Joubert syndrome is a clinically and genetically heterogeneous group of disorders characterized by hypoplasia of the cerebellar vermis with the characteristic neuroradiologic 'molar tooth sign,' and accompanying neurologic symptoms, including dysregulation of breathing pattern and developmental delay. Other ... Joubert syndrome is a clinically and genetically heterogeneous group of disorders characterized by hypoplasia of the cerebellar vermis with the characteristic neuroradiologic 'molar tooth sign,' and accompanying neurologic symptoms, including dysregulation of breathing pattern and developmental delay. Other variable features include retinal dystrophy and renal anomalies (Saraiva and Baraitser, 1992; Valente et al., 2005). - Genetic Heterogeneity of Joubert Syndrome See also JBTS2 (608091), caused by mutation in the TMEM216 gene (613277) on chromosome 11q13; JBTS3 (608629), caused by mutation in the AHI1 gene (608894) on chromosome 6q23; JBTS4 (609583), caused by mutation in the NPHP1 gene (607100) on chromosome 2q13; JBTS5 (610188), caused by mutation in the CEP290 gene, also called NPHP6 (610142), on chromosome 12q21.32; JBTS6 (610688), caused by mutation in the TMEM67 gene (609884) on chromosome 8q21; JBTS7 (611560), caused by mutation in the RPGRIP1L gene (610937) on chromosome 16q12.2; JBTS8 (612291), caused by mutation in the ARL13B (608922) on chromosome 3q11.2; JBTS9 (612285), caused by mutation in the CC2D2A gene (612013) on chromosome 4p15.3; JBTS10 (300804), caused by mutation in the CXORF5 gene (300170) on chromosome Xp22.3; JBTS11 (see 613820), caused by mutation in the TTC21B gene (612014) on chromosome 2q24; JBTS12 (see 200990), caused by mutation in the KIF7 gene (611254) on chromosome 15q26; JBTS13 (614173), caused by mutation in the TCTN1 gene (609863) on chromosome 12q24; JBTS14 (614424), caused by mutation in the TMEM237 gene (614423) on chromosome 2q33; JBTS15 (614464), caused by mutation in the CEP41 gene (610523) on chromosome 7q32; JBTS16 (614465), caused by mutation in the TMEM138 gene (614459) on chromosome 11q; JBTS17 (614615), caused by mutation in the C5ORF42 gene (614571) on chromosome 5p13; JBTS18 (614815), caused by mutation in the TCTN3 gene (613847) on chromosome 10q24; JBTS19 (see 614844), caused by mutation in the ZNF423 gene (604577) on chromosome 16q12; and JBTS20 (614970), caused by mutation in the TMEM231 gene (614949) on chromosome 16q23.
De Haene (1955) collected from the literature 4 cases of total and 7 cases of partial agenesis of the vermis of the cerebellum, and added the only familial example: 3 brothers (1 autopsy) died at ages 4 to ... De Haene (1955) collected from the literature 4 cases of total and 7 cases of partial agenesis of the vermis of the cerebellum, and added the only familial example: 3 brothers (1 autopsy) died at ages 4 to 8 years, the illness being characterized by tremor and hypotonia. Boltshauser and Isler (1977), who suggested the designation Joubert syndrome based on the article by Joubert et al. (1969) (see JBTS17, 614615), described 3 cases, 2 of them sibs. Detailed neuropathologic findings on 1 of these patients were reported by Friede and Boltshauser (1978). Boltshauser et al. (1981) reported 2 affected sisters whose parents were consanguineous. Egger and Baraitser (1984) suggested that the sibs reported by Gustavson et al. (1971) and by Haumont and Pelc (1983) had the Joubert syndrome, not the Mohr syndrome (252100). Kendall et al. (1990) reviewed the radiologic findings in 16 consecutive cases. Cantani et al. (1990) reviewed 53 published cases. In the children of healthy, consanguineous Turkish parents, van Dorp et al. (1991) observed a severely retarded male child with neurologic anomalies including Dandy-Walker malformation, hypoplasia of the corpus callosum, occipital meningoencephalocele, and bilateral coloboma of the optic nerve with retrobulbar cystic mass. The detailed findings at autopsy in an affected female fetus from the mother's second pregnancy were presented. The fetus showed hypognathia, occipital meningoencephalocele, and empty posterior fossa. Squires et al. (1991) described an affected infant, born to nonconsanguineous parents, who had episodic tachypnea, agenesis of the cerebellar vermis, a complex cardiac malformation, cutaneous dimples over the wrists and elbows, telecanthus, and micrognathia. Lindhout et al. (1980) and Laverda et al. (1984) described associated chorioretinal coloboma (see 243910). Saraiva and Baraitser (1992) reviewed 72 previously reported patients and 29 new patients with the possible diagnosis of Joubert syndrome. They presented data on 94 patients that fulfilled their criteria and proposed a classification into 2 groups: those with retinal dystrophy and those without. Retinal dystrophy ran true in families and was never absent when renal cysts were reported. Maria et al. (1999) reviewed the clinical features of Joubert syndrome and provided revised diagnostic criteria. They pointed out that careful examination of the face shows a characteristic appearance: large head, prominent forehead, high rounded eyebrows, epicanthal folds, ptosis (occasionally), upturned nose with evident nostrils, open mouth (the mouth tends to have an oval shape early on, a 'rhomboid' appearance later, and finally can appear triangular with downturned mouth angles), tongue protrusion and rhythmic tongue motions, and occasionally low-set and tilted ears. Neuroophthalmologic examination shows oculomotor apraxia. Most children with this disorder have hyperpnea intermixed with central apnea in the neonatal period. Neuroimaging of the head in the axial plane demonstrates the 'molar tooth sign,' that is, deep posterior interpeduncular fossa, thick and elongated superior cerebellar peduncles, and hypoplastic or aplastic superior cerebellar vermis. See their Table 1 for the proposed revised diagnostic criteria. Fennell et al. (1999) reported