Joubert syndrome is a malformation syndrome affecting brainstem and cerebellum, resulting in early hypotonia, subsequent truncal ataxia, delayed milestones, and, finally, cognitive impairment of varying degrees. Although a rare condition, its pathogenetic understanding is likely to contribute significantly to the organization and function of the hindbrain. Molar tooth sign is the diagnostic neuroimaging finding on axial cuts through the midbrain/hindbrain region. Recent experience has shown that some mutations (in particular NPHP1, C5orf42, autosomal recessive SUFU variants) tend to be associated with a mild molar tooth, which may be easily overlooked. It is worth considering heterozygous dominant (familial or de novo) SUFU variants associated with congenital ocular motor apraxia if a mild molar tooth is found. In this article, the author gives an update of the diagnostic workup, quotes newly provided healthcare recommendations for this potential multisystem disorder, refers to other cerebello-oculo-renal syndromes, and summarizes the actual knowledge about molecular genetics. The genetic situation is complex in view of marked genetic heterogeneity and modifier genes. More than 40 different associated genes have been reported; however, in about 30% of affected individuals, a pathogenic mutation is still unknown; increasing use of whole-exome sequencing will lower this percentage. All genes are related to the primary (nonmotile) ciliary-basal body apparatus. Joubert syndrome can be grouped among the ciliopathies. Joubert syndrome is now the best-studied hindbrain malformation.
Historical note and terminology
In 1969, Marie Joubert and colleagues reported a previously undescribed syndrome of episodic hyperpnea, abnormal eye movements, ataxia, and retardation associated with agenesis of the cerebellar vermis (33). They observed this condition in four siblings of a family; there was remote consanguinity of the parents. Boltshauser and Isler added three cases and suggested the designation “Joubert syndrome” (08). Friede and Boltshauser published the first detailed postmortem report in 1978 (25). Maria and colleagues drew attention to characteristic MRI findings (molar tooth appearance of midbrain) and gave detailed neuro-ophthalmologic findings (41). So far, larger series reported are from Maria and colleagues and Boltshauser and colleagues (41; 64; 26). Studies of larger American patient series were particularly supported by a patient organization called the Joubert Syndrome Foundation, later named Joubert Syndrome and Related Disorders Foundation. Diagnostic criteria were discussed on October 16, 1998, in Montreal at a satellite symposium of the Child Neurology Society Meeting; this symposium was devoted to Joubert syndrome.
The publication by Gleeson and colleagues reporting a Molar Tooth Sign in apparently different syndromes was responsible for the change in terminology to “Joubert Syndrome and Related Disorders.” However, this change also created confusion among parents and professionals. It is preferable to stick to “Joubert Syndrome,” realizing that this is an umbrella term encompassing a genetically heterogeneous group of ciliopathies sharing the neuroimaging hallmark of a molar tooth (27).