The term Joubert syndrome (JS) has been coined to describe all disorders presenting with molar tooth sign on brain neuroimaging. Joubert syndrome is a clinically and genetically heterogeneous group of disorders also characterized by accompanying neurologic symptoms, including dysregulation of breathing pattern and developmental delay. Retinal dystrophy and renal anomalies are also included in the clinical spectrum.
Neurological signs are present from the neonatal period and include hypotonia progressing to ataxia, global developmental delay, ocular motor apraxia, and breathing dysregulation. These signs are variably associated with multiorgan involvement, mainly of the retina, kidneys, skeleton, and liver. Notable clinical and genetic overlap exists between distinct ciliopathies, which can co-occur even within families.
Diagnosis is based on the main clinical features (hypotonia, ataxia, development delay and oculomotor apraxia), which must be accompanied by the presence of the molar tooth sign on magnetic resonance imaging (MRI). Of note, the differential diagnosis of the imaging of posterior fossa anomalies includes arachnoid cyst, Blake's pouch cyst, Dandy-Walker malformation, vermian agenesis, rhombencephalosynapsis, Chiari II malformation, ischemia, and tumors.
To date mutations in one of the following genes are identified in about 50% of individuals with JS: NPHP1, CEP290, AHI1, TMEM67 (MKS3), RPGRIP1L, CC2D2A, ARL13B, INPP5E, OFD1, TMEM216, KIF7, TCTN1, TCTN2, TMEM237, CEP41, TMEM138, C5orf42, TMEM231, and TCTN3. The other loci at which mutations may cause the syndrome are still unknown. All of these genes encode for proteins of the primary cilium or its apparatus.
The primary cilium is a subcellular organelle that has key roles in development and in many cellular functions: so Joubert syndrome is part of the ciliopathies family. Through both motility and sensory functions, cilia play critical roles in development, homeostasis, and disease. The cilium is assembled from mature (mother) centrioles or basal bodies, which serve to nucleate growth of axonemes that give rise to two structurally distinct variants, motile and nonmotile cilia. Ciliary defects have been described in retinopathies such as retinitis pigmentosa and Leber congenital amaurosis (defects in photoreceptor ciliary protein complexes), renal syndromes with nephronophthisis and cystic dysplastic kidneys, and liver conditions such as fibrosis and biliary cirrhosis. Recognizing the diverse presentations of the ciliopathies and screening strategies following diagnosis is an important part of the treatment plan of children with cilia-related disorders.
The management of Joubert syndrome
Infants and children with abnormal breathing may require stimulatory medications (e.g., caffeine); supplemental oxygen; mechanical support; or tracheostomy in rare cases. Speech therapy and occupational therapy are often recommended. Polydactyly may be corrected with surgery.
Psychotropic medications may be used to treat behavioral problems, but no single medication has been uniformly accepted as a gold standard.
Liver failure and/or fibrosis should be managed by a gastroenterologist with arrangements for surgical intervention such as portal shunting for esophageal varices and portal hypertension, as appropriate.
