Diseases of the nonmotile cilia are commonly associated with a spectrum of fibrocystic changes in the kidneys and the liver, including PKD, nephronophthisis (NPHP) and renal cystic dysplasia, congenital hepatic fibrosis, Caroli's disease, and polycystic liver disease (20
). Other features include developmental anomalies of the cerebellum and midbrain, retinal degeneration, colobomas of the retina and iris, polydactyly, abnormal bone growth, obesity, anosmia and other sensory defects, situs defects, and pancreatic cysts or dysplasia (). Autosomal dominant (ADPKD) and recessive (ARPKD) polycystic kidney diseases and NPHP are the most common hepatorenal fibrocystic diseases. Pleiotropic syndromic ciliopathies with multisystem involvement include Joubert syndrome (JS) and related cerebellar disorders, Bardet-Biedl (BBS), Alstrom syndrome, Meckel-Gruber (MKS), Senior-Loken syndrome, and oral-facial-digital type 1 (OFD1) syndromes. Skeletal ciliopathies include Jeune chondrodysplasia, cranioectodermal dysplasia, short-rib polydactyly, and Ellis-Van Creveld (EVC) syndromes.
Liver disease in ciliopathies is not a primary disease of the hepatocytes but rather is a developmental defect of the portobiliary system, termed ductal plate malformation (DPM) (21
). DPM is defective remodeling of the biliary system characterized by retention of excessive numbers of embryonic bile duct remnants, abnormal portal veins, and periportal fibrosis. DPM of the peripheral biliary system causes congenital hepatic fibrosis, whereas DPM of the central biliary tree results in Caroli's disease. The combination of the two is referred to as Caroli's syndrome. The characteristics of liver disease in ARPKD and ADPKD are different. ARPKD is characterized by congenital hepatic fibrosis and Caroli's disease and is often complicated by portal hypertension, whereas ADPKD patients develop polycystic liver disease and typically do not have portal hypertension (20
). In contrast to Caroli's disease/Caroli's syndrome, in which liver cysts are dilated parts of the bile tree itself, polycystic liver disease is characterized by isolated cysts that are not in continuity with the bile tree.
JS and related cerebellar disorders are a heterogeneous group of disorders in which the defining common pathology is the so-called “molar tooth sign” on axial brain MRI that is caused by a combination of mid- and hindbrain anomalies, including cerebellar vermis hypoplasia and abnormal superior cerebellar peduncles (23
). Oculomotor apraxia and speech apraxia are typical. Variable features in JS include retinal degeneration, colobomas, renal disease (commonly in the form of NPHP), congenital hepatic fibrosis/Caroli's syndrome, and polydactyly. BBS is characterized by retinal degeneration, cognitive impairment, obesity, and hypothalamic hypogonadism in male patients; variable features include renal disease, congenital hepatic fibrosis, polydactyly, cardiac defects, situs inversus, and abnormalities of internal genital organs in female patients (24
). Älstrom syndrome is also characterized by retinal dystrophy, obesity, cardiomyopathy, progressive sensorineural hearing impairment, and insulin resistance. MKS represents the most severe end of the nonmotile ciliopathy spectrum, with the typical triad of occipital encephalocele, cystic dysplastic kidneys, and postaxial polydactyly (25
). Congenital hepatic fibrosis is an invariable feature in MKS. OFD1 is an X-linked dominant, male-lethal, nonmotile ciliopathy characterized by prominent external features, including oral clefts, hamartomas, or cysts of the tongue, and digital anomalies and visceral involvement, including PKD and biliary and pancreatic cystic disease (26
). Jeune chondrodysplasia, which is also referred to as asphyxiating thoracic dysplasia, is characterized by small thorax due to short ribs, short stature that is mainly caused by short limbs, and polydactyly (27
). Jeune patients who survive the small thorax-related respiratory distress develop NPHP, retinopathy, and fibrocystic disease of the pancreas. EVC is characterized by short stature associated with short limbs, congenital cardiac defects, teeth abnormalities, congenital hepatic fibrosis, and situs anomalies in some cases (28
). Cranioectodermal dysplasia is characterized by frontal predominance and widely spaced eyes; teeth, hair, and nail abnormalities; congenital hepatic fibrosis; and a NPHP-like renal pathology (29
Genetic heterogeneity (multiple genes causing similar clinical phenotype) and genotypic and phenotypic overlap are two characteristics of syndromic ciliopathies (30
). There are multiple genes identified for JS and related cerebellar disorders, BBS, and MKS, still not accounting for all patients. These disorders were originally defined based on their most prominent clinical features. As we understand these disorders better, we realize that the borders between them are blurred at the phenotypic and genotypic levels.