Human disorders caused by defects of the cilia and/or centrosome (ciliopathies) are a group of distinct syndromes with overlapping features. Human ciliopathies include polycystic kidney diseases (PKD), nephronophthisis (NP), Joubert (JS) and related cerebello-oculo-renal syndromes (CORS), Bardet-Biedl (BBS), Meckel-Gruber (MGS), Oral-Facial-Digital (OFD), and Alstrom syndromes (AS). Autosomal recessive polycystic kidney disease (ARPKD), the most common pediatric ciliopathy, is characterized by cystic degeneration of the kidneys and congenital hepatic fibrosis (CHF) of the liver. JS is characterized by a distinctive cerebellar and brainstem malformation (molar tooth sign), developmental delays, episodic hyperpnea/apnea and atypical eye movements. Other features identified in JS/CORS patients include retinal dystrophy, renal disease, CHF, ocular colobomas, occipital encephalocele, and polydactyly. BBS is characterized by retinal dystrophy, truncal obesity, postaxial polydactyly, cognitive impairment, male hypogonadotrophic hypogonadism, female genitourinary malformations, and renal dysfunction. AS is characterized by retinal dystrophy, obesity, progressive sensorineural hearing impairment, dilated cardiomyopathy, the insulin resistance .syndrome, developmental delay and renal and hepatic disease. OFD-I is characterized, by polycystic kidney disease, facial dysmorphism, and oral, digital and brain anomalies including cerebellar agenesis with or without Dandy-Walker malformation. Although at least a subset of the patients with JS/CORS, BBS, OFD, and AS are known to have significant kidney and liver involvement, the characteristics of kidney and liver disease in these syndromes are poorly defined mostly because of the limited data available only from retrospective reports.

In this protocol, we will clinically evaluate up to 300 children and adults with ARPKD/CHF and other rare ciliopathies with special emphasis on delineating the kidney and liver involvement. We will perform mutation analysis of the related genes when needed. Routine admissions will last 4-5 days and will occur approximately every 12 months. This protocol will provide longitudinal information regarding progression of renal and hepatic disease in a large cohort of patients, and will elucidate genotype-phenotype correlations. The protocol will also allow the investigators to acquire sufficient expertise in ARPKD to design therapeutic interventions in the future.