Associated nonurinary congenital anomalies among infants with congenital anomalies of kidney and urinary tract (CAKUT)

Infants with congenital anomalies of kidney and urinary tract (CAKUT) often have other associated anomalies. The purpose of this investigation was to assess the prevalence and the types of associated anomalies in CAKUT in a defined population from northeastern France. The associated anomalies in CAKUT were collected in all livebirths, stillbirths and terminations of pregnancy during 26 years in 346,831 consecutive births of known outcome in the area covered by our population based registry of congenital anomalies. Of the 1678 infants with CAKUT born during this period (prevalence at birth of 48.4 per 10,000), 563 (34%) had associated anomalies. There were 119 (7%) patients with chromosomal abnormalities including 33 trisomies 18 (2%), and 168 (10%) nonchromosomal recognized dysmorphic conditions. There were no predominant recognized dysmorphic conditions, but VA(C)TER(L) association (3%). However, other recognised dysmorphic conditions were registered including Meckel–Gruber syndrome (2%), and prune belly syndrome (1%). Two hundred seventy six (16%) of the patients had multiple congenital anomalies, non syndromic, non chromosomal (MCA). Anomalies in the musculoskeletal, the digestive, the cardiovascular and the central nervous systems were the most common other anomalies. Prenatal diagnosis was obtained in 71% of dysmorphic syndromes with CAKUT. In conclusion the overall prevalence of associated anomalies, which was one in three infants, emphasizes the need for a thorough investigation of infants with CAKUT. The most commonly associated major nonurinary anomalies involved the musculoskeletal system, followed by the digestive, the cardiovascular and the central nervous systems. A routine screening for other anomalies may be considered in infants and in fetuses with CAKUT. One should be aware that the anomalies associated with CAKUT can be classified into a recognizable anomaly syndrome or pattern in one out of six infants with CAKUT.     

Conditional loss of kidney microRNAs results in congenital anomalies of the kidney and urinary tract (CAKUT)

MicroRNAs have emerged as essential regulators of gene expression and may play important roles in a variety of human disorders. To understand the role of microRNA-mediated gene regulation in the kidney, we deleted the microRNA-processing enzyme Dicer in developing renal tubules and parts of the ureteric bud in mice. Genetic deletion of Dicer resulted in renal failure and death of the animals at 4–6 weeks of age. Interestingly, the kidneys of microRNA-deficient animals were small due to a reduced number of nephrons and showed massive hydronephrosis due to ureteropelvic junction obstruction. This phenotype is reminiscent of congenital anomalies of the kidney and urinary tract (CAKUT), an important group of human disorders characterized by a combination of renal hypoplasia with congenital abnormalities of the urinary tract. We used metanephric kidney cultures to examine the developmental defects underlying these pathologies. Dicer knockout kidneys showed a significant reduction of tubular branching explaining renal hypoplasia. Moreover, the ureters of these kidneys showed an altered morphology and impaired motility. These functional changes went along with altered expression of smooth muscle actin implying a defect in the differentiation of ureteric smooth muscle cells. In addition, we show the polycystic kidney disease gene Pkd1 to be a target of miR-20 implying that this interaction may contribute to the molecular basis for the cystogenesis in our model. In conclusion, these data demonstrate an essential role for microRNA-dependent gene regulation in mammalian kidney development and suggest that deregulation of microRNAs may underlie CAKUT, the most important group of renal disorders in humans.     

A truncating NRIP1 variant in an Arabic family with congenital anomalies of the kidneys and urinary tract

Congenital anomalies of the kidneys and urinary tract (CAKUT) constitute the most common cause of early-onset chronic kidney disease. In a previous study, we identified a heterozygous truncating variant in nuclear receptor-interacting protein 1 (NRIP1) as CAKUT causing via dysregulation of retinoic acid signaling. This large family remains the only family with NRIP1 variant reported so far. Here, we describe one additional CAKUT family with a truncating variant in NRIP1. By whole-exome sequencing, we identified one heterozygous frameshift variant (p.Asn676Lysfs*27) in an isolated CAKUT patient with bilateral hydroureteronephrosis and right grade V vesicoureteral reflux (VUR) and in the affected father with left renal hypoplasia. The variant is present twice in a heterozygous state in the gnomAD database of 125,000 control individuals. We report the second CAKUT family with a truncating variant in NRIP1, confirming that loss-of-function mutations in NRIP1 are a novel monogenic cause of human autosomal dominant CAKUT.     

Novel compound heterozygous pathogenic variants in nucleotide-binding protein like protein (NUBPL) cause leukoencephalopathy with multi-systemic involvement

NUBPL (Nucleotide-binding protein like) protein encodes a member of the Mrp/NBP35 ATP-binding proteins family, deemed to be involved in mammalian complex I (CI) assembly process. Exome sequencing of a patient presenting with infantile-onset hepatopathy, renal tubular acidosis, developmental delay, short stature, leukoencephalopathy with minimal cerebellar involvement and multiple OXPHOS deficiencies revealed the presence of two novel pathogenic compound heterozygous variants in NUBPL (p.Phe242Leu/p.Leu104Pro). We investigated patient's and control immortalised fibroblasts and demonstrated that both the peripheral and the membrane arms of complex I are undetectable in mutant NUBPL cells, resulting in virtually absent CI holocomplex and loss of enzyme activity. In addition, complex III stability was moderately affected as well. Lentiviral-mediated expression of the wild-type NUBPL cDNA rescued both CI and CIII assembly defects, confirming the pathogenicity of the variants. In conclusion, this is the first report describing a complex multisystemic disorder due to NUBPL defect. In addition, we confirmed the role of NUBPL in Complex I assembly associated with secondary effect on Complex III stability and we demonstrated a defect of mtDNA-related translation which suggests a potential additional role of NUBPL in mtDNA expression.     

