Joubert's syndrome

Synonyms: Joubert-Boltshauser syndrome, cerebelloparenchymal disorder IV, familial cerebellar vermis agenesis, cerebello-oculo-renal syndrome.¹

Joubert's syndrome is a rare autosomal recessive condition characterised by partial or complete absence of the cerebellar vermis, leading to neonatal breathing abnormalities, jerky eye movements, hypotonia, ataxia, impaired equilibrium, and mental handicap.²

Epidemiology

The incidence of Joubert's syndrome has been estimated to range between 1/80,000 and 1/100,000 live births, although this may be an underestimate.³

Genetics

Joubert's syndrome is transmitted as an autosomal recessive trait (genetic heterogeneity - chromosome 9 is a possible candidate⁴). Mutations in five genes have been identified, including AHI1, NPHP1 and RPGRIP1L.⁵⁶

Recurrence risk is 25% in most families, although X-linked inheritance should also be considered.

Presentation

Onset is in early infancy with abnormally rapid breathing, jerky eye movements, mental retardation, hemifacial spasms, seizures and ataxia:

• Eyes: abnormal eye movements, chorioretinal coloboma, ptosis, and retinal dysplasia.

• Mouth: tongue tumours and protrusion.

• Hand and foot: polydactyly.

• Neurological: hypotonia, hypoplasia or aplasia of the cerebellar vermis, occasional occipital meningo-encephalocele, hemifacial spasms and ataxia.

• Gastrointestinal: duodenal atresia or fibrosis.

• Renal: cystic kidneys.

• Mental and motor retardation.

• Behavioural problems: self-mutilation.

• Neonatal apnoea followed by episodic hyperpnoea which may improve and subsequently disappear.

Investigations

• The diagnosis of Joubert's syndrome is confirmed with MRI, which shows classic neuroradiological finding of a complex midbrain-hindbrain malformation known as the 'molar tooth sign' (MTS), originating from the association of cerebellar vermis hypoplasia, horizontally-oriented and thickened superior cerebellar peduncles and a deepened interpeduncular fossa ('molar tooth sign').²⁷

• Detection of the MTS should be followed by a diagnostic protocol to assess multi-organ involvement.

• MRI findings also include dilated cisterna magna, occipital meningo-encephalocele, Dandy-Walker malformation, hypoplasia of the corpus callosum, retrobulbar cystic mass.

• Abdominal ultrasound may show cystic kidneys.

• Genetic testing is not currently available but the physical abnormalities may be detected at antenatal ultrasound. A fetal MRI scan at between 20 and 22 weeks of gestation has been shown to be an effective method of antenatal diagnosis.⁸

Differential diagnosis

Other autosomal recessive ataxias, eg Friedreich's ataxia, ataxia-telangiectasia.⁹

Associated disorders

Leber's amaurosis (blindness with normal optic fundi and brain and kidney abnormalities) may be associated.

Management

• Treatment is symptomatic and supportive and will include physiotherapy, and occupational and speech therapy.

• The parents will need a great deal of support.

Prognosis

• This depends on the degree of malformation or agenesis of the cerebellar vermis.

• Some will have a mild form with mild physical disability and good mental development.

• In others, there may be severe physical disability, moderate mental retardation and death in infancy or early childhood.