Clinical characteristics: Classic Joubert syndrome (JS) is characterized by three primary findings:
A distinctive cerebellar and brain stem malformation called the molar tooth sign (MTS)
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. Additional findings can include retinal dystrophy, renal disease, ocular colobomas, occipital encephalocele, hepatic fibrosis, polydactyly, oral hamartomas, and endocrine abnormalities. Both intra- and interfamilial variation are seen.
Diagnosis/testing: The clinical diagnosis of JS is based on the presence of characteristic clinical features and MRI findings. To date pathogenic variants in 34 genes are known to cause JS; 33 of these are autosomal recessive and one is X-linked. A molecular diagnosis of JS can be established in about 62%-94% of individuals with a clinical diagnosis of JS by identification of biallelic pathogenic variants in one of the 33 autosomal recessive JS-related genes or a heterozygous pathogenic variant in the one X-linked JS-related gene.
Management: Treatment of manifestations: Infants and children with abnormal breathing may require stimulatory medications (e.g., caffeine); supplemental oxygen; mechanical support; or tracheostomy in rare cases. Other interventions may include speech therapy for oromotor dysfunction; occupational and physical therapy; educational support, including special programs for the visually impaired; and feedings by gastrostomy tube. Surgery may be required for polydactyly and symptomatic ptosis and/or strabismus. Nephronophthisis, end-stage renal disease, liver failure and/or fibrosis are treated with standard approaches.
Surveillance: Annual evaluations of growth, vision, and liver and kidney function; periodic neuropsychologic and developmental testing.
Agents/circumstances to avoid: Nephrotoxic medications such as nonsteroidal anti-inflammatory drugs in those with renal impairment; hepatotoxic drugs in those with liver impairment.
Genetic counseling: JS is predominantly inherited in an autosomal recessive manner. JS caused by pathogenic variants in 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. Once the pathogenic variants have been identified in an affected family member, carrier testing for at-risk family members, prenatal testing for pregnancies at increased risk, and preimplantation genetic testing are possible. For pregnancies known to be at increased risk for JS, prenatal diagnosis by ultrasound examination with or without fetal MRI has been successful.
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