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.

Currarino syndrome: a comprehensive genetic review of a rare congenital disorder

“…No mutation was observed, making an involvement of SHH in these diseases rather unlikely. This assumption has been corroborated by Coutton et al [ 87 ]. These authors reported a patient with CS and a microform of holoprosencephaly, who carried a 2.7 Mb deletion in 7q36.3 without affecting the SHH gene.…”

Spectrum ofMNX1Pathogenic Variants and Associated Clinical Features in Korean Patients with Currarino Syndrome

“…Large deletions or chromosome rearrangement involving 7q36 are related with holoprosencephaly (HPE) and CS due to haploinsufficiency of sonic hedgehog ( SHH ) and MNX1 . Some previous studies reported patients with a deletion or chromosome rearrangement involving 7q36 [ 3 4 14 17 27 28 29 30 31 32 33 34 ]. In these patients, microcephaly was the predominant craniofacial finding of HPE, and hypotelorism, ptosis, and midface hypoplasia were commonly associated.…”

“…A 10.3-Mb duplication of 7q34-q35 and an 8.8-Mb deletion on 7q36 were identified by comparative genomic hybridization (CGH) array in the patient. Another study reported a patient with a 2.7-Mb deletion 7q36.3 excluding SHH [ 28 ]. The patient presented with microcephaly and incomplete CS triad without anorectal malformation.…”

“…According to the diagnostic algorithm proposed by Cuturilo et al [ 4 ], patients with CS exhibiting growth delay and/or developmental delay and/or facial dysmorphic features should be evaluated by a chromosomal microarray. Large deletions and complex rearrangements involving the 7q36 region have been identified in many previous reports [ 3 4 14 17 27 28 29 30 31 32 33 34 ]. Almost all cases described in these studies exhibited various associated anomalies.…”

Currarino syndrome: does the presence of a genetic anomaly correlate with a more severe phenotype? A multicentre study

“…Microcephaly was the most frequent condition (5 patients, 11% of the entire series), followed by holoprosencephaly (2), neurodevelopmental delay (2) and hypoplasia of the corpus callosus and optical nerves (1). Holoprosencephaly results from incomplete midline cleavage of the prosencephalon and is the most common forebrain defect in humans [23]. The association between CS and holoprosencephaly has already been described as a very rare condition due to a deletion in the long arm of chromosome 7, in the 7q36 region, including both MNX1 and SHH (sonic hedgehog) genes [23]; this alteration was detected in both our patients with holoprosencephaly.…”