A Family Study and the Natural History of Prenatally Detected Unilateral Multicystic Dysplastic Kidney

The renal coloboma syndrome (OMIM 120330) is caused by mutations in the PAX2 gene. Typical findings in these patients include renal hypoplasia, renal insufficiency, vesicoureteric reflux, and optic disc coloboma. A family with a novel heterozygous 10-bp deletion in exon 2 of the PAX2 gene leading to a truncating mutation and variable phenotype across three generations is reported. The first presentation of multicystic dysplastic kidney in this syndrome is reported. The possibility that abnormal PAX2 protein in this case may cause a dominant negative effect also is discussed. The finding of multicystic dysplastic kidney in renal coloboma syndrome could suggest that PAX2 may play a role in early ureteric obstruction and subsequent renal maldevelopment.

Section: Discussionsupporting

confidence: 52%

Multicystic Dysplastic Kidney and Variable Phenotype in a Family with a Novel Deletion Mutation of PAX2

Fletcher

Berman³

et al. 2005

“…Indeed, serial ultrasonography before and after birth demonstrates that MCDK can enlarge and then involute to an "aplastic" phenotype (25). Hiroaka et al (26) described a similar tendency to involute in patients born with small noncystic kidneys that had minimal function as assessed by 99m Technetium-dimercaptosuccinic acid renograms; these organs were presumably dysplastic, although histology was unavailable.…”

Section: Rd Is a Dynamic Disordermentioning

confidence: 99%

“…Sometimes, these families have multiorgan syndromes, discussed below; in other cases, the anomaly is restricted to CAKUT. MCDK can occasionally be familial (25,50), and kindreds are reported in which some individuals have renal aplasia, or "absent kidneys," whereas others have large dysplastic organs (51,52); some of this phenotypic heterogeneity might be explained by the tendency of RD toward involution. Nishimura et al (41) reported an association with a polymorphism of AT2 in US and European patients with diverse urinary tract malformations, including MCDK.…”

Section: Genetics Of Human Rdmentioning

confidence: 99%

Evolving Concepts in Human Renal Dysplasia

Woolf¹,

Price²,

Scambler³

et al. 2004

153

128

Abstract. Human renal dysplasia is a collection of disorders in which kidneys begin to form but then fail to differentiate into normal nephrons and collecting ducts. Dysplasia is the principal cause of childhood end-stage renal failure. Two main theories have been considered in its pathogenesis: A primary failure of ureteric bud activity and a disruption produced by fetal urinary flow impairment. Recent studies have documented deregulation of gene expression in human dysplasia, correlating with perturbed cell turnover and maturation. Mutations of nephrogenesis genes have been defined in multiorgan dysmorphic disorders in which renal dysplasia can feature, including Fraser, renal cysts and diabetes, and Kallmann syndromes. Here, it is possible to begin to understand the normal nephrogenic function of the wild-type proteins and understand how mutations might cause aberrant organogenesis.Congenital anomalies of the kidney and urinary tract (CAKUT) account for one third of all anomalies detected by routine fetal ultrasonography (1). A recent UK audit of childhood end-stage renal failure reported that CAKUT was the cause in~40% of 882 individuals (2). Acquired glomerulonephritis and congenital nephrotic syndromes, respectively, accounted for just 18% and 8% of cases, with other diseases being rare (nephronophthisis, 5%; cystinosis, 3%; polycystic kidney diseases [PKD], 3%). With improvements in dialysis and transplantation, a new cohort of children with severe CAKUT is surviving to adulthood (3,4). The spectrum of diseases encompassed by the term "CAKUT" is wide, including kidney anomalies such as aplasia, hypoplasia, multicystic dysplastic kidneys, ureteric anomalies such as megaureter, ureteropelvic junction obstruction, ureterovesical junction obstruction or incompetence, duplex kidneys/ureters, and anomalies of the bladder and urethra (5). Approximately half of the CAKUT cases associated with end-stage renal failure in children have patent urinary tracts, whereas the rest have obstructive nephropathy (2). The latter are mainly boys with bladder outflow obstruction (BOO) and posterior urethral valves (2,6). Some renal functional impairment may be superimposed postnatally from bacterial pyelonephritis and/or persistent urinary flow impairment causing renal atrophy and fibrosis. However, the primary "hit" in CAKUT is clearly a developmental one, and the main renal pathology is renal dysplasia (RD). In her landmark book Normal and Abnormal Development of the Kidney published in 1972 (7), Edith Potter emphasized that one must understand normal development to generate realistic hypotheses on the pathogenesis of congenital malformations. Here, we summarize normal human kidney development, using Potter's work (7) as a basis but also incorporating recent summaries (8,9).The metanephric human kidney precursor forms 28 d after fertilization when ureteric bud (UB) branches from the mesonephric duct (MD). In the next few days, renal mesenchyme (RM) condenses from intermediate mesoderm around the UB tip, or ampulla. Ultimately...

“…Approximately 1000 UK children have end-stage renal failure, and in approximately half of these individuals, the cause is a congenital abnormality of both kidneys (2), usually renal dysplasia, in which kidneys begin to form but contain undifferentiated and metaplastic tissues, sometimes with cysts (3). Some such organs spontaneously involute to give an aplastic phenotype (4,5), and therefore a spectrum of anomalies is recognized, called renal "adysplasia" (6,7). Severe bilateral renal adysplasia occurs in approximately one in 10,000 births (3).…”

mentioning

confidence: 99%

De Novo Uroplakin IIIa Heterozygous Mutations Cause Human Renal Adysplasia Leading to Severe Kidney Failure

Jenkins¹,

Bitner‐Glindzicz²,

Malcolm³

et al. 2005

117

Human renal adysplasia usually occurs sporadically, and bilateral disease is the most common cause of childhood end-stage renal failure, a condition that is lethal without intervention using dialysis or transplantation. De novo heterozygous mutations in Uroplakin IIIa (UPIIIa) are reported in four of 17 children with kidney failure caused by renal adysplasia in the absence of an overt urinary tract obstruction. One girl and one boy in unrelated kindreds had a missense mutation at a CpG dinucleotide in the cytoplasmic domain of UPIIIa (Pro273Leu), both of whom had severe vesicoureteric reflux, and the girl had persistent cloaca; two other patients had de novo mutations in the 3 UTR (963 T3 G; 1003 T3 C), and they had renal adysplasia in the absence of any other anomaly. The mutations were absent in all sets of parents and in siblings, none of whom had radiologic evidence of renal adysplasia, and mutations were absent in two panels of 192 ethnically matched control chromosomes. UPIIIa was expressed in nascent urothelia in ureter and renal pelvis of human embryos, and it is suggested that perturbed urothelial differentiation may generate human kidney malformations, perhaps by altering differentiation of adjacent smooth muscle cells such that the metanephros is exposed to a functional obstruction of urine flow. With advances in renal replacement therapy, children with renal failure, who would otherwise have died, are surviving to adulthood. Therefore, although the mechanisms of action of the UPIIIa mutations have yet to be determined, these findings have important implications regarding genetic counseling of affected individuals who reach reproductive age.