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).

Design and Implementation of the Hepatorenal Fibrocystic Disease Core Center Clinical Database: A Centralized Resource for Characterizing Autosomal Recessive Polycystic Kidney Disease and Other Hepatorenal Fibrocystic Diseases

“…As shown in Table 1, our analyses indicate that the annualized incidence of ARPKD is 1:26,485 live births, from which we estimate that there are ~120 new ARPKD neonatal survivors per year in the United States. This calculated incidence corresponds to the reported incidence of 1:20,000 live births derived from previous genetic studies (10). We used a similar strategy to calculate the annualized prevalence of ARPKD (Table 2).…”

Neonatal diabetes mellitus, congenital hypothyroidism, hepatic fibrosis, polycystic kidneys, and congenital glaucoma: A new autosomal recessive syndrome?

“…The presence of enlarged kidneys with multiple small cysts and poor differentiation of the corticomedullary junction, and normal kidney function in both sibs is suggestive of autosomal recessive polycystic kidney disease (ARPKD). ARPKD occurs in 1 in 6,000–1 in 40,000 live births [Zerres et al, 1998]. It is characterized by the combination of renal cystic disease and congenital hepatic fibrosis (CHF).…”

PKHD1 protein encoded by the gene for autosomal recessive polycystic kidney disease associates with basal bodies and primary cilia in renal epithelial cells

“…Some patients (Ͻ30%) die during early childhood because of respiratory and͞or renal dysfunction (5,7). Fibrosis of the liver and kidneys is also commonly seen (2,8,9), and chronic lung disease can be observed in 11% of surviving ARPKD patients (7).…”