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Joubert syndrome and related disorders
Joubert syndrome (JS) and related disorders (JSRD) are a group of developmental delay/multiple congenital anomaly syndromes in which the mandatory feature is the ``molar tooth sign'' (MTS), a complex midbrain-hindbrain malformation recognizable on brain imaging. The MTS is characterized by cerebellar vermis hypodysplasia, thickening and malorientation of the superior cerebellar peduncles and abnormally deep interpeduncular fossa.
ORPHA:140874Classification level: Group of disorders
- Prevalence: Unknown
- Inheritance: Autosomal recessive or X-linked recessive
- Age of onset: Infancy, Neonatal
- ICD-10: -
- OMIM: -
- UMLS: -
- MeSH: -
- GARD: -
- MedDRA: -
The prevalence of JSRD at birth has been estimated to be between 1/80,000 and 1/100,000 live births, although this frequency is probably underestimated.
The neurological features of JSRD include neonatal hypotonia, developmental delay, which is particularly related to language and motor skills, mild to severe intellectual disability, ataxia, and abnormal eye movements including oculomotor apraxia and primary position nystagmus. A subset of patients present neonatal breathing abnormalities, that are characterized by episodes of apnea and hyperpnea starting shortly after birth and improving with age. These neurological manifestations may occur alone or be variably associated with multiorgan features, mainly retinal dystrophy, nephronophthisis, hepatic fibrosis and polydactyly, with both inter- and intra-familial variability. Depending on the associated multiorgan involvement, JSRD is classified in six clinical subgroups: Pure JS; JS with ocular defect; JS with renal defect; JS with oculorenal defect; JS with hepatic defect; and JS with orofaciodigital defect (see these terms).
Twelve causative genes have been identified to date, all encoding proteins that are part of the primary cilium or its apparatus, making JSRD part of the expanding group of diseases called ``ciliopathies''.
The diagnosis of JSRD should be suspected in all infants presenting with hypotonia, abnormal eye movements and developmental delay, especially if breathing abnormalities are also present. In children, the diagnosis is suspected in presence of neurological signs suggestive of cerebellar involvement (ataxia, developmental delay, intellectual disability, abnormal eye movements) variably associated with involvement of other organs. Brain magnetic resonance imaging is necessary and sufficient to confirm or exclude the diagnosis of JSRD based on the detection of the MTS. This should be followed by a specific diagnostic protocol to assess the potential multiorgan involvement.
Differential diagnosis must consider in particular the other ciliopathies (such as nephronophthisis, Senior-Loken syndrome, and Bardet-Biedl syndrome; see these terms), distinct cerebellar and brainstem congenital defects and disorders with cerebro-oculo-renal manifestations.
Mutational analysis of causative genes is available in few laboratories worldwide on a diagnostic or research basis. The identification of the molecular defect in at-risk couples enables early prenatal genetic testing, whereas fetal brain neuroimaging may remain uninformative until the end of the second trimester of pregnancy.
With the exception of rare X-linked recessive cases, JSRDs are transmitted in an autosomal recessive manner.
Management and treatment
Optimal management requires a multidisciplinary approach, with particular attention to respiratory and feeding problems in neonates and infants, while cognitive and behavioral assessments are recommended to provide young patients with adequate neuropsychological support and rehabilitation.
After the first months of life, when prognosis is primarily linked to the extent and severity of breathing abnormalities, global prognosis varies considerably among JSRD subgroups, depending on the extent and severity of organ involvement.