Classic Joubert syndrome is characterized by three primary findings: A distinctive cerebellar and brain stem malformation called the molar tooth sign (MTS) . Hypotonia. Developmental delays . Often these findings are accompanied by episodic tachypnea or apnea and/or atypical eye movements. In general, the breathing abnormalities improve with age, truncal ataxia develops over time, and acquisition of gross motor milestones is delayed. Cognitive abilities are variable, ranging from severe intellectual disability to normal. The designation Joubert syndrome and related disorders (JSRD) is used to describe individuals with JS who have additional findings including retinal dystrophy, renal disease, ocular colobomas, occipital encephalocele, hepatic fibrosis, polydactyly, oral hamartomas, and endocrine abnormalities. Both intra- and interfamilial variation are seen.
The diagnosis of JSRD is based on the presence of characteristic clinical features and magnetic resonance images (MRI) through the junction of the midbrain and pons (isthmus region) that resemble a molar tooth. To date mutations in one of the following 18 genes are identified in about 50% of individuals with a JSRD: NPHP1, CEP290, AHI1, TMEM67 (MKS3), RPGRIP1L, CC2D2A, ARL13B, INPP5E, OFD1, TMEM216, KIF7, TCTN1, TCTN2, TMEM237, CEP41, TMEM138, C5orf42, and TTC21B; the other genes in which mutations are causative are unknown. Molecular genetic testing is clinically available for most of the known genes.
JSRDs are predominantly inherited in an autosomal recessive manner. JSRD caused by mutation of OFD1 is inherited in an X-linked manner. Digenic inheritance has been reported. For autosomal recessive inheritance: at conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk family members and prenatal testing for pregnancies at increased risk are possible if the disease-causing mutations have been identified in the family. For pregnancies at known increased risk for Joubert syndrome prenatal diagnosis by ultrasound examination with or without fetal MRI has been successful.