on cognitive, behavioral, and developmental findings of follow-up studies of Joubert syndrome. The parents' reports of behaviors showed problems with temperament, hyperactivity, aggressiveness, and dependency, as well as problems in physical development and care that were thought to be related to the neurologic handicaps. Parents' reports of developmental attainments revealed that only 3 of 40 children were functioning in the borderline range, with the rest scoring in the severely impaired range. The studies reported by Yachnis and Rorke (1999) suggested that, in addition to vermal agenesis, Joubert syndrome is characterized by malformation of multiple brainstem structures. The latter could explain certain clinical features of the syndrome, including episodic hyperpnea and oculomotor apraxia. Brainstem malformation is represented by the 'molar tooth sign' on magnetic resonance imaging (Maria et al., 1999). Raynes et al. (1999) described 3 sisters with Joubert syndrome, 2 of whom were monozygotic twins with highly discordant phenotypes. The twins were born at 34 weeks' gestation with discordant birth weights. Their anatomic, neurologic, and developmental status also differed greatly: twin B was able to walk and run, and was verbal, unlike twin A who was wheelchair-bound, severely retarded, nonverbal, and autistic. Abnormal eye movements and retinal dysplasia were features in all 3 girls, but none had renal cysts demonstrable by ultrasonography. Magnetic resonance images showed the 'molar tooth sign,' the radiologic hallmark of Joubert syndrome, although only 1 twin, the more severely handicapped, had severe hypoplasia of the cerebellar hemispheres. Raynes et al. (1999) discussed the basis for the phenotypic discordance in the twins. Valente et al. (2005) reported 2 families with Joubert syndrome linked to chromosome 9q (JBTS1). In a family of Italian origin, 2 sibs had hypotonia that evolved into ataxia, marked oculomotor apraxia, and moderate visual reduction with mild pigmentary changes. Intelligence and kidney function were normal in both patients. In the second family, originating from Oman, an affected child had a typical neurologic phenotype with mental retardation, but no breathing dysregulation. Fundus exam and kidney function were normal. All of these patients had the molar tooth sign on MRI. In a retrospective review of midsagittal T1-weighted brain MRI studies of 20 patients with Joubert syndrome ranging in age from 18 days to 23 years, Spampinato et al. (2008) found absence of decussation of the superior cerebellar peduncles in all 6 patients over 30 months of age. Decussation was well seen on brain scans of 16 healthy controls over 30 months of age, but could not be visualized in any individuals, healthy or patients, under 30 months of age. Spampinato et al. (2008) concluded that the lack of superior cerebellar commissural fibers in Joubert syndrome accounted in part for the classic molar tooth sign observed in patients with the disorder. Braddock et al. (2007) analyzed the dysmorphic facial features of 34 children and young adults with Joubert syndrome who were not classified by molecular analysis. Findings included long face, frontal prominence, bitemporal narrowing, ptosis, prominent nasal bridge and tip, prognathism, eyebrow abnormalities, trapezoid-shaped mouth, lower lip eversion, and thick ear lobes. Anthropometric analysis showed several significant differences in measurements including bizygomatic, frontal, nasal, and mandibular dimensions. Facial characteristics appeared to become more distinct with age. Despite these findings, Braddock et al. (2007) noted that there was extreme variability likely resulting from genetic heterogeneity.
In affected members of 7 families with Joubert syndrome, Bielas et al. (2009) identified 5 different homozygous mutations in the INPP5E gene (see, e.g., 613037.0002-613037.0005). Three families were from the United Arab Emirates, 1 from Turkey, 1 from ... In affected members of 7 families with Joubert syndrome, Bielas et al. (2009) identified 5 different homozygous mutations in the INPP5E gene (see, e.g., 613037.0002-613037.0005). Three families were from the United Arab Emirates, 1 from Turkey, 1 from Egypt, and 2 from Italy. All of the mutations were in the catalytic domain of the protein, and all mutant proteins showed decreased phosphatase activity. The findings implied a link between PtdIns signaling and ciliopathies. - Exclusion Studies Because of its expression in the developing cerebellum and because of an associated mutation of Wnt1 in the 'swaying' mouse, Pellegrino et al. (1997) evaluated the WNT1 gene (164820) as a candidate gene for Joubert syndrome. The investigators ascertained a cohort of 50 patients with Joubert syndrome to evaluate the presence of associated malformations and to initiate studies leading to the identification of the responsible gene. Only 8% of patients had polydactyly, 4% had colobomas, 2% had renal cysts, and 2% had soft tissue tumors of the tongue. No mutations of the WNT1 gene were found in the patients of the cohort. Blair et al. (2002) undertook mutation analysis of several functional candidate genes in a total of 26 unrelated JBTS patients and excluded EN1 (131290), EN2 (131310), and FGF8 (600483) from a direct pathogenic role in JBTS. The BARHL1 gene (605211), which localizes to 9q34 and had previously been proposed as a strong positional candidate gene for JBTS, was also investigated and excluded from involvement in JBTS that is linked to 9q34. In 2 sibs and 1 unrelated patient with Joubert syndrome, Gould and Walter (2004) demonstrated no abnormality of the BARHL1 gene or the BARX1 gene (603260) on 9q12. - Modifier Genes Khanna et al. (2009) presented evidence that a common allele in the RPGRIP1L gene (A229T; 610937.0013) may be a modifier of retinal degeneration in patients with ciliopathies due to other mutations, including JBTS.