Co-occurrence of Joubert syndrome and Jeune asphyxiating thoracic dystrophy

Abstract

Ciliary disorders share typical features, such as polydactyly, renal and biliary cystic dysplasia, and retinitis pigmentosa, which often overlap across diagnostic entities. We report on two siblings of consanguineous parents and two unrelated children, both of unrelated parents, with co-occurrence of Joubert syndrome and Jeune asphyxiating thoracic dystrophy, an association that adds to the observation of common final patterns of malformations in ciliary disorders. Using homozygosity mapping in the siblings, we were able to exclude all known genes/loci for both syndromes except for INVS, AHI1, and three genes from the previously described Jeune locus at 15q13. No pathogenic variants were found in these genes by direct sequencing. In the third child reported, sequencing of RPGRIP1L, ARL13B, AHI1, TMEM67, OFD1, CC2D2A, and deletion analysis of NPHP1 showed no mutations. Although this study failed to identify a mutation in the patients tested, the co-occurrence of Joubert and Jeune syndromes is likely to represent a distinct entity caused by mutations in a yet to be discovered gene. The mechanisms by which certain organ systems are affected more than others in the spectrum of ciliary diseases remain largely unknown.

FIG. 1

Patient I. A: Elongated superior cerebellar peduncles contribute to the molar tooth sign demonstrated in T1 MRI. B: Marked hypoplasia of the ribs, with decreased anterior–posterior diameter and thoracic volume. The anterior ends of the ribs are expanded. C: Hand radiographs demonstrate generalized brachydactyly and wide, cone-shaped epiphyses in the proximal phalanges. D: Pelvic radiograph demonstrates trident shape of horizontal acetabular roofs, bilateral coxa valga, and bilateral irregular widening of the proximal femoral epiphyses.

FIG. 2

Patient II. A: T2-weighted MRI demonstrating the molar tooth sign. B: Thoracic hypoplasia with broad costochondral junctions and abnormal clavicles. C: Saggital T2 MRI view demonstrates narrowing of the subarachnoid space at the C1 level, contributing to enlargement of the subarachnoid space caudally.

FIG. 3

Patient III. A: Hypoplastic thorax with decreased chest circumference, protuberant abdomen, and rhizomelic limb shortening are shown. A depressed nasal root, prominent forehead, and postaxial polydactyly are also present. B: Medial spurs of the acetabular roof as well as a narrow sacroiliac notch are seen. The ilia are generally hypoplastic. C: Postaxial polydactyly of the right hand with two phalangeal bones in the extra digit, a bifid metacarpal, and brachydactyly. [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]

FIG. 4

Patient IV. A: The mildly hypoplastic pelvis demonstrates narrow sacroiliac notches with inferolateral notches and flared iliac bones. B: Thickened and elongated superior cerebellar peduncles and a deep interpeduncular fossa are seen as part of the molar tooth sign displayed in an axial T1 view. C: Saggital T1 MRI demonstrates dysplastic cerebellar hemispheres and a hypoplastic corpus callosum.