Joubert syndrome

JS is, with rare exceptions, inherited in an autosomal recessive manner; OFD1-related JS is X-linked, and SUFU-related JS may follow an autosomal recessive or autosomal dominant pattern. For autosomal recessive forms, the recurrence risk for siblings of an affected proband is 25%. Prenatal molecular testing is technically possible once the familial pathogenic variants have been identified.

The diagnosis of JS rests on the identification of the molar tooth sign on axial brain MRI, comprising an abnormally deep interpeduncular fossa, prominent and thickened superior cerebellar peduncles, and cerebellar vermis hypoplasia. High-quality MRI with thin (≤3 mm) axial cuts through the posterior fossa, combined with standard axial, coronal, and sagittal sequences, is used to demonstrate these features. Confirmation of the genetic basis requires molecular genetic testing, as no biochemical marker is available and the imaging features alone do not identify the underlying gene.

Main differential diagnoses include:

• Dandy-Walker malformation: posterior fossa anomaly with cystic dilatation of the fourth ventricle and vermis hypoplasia or agenesis, but without the molar tooth sign on axial MRI; ZIC1, ZIC4, FOXC1, and others
• Poretti-Boltshauser syndrome: cerebellar dysplasia with cerebellar cysts, ataxia, oculomotor apraxia, and cognitive impairment without the molar tooth sign; LAMA1
• : lethal perinatal ciliopathy with occipital encephalocele, cystic kidney dysplasia, and polydactyly, forming a phenotypic continuum with severe JS; MKS1, TMEM67, CC2D2A, CEP290, and others

• Establishing the molecular diagnosis confirms the clinical suspicion and often ends a diagnostic odyssey.
• Identification of the causative gene enables specific and individualised surveillance – including monitoring for retinal dystrophy, kidney disease, and hepatic involvement – and is a prerequisite for targeted medical care.
• Identification of the familial pathogenic variants enables predictive testing and reproductive counselling for at-risk relatives.

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