Prenatal diagnosis of autosomal recessive polycystic kidney disease (ARPKD): Molecular genetics, clinical experience, and fetal morphology

Abstract

Autosomal recessive polycystic kidney disease (ARPKD) is one of the most common hereditary renal cystic diseases and has a high infant mortality. Prenatal diagnosis using fetal sonography can be unreliable, especially in early pregnancy. The ARPKD locus has been mapped to proximal chromosome 6p allowing haplotype-based prenatal diagnosis in "at-risk" families. From December 1994 to March 1997, we received 258 inquiries regarding prenatal evaluation and we have completed analyses in 212 families. To date, 65 prenatal analyses have been performed in 57 families. In the majority of the requesting families (45/57), the index children are deceased and their DNA was extracted from paraffin-embedded tissue. Eighteen fetuses were homozygous for the disease-associated haplotypes. In 12 of these fetuses, pathoanatomical examination demonstrated typical ARPKD changes consisting of dilated collecting ducts and the characteristic hepatic ductal plate malformation. These changes were detected in two fetuses as early as 13 weeks gestational age. These cases represent the earliest demonstration of ARPKD-associated histopathology reported to date. One high risk fetus was carried to term and turned out to be unaffected. However, the diagnosis of ARPKD remained doubtful in the index patient. Forty-three fetuses were either heterozygous or homozygous for a nondisease-associated haplotype and all infants born were phenotypically unaffected at birth. In four cases, a recombination event occurred between the flanking markers and no genotypic prediction was possible. Three of these pregnancies were terminated and necropsy of the fetuses confirmed ARPKD, while one fetus was carried to term and showed no abnormalities at birth. These results show that haplotype-based prenatal testing is feasible and reliable in pregnancies "at risk" for ARPKD. An absolute prerequisite for these studies is an accurate diagnosis of ARPKD in previously affected sib(s).

Fibrocystin/Polyductin Modulates Renal Tubular Formation by Regulating Polycystin-2 Expression and Function

“…13 The estimated incidence of ARPKD is approximately 1 in 20,000 live births. 14 The clinical characteristics of ARPKD include ectasia of the renal collecting ducts and hepatic biliary ducts with associated renal and hepatic fibrosis. 15 Approximately 50% of patients with ARPKD present with their disease as neonates 16 and are born with two very large kidneys with 60 to 90% of the renal tubules being ectatic.…”

Biliary and Pancreatic Dysgenesis in Mice Harboring a Mutation in Pkhd1

“…ARPKD is a significant cause of pediatric morbidity and mortality with an estimated incidence of 1 in 20,000 live births. 1 The clinical spectrum is variable with ϳ30 to 50% of affected neonates dying shortly after birth and other patients surviving to adulthood. [2][3][4] The most severely affected fetuses have enlarged echogenic kidneys in utero with associated oligohydramnios indicative of intrauterine renal failure.…”

Biliary Dysgenesis in the PCK Rat, an Orthologous Model of Autosomal Recessive Polycystic Kidney Disease

“…[5][6][7][8] PKD is a multiorgan genetic disease and can be inherited as autosomal dominant (ADPKD) or autosomal recessive (ARPKD). In ARPKD, ϳ30% of affected neonates die because of greatly enlarged kidneys detected in utero or in the perinatal period.…”