemia is an early and common feature of HNF1B nephropathy. A strong association of sUA with renal function and parathyroid hormone limits its utility as a reliable marker to predict HNF1B mutation among patients with kidney anomalies

LONG-TERM OUTCOME AND TREATMENT PRACTICES IN DISTAL RENALTUBULAR ACIDOSIS

WOS: 000443998400046