Neonatal presentation of autosomal dominant polycystic kidney disease with a maternal history of tuberous sclerosis

Background. Childhood presentation of polycystic kidney disease has been reported with tuberous sclerosis complex (TSC). Recently some such cases have been shown to be due to combined deletion of the PKD1 and TSC2 genes, which lie close together on chromosome 16. The phenomenon of anticipation, whereby disease presentation occurs at a progressively earlier age in each generation, has been suggested to occur in autosomal dominant polycystic kidney disease (ADPKD). We have carried out a genetic study of a family in which these issues became clinically relevant. Neonatal presentation of polycystic kidneys occurred in an individual with a maternal family history of epilepsy and features of TSC without renal cystic disease. Methods. Detailed historical and clinical profiles were gathered for three generations of the maternal and paternal families. Both parents underwent renal ultrasound scanning. Genomic DNA was obtained from affected and unaffected individuals from the maternal family and used for linkage analysis to gene loci for TSC. Results. Renal cysts were not present in the mother by ultrasound. Linkage to TSC2 was found for members of the maternal family with clinical features of TSC. While a diagnosis of TSC was confirmed in her mother the child was found not to have inherited the disease-related allele. The father was found to have asymptomatic bilateral polycystic kidneys consistent with ADPKD. The presence of ADPKD in other paternal relatives could not be confirmed. Conclusions. The index case was found to have paternally inherited ADPKD with unusually early presentation. While at risk for concomitant maternal inheritance of TSC this diagnosis was ruled out by linkage analysis studies. The ability to clarify the true nature of a complex inherited condition greatly facilitates future management and counselling. The mechanisms underlying phenotypic heterogeneity in ADPKD remain to be clearly defined and are the subject of ongoing investigation.