Adult presentations of variable kidney and liver phenotypes secondary to biallelic PKHD1 pathogenic variants

The polycystic kidney and hepatic disease 1 ( PKHD1 ) gene located on chromosome 6p12 encodes for a large transmembrane protein called fibrocystin. Biallelic pathogenic variants in this gene cause autosomal recessive polycystic kidney disease (ARPKD). ARPKD often leads to both early-onset polycystic kidney disease as well as congenital hepatic fibrosis. In addition to the early onset phenotypes, some patients present much later with adult-onset liver involvement which is often labeled as Caroli’s syndrome. The kidney phenotype can resemble medullary sponge kidney disease with nephrolithiasis as well as atypical cystic kidney disease. Here, we present two families, each with 2 affected siblings, where the presenting liver and kidney features were variable among the siblings, with presentations including late-onset liver phenotypes, kidney features which had been labeled as medullary sponge kidney, and cystic kidney disease. Molecular genetic investigations identified biallelic pathogenic variants in PKHD1 in the affected siblings, including a novel nonsense allele. These cases emphasize the adult-onset and variable and sometimes discordant phenotypes that may be observed with PKHD1 biallelic pathogenic variants.