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.

- INCLUSION CRITERIA:

Children and adults who carry a clinical diagnosis of a known ciliopathy such as ARPKD,
CHF, JSRD, BBS, OFD1, AS and those patients who have typical features suggestive of a
ciliopathy but not fulfilling the diagnostic criteria for any

of the known disorders (unknown types of PKD and/or CHF, retinal degeneration, variants of
molar tooth sign such as Dandy-Walker variants). This might rarely include adults who are
unable to give informed consent.

Among patients who have received a kidney or liver allograft, those with stable graft
function and without severe transplantrelated

complications are eligible for enrollment.

EXCLUSION CRITERIA:

Infants under 6 months of age

Medically fragile patients who require frequent hospitalizations due to complications of
end-stage renal disease (uncontrolled hypertension, severe electrolyte imbalances), hepatic
disease (current variceal bleeding, overt encephalopathy, intractable recurrent
cholangitis), severe cardiomyopathy as seen in some AS patients, or severe respiratory
abnormalities as seen in some JSRD patients with severe brain stem involvement.