A family study of vesicoureteric reflux

Abstract

SUMMARY Vesicoureteric reflux is now considered to be due essentially to congenital malformation of the vesicoureteric junction. It is also considered to be a major cause of renal failure in early adult life. The condition is associated with recurrent urinary tract infection and in some instances with renal scarring. When reflux is detected clinically, in the investigation of patients with recurrent urinary tract infection, renal scarring is often already present. The reflux tends to disappear in later childhood.A family study has been made based on 186 index patients with established primary reflux, with special attention to a history of genitourinary symptoms in the sibs and parents of these patients. There were 39 sibs under the age of 4 years. For these the parents were offered investigation by micturating cystogram. The parents of 20 accepted. Reflux was shown in 3, and in 2 of these there was already renal scarring. The proportion of all infants and young children who have reflux is not accurately known, but the few published surveys of screening of normal infants and young children by micturating cystogram suggest that the prevalence is of the order of 1%. The prevalence in sibs is, then, about 10 times higher. There was a main group of 214 sibs over the age of 4 years. For these the parents were offered investigation by intravenous pyelogram only for those sibs who had a history of recurrent urinary tract infection. If renal scarring was found then a micturating cystogram was done. Of 110 sisters, 12 were 'symptomatic', renal scarring was found in 5 of these (1 was on haemodialysis), and reflux was still present in 3. Of 104 brothers 7 were 'symptomatic', renal scarring was found in 2 and reflux was present in both. For comparison, the published reports of several surveys of schoolgirls indicate that about 2 in 100 have recurrent urinary tract infection, and in about a quarter of these (0.5%) reflux was present and in about one-eighth (0-25%) renal scarring was present. The prevalence in sibs is, then, 10 to 20 times higher. Similarly in the parents: of 183 mothers 7 (1 was on haemodialysis) and of 181 fathers 2 had renal scarring.The family findings are consistent with multifactorial inheritance, as with other common malformations.Routine investigation, in infancy, of younger sibs of patients with vesicoureteric reflux would identify patients in whom the reflux was recognised very early. These would be valuable for the study of the natural history and management of the disorder, and the degree to which it was possible to prevent the development of renal scarring.

Vesicoureteral Reflux

“…73 Feather et al concluded that the VUR phenotype may result from an alteration in a number of different genes on different chromosomes. 73 Early family segregation studies suggested that more than one genetic alteration may be responsible for VUR in some families 74,75 It appears that in some families VUR can result from one DNA change, whereas in others more than one DNA change is required. Given the genetic variability, phenotypic variability is not surprising.…”

RET Gly691Ser mutation is associated with primary vesicoureteral reflux in the French-Canadian population from Quebec

“…Therefore, the Gly691Ser mutation could generate a spectrum of deficiencies of ureteral development manifesting as incomplete penetrance of disease phenotype. The possible genetic causes of the disease in the remaining 29% of patients in our group who do not carry the Gly691Ser mutation could include mutations in the unscreened regulatory regions of RET, deficiencies of another gene or multiple genes involved in urinary tract development [Devriendt et al, 1998;Eccles and Jacobs, 2000;Burger and Smith, 1971;Chapman et al, 1985;Eccles, 1998;Jerkins and Noe, 1982;de Vargas et al, 1978]. For example, the disruption of ROBO2 was recently found to confer risk of VUR [Lu et al, 2007].…”

“…This increased to 50% and 100%, respectively, when only the youngest individuals were considered [Stephens et al, 1955;Mebust and Foret, 1972;Uehling et al, 1992;Connolly et al, 1996;Kaefer et al, 2000]. Numerous studies failed to firmly establish the inheritance pattern of pVUR and it is unclear whether it is a monogenic or a polygenic disorder [Middleton et al, 1975;de Vargas et al, 1978;Jerkins and Noe, 1982;Chapman et al, 1985;Devriendt et al, 1998;Eccles and Jacobs, 2000;Pasch et al, 2004]. Despite the wide range of approaches used, very few predisposing genes or regions are known, either because only few families showed linkage to genes or regions studied or due to lack of published evidence to connect data generated in animal studies to humans.…”

A Locus for Renal Malformations Including Vesico-Ureteric Reflux on Chromosome 13q33–34

“…Previous studies have shown that VUR can occur in families, and genetic factors likely play an important role in the pathogenesis (9 -11,16). Different modes of inheritance of VUR have been suggested, including a dominant single gene and polygenic inheritance (27)(28)(29). Although cases of 13q deletion syndrome have been identified occasionally with renal malformations, VUR and ESRD previously have not been associated with 13q deletion (30 -33).…”