Clinical and Molecular Characterization Defines a Broadened Spectrum of Autosomal Recessive Polycystic Kidney Disease (ARPKD)

Abstract

The autosomal recessive form of polycystic kidney disease (ARPKD) is generally considered an infantile disorder with the typical presentation of greatly enlarged echogenic kidneys detected in utero or within the neonatal period, often resulting in neonatal demise. However, there is an increasing realization that survivors often thrive into adulthood with complications of the ductal plate malformation, manifesting as congenital hepatic fibrosis and Caroli disease, becoming prominent. Previous natural history studies have concentrated almost exclusively on the infantile presenting group. However, developments in understanding the genetic basis of ARPKD, through identification of the disease gene, PKHD1, have allowed exploration of the etiology in patients with ARPKD-like disease or congenital hepatic fibrosis presenting later in childhood or as adults. In the current study we retrospectively reviewed the clinical records, and where possible performed PKHD1 mutation screening, in patients diagnosed with ARPKD or congenital hepatic fibrosis at the Mayo Clinic, Rochester, MN, from 1961 to 2004. Of a total of 133 cases reviewed, 65 were considered to meet the diagnostic criteria with an average duration of follow-up of 8.6 +/- 6.4 years. Fifty-five cases had ARPKD and 10 had isolated congenital hepatic fibrosis with no or minimal renal involvement. The patients were analyzed as 3 groups categorized by the age at diagnosis; <1 years (n = 22), 1-20 years (n = 23), and >20 years (n = 20). The presenting feature in the neonates was typically associated with renal enlargement, but in the older groups, more often involved manifestations of liver disease, including hepatosplenomegaly, hypersplenism, variceal bleeding, and cholangitis. During follow-up, 22 patients had renal insufficiency and 8 developed end-stage renal disease (ESRD), most from the neonatal group. Liver disease was evident on follow-up in all diagnostic groups but particularly prevalent in those diagnosed later in life. A total of 12 patients died, 6 in the neonatal period, but 86% of patients were alive at 40 years of age. The likelihood of being alive without ESRD differed significantly between the diagnostic groups with 36%, 80%, and 88% survival in the 3 diagnostic groups, respectively, 20 years after the diagnosis. Considerable evidence of intrafamilial phenotype variability was observed. Mutation analysis was performed in 31 families and at least 1 mutation was detected in 25 (81%), with 76% of mutant alleles detected in those cases. Consistent with the relatively mild disease manifestations in this population, the majority of changes were missense (79%) and no case had 2 truncating changes. Mutations were detected in all diagnostic groups, indicating that congenital hepatic fibrosis with minimal kidney involvement can result from PKHD1 mutation. The finding of 6 cases with no detected mutations may represent missed mutations or possible evidence of genetic heterogeneity. The current study indicates a broadened spectrum for the ARPKD phenotype and that ...

Biliary and Pancreatic Dysgenesis in Mice Harboring a Mutation in Pkhd1

“…Mutation analyses of ARPKD patients included individuals with predominant liver disease manifest as congenital hepatic fibrosis or Caroli's disease and only mild renal involvement. 6,7,10,[12][13][14]40 In such families, the mutations invariably include at least one predicted amino acid substitution that may act in a hypomorphic manner. In the case of the Pkhd1 del4 mouse model, the transcript bears a deletion of 66 amino acids that includes part of exon 4 and all of exon 5.…”

Posterior reversible encephalopathy syndrome in a uremic patient with autosomal recessive polycystic kidney disease

“…ARPKD is an inherited disorder characterized by various combinations of bilateral renal cysts and congenital hepatic fibrosis [6,14]. It has an estimated prevalence of 1 in 20000 live births.…”

Hereditary polycystic kidney disease: genetic diagnosis and counseling

“…Hepatosplenomegaly, portal hypertension and Caroli disease, in the presence of systemic hypertension and renal failure, serve to confirm the diagnosis (C). 9 In these cases, the kidney may be reduced in size (C). 10 …”