Clinical and molecular features of Joubert syndrome and related disorders

Abstract

Joubert syndrome (JBTS; OMIM 213300) is a rare, autosomal recessive disorder characterized by a specific congenital malformation of the hindbrain and a broad spectrum of other phenotypic findings that is now known to be caused by defects in the structure and/or function of the primary cilium. The complex hindbrain malformation that is characteristic of JBTS can be identified on axial magnetic resonance imaging and is known as the molar tooth sign (MTS); other diagnostic criteria include intellectual disability, hypotonia, and often, abnormal respiratory pattern and/or abnormal eye movements. In addition, a broad spectrum of other anomalies characterize Joubert syndrome and related disorders (JSRD), and may include retinal dystrophy, ocular coloboma, oral frenulae and tongue tumors, polydactyly, cystic renal disease (including cystic dysplasia or juvenile nephronophthisis), and congenital hepatic fibrosis. The clinical course can be variable, but most children with this condition survive infancy to reach adulthood. At least eight genes cause JSRD, with some genotype-phenotype correlations emerging, including the association between mutations in the MKS3 gene and hepatic fibrosis characteristic of the JSRD subtype known as COACH syndrome. Several of the causative genes for JSRD are implicated in other ciliary disorders, such as juvenile nephronophthisis and Meckel syndrome, illustrating the close association between these conditions and their overlapping clinical features that reflect a shared etiology involving the primary cilium.

Figure 1

The Molar Tooth Sign (MTS). The typical appearance of the cerebellar vermis on (A) axial and (B) mid-sagittal imaging in a normal individual. C: In a patient with JSRD, the molar tooth sign (MTS) is apparent (between arrows) reflecting a deepened interpeduncular fossa, thickened, elongated superior cerebellar peduncles, and vermis hypoplasia. D: The sagittal image from the same individual with JSRD demonstrates an abnormally positioned and elevated fourth ventricle (arrowhead) with hypoplastic cerebellar vermis (surrounded by five small arrows). E: The “mild” MTS on sagittal imaging of an individual with JSRD due to homozygous NPHP1 mutations shows thin, elongated superior cerebellar peduncles (arrows); in (F), the axial image shows a less severe elevation of the fourth ventricle (arrowhead) with less vermis hypoplasia (outlined by small arrows). Derived from [Parisi et al., 2007; Parisi et al., in press].

Figure 2

Clinical features in JSRD. A: Facial features in a girl with JSRD/COACH syndrome at 27 months of age showing broad forehead, arched eyebrows, strabismus, eyelid ptosis (on subject’s right in particular), and open mouth configuration indicating reduced facial tone. B: Oral findings in a subject with oral-facial-digital syndrome-like features of JSRD showing midline upper lip cleft (arrowhead), midline groove of tongue, and bumps of the lower alveolar ridge (arrow). C: Left hand of an infant with JSRD and postaxial polydactyly (arrow). D: Right foot of an infant with JSRD and preaxial polydactyly of the hallux. E: View from above of an infant with a small occipital encephalocele showing the protrusion of the occiput of the skull (arrow). (Facial photograph used with permission of the family.)

Figure 3

Proposed algorithm for genetic testing in JSRD based on clinical features. * See figure 1E, F for example of the “mild” MTS. § Testing for INPP5E mutations in individuals with liver disease may be warranted, but insufficient data are available to make a determination for this gene. BUN, blood urea nitrogen; Cr, creatinine; AST, aspartate aminotransferase; ALT, alanine aminotransferase. Derived from [Doherty, 2009].