Trial Information

Clinical and Molecular Investigations Into Ciliopathies

Human diseases caused by defects of the primary cilium (ciliopathies) are a group of
distinct disorders with overlapping features. Clinical features of ciliopathies include
fibrocystic disease of the kidneys and liver, retinal degeneration, obesity, structural and
functional defects of the central nervous system and the eyes, abnormal bone growth,
abnormal sidedness of internal organs and polydactyly. Human ciliopathies characterized by
variable combinations of these features include autosomal recessive (ARPKD) and dominant
(ADPKD) polycystic kidney diseases, nephronophthisis (NPHP), Joubert syndrome and related
disorders (JSRD), Bardet-Biedl (BBS), Meckel-Gruber (MKS), Oral-Facial-Digital-type 1
(OFD1), and Alstrom syndromes (AS) and skeletal disorders such as Jeune syndrome (JS) and
cleidocranial dysplasia. ARPKD, the most common pediatric ciliopathy, is characterized by
cystic degeneration of the kidneys and congenital hepatic fibrosis of the liver. JSRD are a
heterogenous group of syndromes characterized by a distinctive cerebellar and brainstem
malformation (molar tooth sign), intellectual disability, abnormal eye movements, and
abnormal respiratory pattern in infancy. Other common features seen in subsets of JSRD
patients include, fibrocystic renal disease, congenital hepatic fibrosis, retinal
degeneration, retinal colobomas, occipital encephalocele, and polydactyly. AS and BBS are
ciliopathies characterized by obesity and retinal degeneration and hepatorenal disease in
most cases. BBS patients also exhibit postaxial polydactyly, cognitive impairment, male
hypogonadotrophic hypogonadism and female genitourinary malformations. Additional features
in AS include metabolic syndrome associated with insulin resistance and hyperlipidemia,
cardiomyopathy and sensorineural deafness. OFD-I is characterized by polycystic kidney
disease and oral, digital and brain anomalies including cerebellar hypoplasia with or
without Dandy- Walker malformation. JS is a skeletal ciliopathy characterized by small
thorax, short- limbed short stature, fibrocystic renal disease and retinal degeneration. The
frequency and characteristics and natural history of specific organ/system disease in
ciliopathies are either unknown or poorly defined, mostly because of the limited data
available from retrospective reports of small numbers of patients.

In this protocol, we will evaluate up to 500 children and adults with various ciliopathies
with special emphasis on delineating the characteristics of individual organ system
involvement including kidney, liver, eye, central nervous system and bone disease and
metabolic derangements associated with obesity/insulin resistance/metabolic syndrome. We
will perform mutation analysis of the related ciliopathy genes as needed. Routine outpatient
evaluations will last 4-5 days and follow up visits will occur approximately every 1-2
years. This protocol will provide longitudinal information regarding progression of
individual organ system disease in a large cohort of ciliopathy patients, and will elucidate
genotype-phenotype correlations. The protocol will also allow the investigators to acquire
sufficient expertise in relatively common ciliopathies such as ARPKD, JSRD and AS to design
therapeutic interventions for specific organ diseases in the future.