Description, nomenclature, and mapping of a novel cerebello-renal syndrome with the molar tooth malformation

Abstract

Cerebello-oculo-renal syndromes (CORSs) and Joubert syndrome (JS) are clinically and genetically heterogeneous autosomal recessive syndromes that share a complex neuroradiological malformation resembling a molar tooth on brain axial images, a condition referred to as "molar tooth on imaging" (MTI) or the "molar tooth sign." The current literature on these syndromes is complex, with overlapping and incomplete phenotypes that complicate the selection of clinically homogeneous cases for genetic purposes. So far, only one locus (JBTS1 on 9q34) has been mapped, in two families with JS. Here, we describe a large consanguineous family with JS and nephronophthisis, representing a novel cerebello-renal phenotype. We have mapped this condition to the pericentromeric region of chromosome 11 and have named the locus "CORS2." The acronym "CORS" is proposed for all loci associated with JS, CORSs, and related phenotypes sharing the MTI, because this neuroradiological sign seems to be the unifying feature of these clinically heterogeneous syndromes.

Figure 1

Pedigree of the family and haplotypes of marker loci spanning the CORS2 locus on chromosome 11p11.2-q12.3. Blackened symbols denote affected individuals. A thin horizontal bar above a symbols indicates a member of the family who was examined clinically and who provided a blood sample. The blackened bar denotes the disease-associated haplotype. Arrow indicates the proband.

Figure 2

Results of brain MRI in affected individuals. A, Patient VI:1. Axial T2-weighted image at the pontine level shows thickened superior cerebellar peduncles and umbrella-shaped fourth ventricle, giving the appearance of a molar tooth. B, Patient VI:1. Axial T2-weighted image at the mesencephalic level shows an abnormally deep interpeduncular fossa and thickened superior cerebellar peduncles. C, Patient VI:3. D, Patient VI:2. Coronal T2-weighted images in panels C and D show cerebellar hemispheres separated only by a thin sagittal cleft (buttock sign). E, Patient VI:3. Sagittal T1-weighted image demonstrates cerebellar vermian aplasia, a fourth ventricle enlarged and deformed. F, Patient VI:3. Sagittal T1-weighted image demonstrates prominent superior cerebellar peduncles running horizontally toward the brain stem.