Disease mechanisms of monogenic congenital anomalies of the kidney and urinary tract

Congenital Anomalies of the Kidney and Urinary Tract (CAKUT) is a developmental disorder of the kidney and/or genito-urinary tract that results in end stage kidney disease (ESKD) in up to 50% of children. Despite the congenital nature of the disease, CAKUT accounts for almost 10% of adult onset ESKD. Multiple lines of evidence suggest that CAKUT is a Mendelian disorder, including the observation of familial clustering of CAKUT. Pathogenesis in CAKUT is embryonic in origin, with disturbances of kidney and urinary tract development resulting in a heterogeneous range of disease phenotypes. Despite polygenic and environmental factors being implicated, a significant proportion of CAKUT is monogenic in origin, with studies demonstrating single gene defects in 10%–20% of patients with CAKUT. Here, we review monogenic disease causation with emphasis on the etiological role of gene developmental pathways in CAKUT.     

DYRK1A-related intellectual disability: a syndrome associated with congenital anomalies of the kidney and urinary tract

PurposeHaploinsufficiency of DYRK1A causes a recognizable clinical syndrome. The goal of this paper is to investigate congenital anomalies of the kidney and urinary tract (CAKUT) and genital defects (GD) in patients with DYRK1A variants.MethodsA large database of clinical exome sequencing (ES) was queried for de novo DYRK1A variants and CAKUT/GD phenotypes were characterized. Xenopus laevis (frog) was chosen as a model organism to assess Dyrk1a’s role in renal development.ResultsPhenotypic details and variants of 19 patients were compiled after an initial observation that one patient with a de novo pathogenic variant inDYRK1A had GD. CAKUT/GD data were available from 15 patients, 11 of whom presented with CAKUT/GD. Studies inXenopus embryos demonstrated that knockdown of Dyrk1a, which is expressed in forming nephrons, disrupts the development of segments of embryonic nephrons, which ultimately give rise to the entire genitourinary (GU) tract. These defects could be rescued by coinjecting wild-type human DYRK1A RNA, but not withDYRK1A^R205* or DYRK1A^L245R RNA.ConclusionEvidence supports routine GU screening of all individuals with de novo DYRK1A pathogenic variants to ensure optimized clinical management. Collectively, the reported clinical data and loss-of-function studies in Xenopus substantiate a novel role for DYRK1A in GU development.     

Chondroectodermal dysplasia (Ellis-van Creveld) with anomalies of CNS and urinary tract

We report on a 19-month-old girl with chondroectodermal dysplasia (Ellis-van Creveld) and other previously undescribed visceral and central nervous system anomalies. These anomalies include cerebral heterotopias, renal agenesis, and congenital megaureter.     

单中心6年先天性肾脏和尿道畸形病因构成分析

目的分析2005至2010年复旦大学附属儿科医院先天性肾脏和尿道畸形（CAKUT）诊断情况,为CAKUT的早期诊断提供线索。方法系统提取住院诊断为CAKUT病例的病史资料,将三聚氰胺事件结石筛查作为特殊暴露因素,与正常暴露因素下进行比较,分析CAKUT病种构成比、首次入院的病因和影像学检查。结果 6年间1358例CAKUT患儿进入分析,在重复入院只计1次的前提下CAKUT占同期住院患儿的1.33%（1358/102442）。男913例,女445例,男女比例为2.05∶1;首次入院时平均年龄为（3.0±3.4）岁。①正常暴露因素下CAKUT的住院构成比2005至2010年呈缓慢增高趋势（P〈0.05）,CAKUT的住院构成比特殊暴露因素较正常暴露因素下高0.67%和0.26%,2008至2009两个年度多筛查出112例达到手术干预指征的CAKUT病例,占同期正常因素暴露下达到手术干预指征CAKUT病例的24.4%[112/（227＋232）]。②CAKUT构成比排序前4位的病种分别为肾盂输尿管连接处梗阻（PUJO）、膀胱输尿管反流（VUR）、双集合系统和输尿管膀胱连接部梗阻（UVJO）,占总CAKUT病例的79.6%;③首诊通过产前B超检查发现异常406例（29.9%）,以PUJO、UVJO和输尿管膨出比例最高;48.5%（658/1358）CAKUT患儿有泌尿系统症状和体征（腹部症状、血尿、排尿异常、尿路感染伴发热和尿路感染）;尿路感染伴发热占41%（270/658）,为CAKUT病种主要的症状,〈2岁患儿是≥2岁患儿的3.2倍（206/64）;其他症状和体征均为≥2岁患儿明显多于〈2岁患儿。98.0%的CAKUT患儿进行B超检查,除VUR的B超异常检出率为68.5%外,其他CAKUT病种的B超异常检出率均〉94.0%;根据B超检查和临床表现,选择性进行了功能状态检查（DTPA、DMSA）1203例,形态学检查（MR、CT或IVP）1009例,反流情况（MCU）400例。结论 CAKUT构成比以PUJO、VUR、双集合系统和UVJO最为常见,泌尿系统B超筛查CAKUT的准确性较好。在人群中常规筛查可检出CAKUT,其成本效益有待进一步研究。     

