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Review
. 2010 Jul 8:5:20.
doi: 10.1186/1750-1172-5-20.

Joubert Syndrome and related disorders

Affiliations
Review

Joubert Syndrome and related disorders

Francesco Brancati et al. Orphanet J Rare Dis. .

Abstract

Joubert syndrome (JS) and related disorders (JSRD) are a group of developmental delay/multiple congenital anomalies syndromes in which the obligatory hallmark is the molar tooth sign (MTS), a complex midbrain-hindbrain malformation visible on brain imaging, first recognized in JS. Estimates of the incidence of JSRD range between 1/80,000 and 1/100,000 live births, although these figures may represent an underestimate. The neurological features of JSRD include hypotonia, ataxia, developmental delay, intellectual disability, abnormal eye movements, and neonatal breathing dysregulation. These may be associated with multiorgan involvement, mainly retinal dystrophy, nephronophthisis, hepatic fibrosis and polydactyly, with both inter- and intra-familial variability. JSRD are classified in six phenotypic subgroups: Pure JS; JS with ocular defect; JS with renal defect; JS with oculorenal defects; JS with hepatic defect; JS with orofaciodigital defects. With the exception of rare X-linked recessive cases, JSRD follow autosomal recessive inheritance and are genetically heterogeneous. Ten causative genes have been identified to date, all encoding for proteins of the primary cilium or the centrosome, making JSRD part of an expanding group of diseases called "ciliopathies". Mutational analysis of causative genes is available in few laboratories worldwide on a diagnostic or research basis. Differential diagnosis must consider in particular the other ciliopathies (such as nephronophthisis and Senior-Loken syndrome), distinct cerebellar and brainstem congenital defects and disorders with cerebro-oculo-renal manifestations. Recurrence risk is 25% in most families, although X-linked inheritance should also be considered. The identification of the molecular defect in couples at risk allows early prenatal genetic testing, whereas fetal brain neuroimaging may remain uninformative until the end of the second trimester of pregnancy. Detection of the MTS should be followed by a diagnostic protocol to assess multiorgan involvement. Optimal management requires a multidisciplinary approach, with particular attention to respiratory and feeding problems in neonates and infants. Cognitive and behavioral assessments are also recommended to provide young patients with adequate neuropsychological support and rehabilitation. After the first months of life, global prognosis varies considerably among JSRD subgroups, depending on the extent and severity of organ involvement.

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Figures

Figure 1
Figure 1
Brain MRI sections in patients with JSRD. A) mid-sagittal T1-weighted image shows a thin midbrain with corresponding enlargement of the interpeduncular fossa (open arrowhead). There is concurrent superior vermian dysplasia (thin arrows); B) parasagittal T1-weighted image shows thickened and maloriented superior cerebellar peduncle (thick arrowheads); C) axial T1-weighted image confirms the deepened interpeduncular fossa (open arrowhead) and abnormal superior cerebellar peduncles (thick arrowheads), comprising the "molar tooth sign"; D) coronal FLAIR image shows midline cerebellar cleft (black arrows) indicating agenesis of the inferior vermis.
Figure 2
Figure 2
Schematic approach to the diagnosis and management of JSRD. Left: clinical manifestations that - in variable association - may lead to the diagnostic suspicion of JSRD. Middle: the detection of the MTS by brain magnetic resonance imaging confirms the diagnosis; in a subset of patients, other CNS defects may be identified. Right: proposed evaluation protocol for multiorgan involvement. *by water restriction or Desmopressin test.

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