ARPKD/CHF is an inherited disease characterized by non-obstructive fusiform dilatation of the renal collecting ducts leading to enlarged spongiform kidneys and ductal plate malformation of the liver resulting in congenital hepatic fibrosis. ARPKD/CHF has a broad spectrum of clinical presentations involving the kidney and liver. Imaging plays an important role in the diagnosis and follow-up of ARPKD/CHF. Combined use of conventional and high-resolution US with MR cholangiography in ARPKD/CHF patients allows detailed definition of the extent of kidney and hepatobiliary manifestations without requiring ionizing radiation and contrast agents.

Background and objectives: Renal function and imaging findings have not been comprehensively and prospectively characterized in a broad age range of patients with molecularly confirmed autosomal recessive polycystic kidney disease (ARPKD).Design, setting, participants, & measurements: Ninety potential ARPKD patients were examined at the National Institutes of Health Clinical Center. Seventy-three fulfilled clinical diagnostic criteria, had at least one PKHD1 mutation, and were prospectively evaluated using magnetic resonance imaging (MRI), high-resolution ultrasonography (HR-USG), and measures of glomerular and tubular function.Results: Among 31 perinatally symptomatic patients, 25% required renal replacement therapy by age 11 years; among 42 patients who became symptomatic beyond 1 month (nonperinatal), 25% required kidney transplantation by age 32 years. Creatinine clearance (CrCl) for nonperinatal patients (103 ؎ 54 ml/min/1.73 m 2 ) was greater than for perinatal patients (62 ؎ 33) (P ‫؍‬ 0.002). Corticomedullary involvement on HR-USG was associated with a significantly worse mean CrCl (61 ؎ 32) in comparison with medullary involvement only (131 ؎ 46) (P < 0.0001). Among children with enlarged kidneys, volume correlated inversely with function, although with wide variability. Severity of PKHD1 mutations did not determine kidney size or function. In 35% of patients with medullary-only abnormalities, standard ultrasound was normal and the pathology was detectable with HR-USG.Conclusions: In ARPKD, perinatal presentation and corticomedullary involvement are associated with faster progression of kidney disease. Mild ARPKD is best detected by HR-USG. Considerable variability occurs that is not explained by the type of PKHD1 mutation.Clin J Am Soc Nephrol 5: 972-984, 2010.

PKHD1, the gene mutated in autosomal recessive polycystic kidney disease (ARPKD)/Congenital hepatic fibrosis (CHF), is an exceptionally large and complicated gene that consists of 86 exons and has a number of alternatively spliced transcripts. Its longest open reading frame contains 67 exons that encode a 4074 amino acid protein called fibrocystin or polyductin. The phenotypes caused by PKHD1 mutations are similarly complicated, ranging from perinatally-fatal PKD to CHF presenting in adulthood with mild kidney disease. To date, more than 300 mutations have been described throughout PKHD1. Most reported cohorts include a large proportion of perinatal-onset ARPKD patients; mutation detection rates vary between 42% and 87%. Here we report PKHD1 sequencing results on 78 ARPKD/CHF patients from 68 families. Differing from previous investigations, our study required survival beyond 6 months and included many adults with a CHF-predominant phenotype. We identified 77 PKHD1 variants (41 novel) including 19 truncating, 55 missense, 2 splice, and 1 small in-frame deletion. Using computer-based prediction tools (GVGD, PolyPhen, SNAP), we achieved a mutation detection rate of 79%, ranging from 63% in the CHF-predominant group to 82% in the remaining families. Prediction of the pathogenicity of missense variants will remain challenging until a functional assay is available. In the meantime, use of PKHD1 sequencing data for clinical decisions requires caution, especially when only novel or rare missense variants are identified.

Objectives-To describe 3 children with mutations in a Meckel syndrome gene (MKS3), with features of autosomal recessive polycystic kidney disease (ARPKD), nephronophthisis, and Joubert syndrome (JS).Study design-Biochemical evaluations, magnetic resonance and ultrasound imaging, electroretinograms, IQ testing, and sequence analysis of the PKHD1 and MKS3 genes were performed. Functional consequences of the MKS3 mutations were evaluated by cDNA sequencing and transfection studies with constructs of meckelin, the protein product of MKS3.Results-These 3 children with MKS3 mutations had features typical of ARPKD, that is, enlarged, diffusely microcystic kidneys and early-onset severe hypertension. They also exhibited early-onset chronic anemia, a feature of nephronophthisis, and speech and oculomotor apraxia, suggestive of JS. Magnetic resonance imaging of the brain, originally interpreted as normal, revealed midbrain and cerebellar abnormalities in the spectrum of the "molar tooth sign" that characterizes JS.Conclusions-These findings expand the phenotypes associated with MKS3 mutations. MKS3-related ciliopathies should be considered in patients with an ARPKD-like phenotype, especially in the presence of speech and oculomotor apraxia. In such patients, careful expert evaluation of the brain images can be beneficial because the brain malformations can be subtle.Human ciliopathies, caused by defects in proteins that reside on the cilia or its basal body, include disorders of both the respiratory (motile) and primary (immotile) cilia. 1 Primary cilia are important organelles that sense extracellular chemical and mechanical stimuli such as fluid flow within kidney tubules and bile ducts. Nephronophthisis is generally characterized by chronic tubulointerstitial nephritis that progresses to renal failure. 24,25 Renal ultrasound shows kidneys of normal or small size with increased echogenicity. In contrast to ARPKD, in which the microscopic cystic dilatations of the collecting ducts appear throughout the cortex and the medulla and result in enlarged kidneys from birth, the renal cysts in nephronophthisis typically localize at the corticomedullary junction and occur after renal failure develops. 24 Blood pressure in juvenile nephronophthisis is typically normal before the onset of renal failure. To date, mutations in 8 different genes (NPHP1,3,4,5,6,7,8,and 9) have been identified in juvenile nephronophthisis. MKS3 mutations have not been associated with NPHP. Approximately 10% to 20% of patients with nephronophthisis have extrarenal organ involvement that resembles other disorders.In this report, we present detailed findings of 3 children who were ascertained by clinical characteristics of ARPKD and JSRD, but who exhibited pathogenic MKS3 mutations. These cases illustrate an overlap among ARPKD, nephronophthisis, and JSRD and extend the clinical spectrum of MKS3-related ciliopathies. MethodsThe patients and their families were evaluated at the NIH Clinical Center under the intramural protocol number 03-HG-0264 appr...