Currarino Syndrome and HPE Microform Associated with a 2.7-Mb Deletion in 7q36.3 Excluding SHH Gene

Abstract

Holoprosencephaly (HPE) is the most common forebrain defect in humans. It results from incomplete midline cleavage of the prosencephalon and can be caused by environmental and genetic factors. HPE is usually described as a continuum of brain malformations from the most severe alobar HPE to the middle interhemispheric fusion variant or syntelencephaly. A microform of HPE is limited to craniofacial features such as congenital nasal pyriform aperture stenosis and single central maxillary incisor, without brain malformation. Among the heterogeneous causes of HPE, point mutations and deletions in the SHH gene at 7q36 have been identified as well as extremely rare chromosomal rearrangements in the long-range enhancers of this gene. Here, we report a boy with an HPE microform associated with a Currarino syndrome. Array CGH detected a de novo 2.7-Mb deletion in the 7q36.3 region including the MNX1 gene, usually responsible for the Currarino triad but excluding SHH, which is just outside the deletion. This new case provides further evidence of the importance of the SHH long-range enhancers in the HPE spectrum.

Keywords: Currarino syndrome; Holoprosencephaly; Long-range enhancers; Microdeletion 7q36; Sonic hedgehog.

Fig. 1

Mapping of the deletion in 7q36.3. a Schematic representation of the 7q36.3 deletion described in our patient. Known protein-coding genes included in the deletion are reported in blue. The boxed section corresponds to the proximal breakpoint of the presented deletion. b Genomic view of the 7q36.3 region close to the SHH gene. Translocation breakpoints of T1-T4 (black arrows) in 7q36.3 and respective deletions in derivative chromosome 7 (rearrangements B, C, D, and E) described by Roessler et al. [1997] are reported (solid bars). The breakpoints are approximated in these cases. Genomic imbalances associated with HPE phenotype are colored in red and with no HPE features in yellow. Chromosomal inversion (7)(q22.1;q36.3) reported by Lettice et al. [2011] is also represented (solid pink bar). The known cis-regulatory enhancers of SHH at 7q36.3 are indicated with colored circles: SHH floor plate enhancers (SFPE1+2) in purple, brain enhancers (SBE1-4) in blue, epithelial enhancers (MACS1, MRCS1 and MFCS4) in yellow, and the limb-specific enhancer (ZRS) is shown in green.

Fig. 2

Craniofacial CT scans of the patient. a Axial CT scan showing congenital pyriform aperture stenosis. b Axial CT scan showing solitary median maxillary incisor (arrow).

Fig. 3

Array CGH analysis of the microdeletion in chromosome 7 of our patient. Array CGH profile of chromosome 7 shows a 2.7-Mb heterozygous deletion in 7q36.3. Genomic position of the first deleted (7:155,686,857) and the last deleted oligonucleotides (7:158,384,574) are indicated with black arrows. The SHH gene (red circle) is located upstream of the first deleted oligonucleotides.