Autosomal recessive polycystic kidney disease (ARPKD) is a rare form of polycystic kidney disease that originates primarily from the collecting duct. It occurs in about 1:20,000 live births. The classic ARPKD phenotype is characterized by an early onset of disease with bilateral renal enlargement and impairment of renal function, congenital liver fibrosis with development of portal hypertension, and dilatation of the bile ducts with the risk of ascending cholangitis. In about 15-37% of the described ARPKD patients, gastrointestinal varices are detected. ARPKD is typically seen in utero or at birth and in the most severe cases includes the Potter sequence, low amniotic fluid levels, pulmonary hypoplasia and bilaterally enlarged echogenic kidneys. While kidney involvement typically occurs early in childhood, liver involvement tends to appear later. ARPKD is generally associated with a shortened life expectancy. A mortality rate of 30‑40% has been described in cases of neonatal respiratory difficulties, and about 50% of patients who survive the neonatal period develop terminal renal failure within the first decade of life. Despite the classic neonatal presentation of ARPKD, there is a significant variability in age at onset and clinical symptoms, including within a family.
The most frequent molecular cause is pathogenic variants in the PKHD1 gene. The heterozygote frequency in the Caucasian population is about 1:70. Therefore, a heterozygous PKHD1 variant is a relatively common random finding and does not necessarily mean an undetected variant on the second allele in an affected patient. No causative PKHD1 variants are identified by sequencing in 13-20% of cases. Genomic deletions or duplications are rarely detectable. In rare cases, causal changes in the DZIP1L gene can be found. Variants in numerous other genes, often from the group of ciliopathies, can also cause an ARPKD-like genotype. In addition, there are very early manifesting forms of autosomal dominant PKD or HNF1B-associated nephropathies that are also known as "phenocopies" (diseases with other molecular genetic causes with similar phenotype).
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