A homozygous HOXA11 variation as a potential novel cause of autosomal recessive congenital anomalies of the kidney and urinary tract

Congenital anomalies of the kidney and urinary tract (CAKUT) is the leading cause of end-stage kidney disease in children. Until now, more than 50 monogenic causes for CAKUT have been described, all of which only explain 10% to 20% of all patients with CAKUT, suggesting the presence of additional genes that cause CAKUT when mutated. Herein, we report two siblings of a consanguineous family with CAKUT, both of which rapidly progressed to chronic kidney disease in early childhood. Whole-exome sequencing followed by homozygosity mapping identified a homozygous variation in HOXA11. We therefore showed for the first time an association between a homozygous HOXA11 variation with CAKUT in humans, expanding the genetic spectrum of the disease.     

Whole-exome sequencing in the molecular diagnosis of individuals with congenital anomalies of the kidney and urinary tract and identification of a new causative gene

PurposeTo investigate the utility of whole-exome sequencing (WES) to define a molecular diagnosis for patients clinically diagnosed with congenital anomalies of kidney and urinary tract (CAKUT).MethodsWES was performed in 62 families with CAKUT. WES data were analyzed for single-nucleotide variants (SNVs) in 35 known CAKUT genes, putatively deleterious sequence changes in new candidate genes, and potentially disease-associated copy-number variants (CNVs).ResultsIn approximately 5% of families, pathogenic SNVs were identified in PAX2, HNF1B, and EYA1. Observed phenotypes in these families expand the current understanding about the role of these genes in CAKUT. Four pathogenic CNVs were also identified using two CNV detection tools. In addition, we found one deleterious de novo SNV in FOXP1 among the 62 families with CAKUT. The clinical database of the Baylor Miraca Genetics laboratory was queried and seven additional unrelated individuals with novel de novo SNVs in FOXP1 were identified. Six of these eight individuals with FOXP1 SNVs have syndromic urinary tract defects, implicating this gene in urinary tract development.ConclusionWe conclude that WES can be used to identify molecular etiology (SNVs, CNVs) in a subset of individuals with CAKUT. WES can also help identify novel CAKUT genes.Genet Med 19 4, 412–420.     

The foetal and neonatal prostate in congenital malformation of the urinary tract

Summary The prostates of 1 stillbirth, 14 neonates and infants as well as of one child with renal tract malformations have been examined.The processes of proliferation of the tubule epithelium, squamous metaplasia and secretion were normal in 7 cases. Impairment of one or more of these features was noted in 7 instances. Another case showed an extreme degree of squamous metaplasia with cyst formation. Marked abnormalities in structure were found in 1 case. The derivatives of one or both Wolffian ducts were found to be absent in 5 cases.No definite correlation appears to exist between the severity of the urinary tract malformation and the findings in the prostate.It is of considerable interest to note that in a large number of cases with urinary tract malformations, the foetal and neonatal prostatic tissue still responded to the various hormonal stimuli to which this organ is subjected during intra-uterine life and that in particular its response to oestrogenic stimulation was hardly ever affected.Associated congenital malformations involving other systems than the urinary tract were present in 10 of the 16 cases.

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Zusammenfassung Die Prostata von einer Totgeburt, 14 Säuglingen und 1 Kleinkind wurde histologisch untersucht. Es bestanden in allen 16 Fällen gleichzeitig Nierenmißbildungen.In 7 Fällen waren Proliferation, Schuppenmetaplasie und Sekretion des prostatischen Epithels normal. Dagegen waren in 7 weiteren Fällen einer oder mehrere dieser Vorgänge beeinträchtigt. In einem anderen Falle wurde ein extremes Ausmaß von Schuppenmetaplasie mit Cystenbildung vorgefunden. Ein Fall zeigte auffallende Abweichungen von der normalen Drüsenstruktur. Die Derivate von einem oder von beiden Wolffschen Gängen waren in 5 Fällen nicht vorhanden.Es war kein wesentlicher Zusammenhang zwischen der Schwere der Nierenmißbildung und den Befunden an der Prostata nachzuweisen.Es muß besonders hervorgehoben werden, daß das prostatische Gewebe in der Mehrzahl der Fälle in normaler Weise auf die verschiedenen hormonalen, insbesondere östrogenen Reize ansprach, denen dieses Organ während des intra-uterinen Lebens ausgesetzt ist.10 der 16 Fälle zeigten gleichzeitig kongenitale Mißbildungen in anderen Systemen.