Genetically induced abnormal cranial development in human trisomy 18 with holoprosencephaly: comparisons with the normal tempo of osteogenic–neural development

Abstract

Craniofacial malformations are common congenital defects caused by failed midline inductive signals. These midline defects are associated with exposure of the fetus to exogenous teratogens and with inborn genetic errors such as those found in Down, Patau, Edwards' and Smith-Lemli-Opitz syndromes. Yet, there are no studies that analyze contributions of synchronous neurocranial and neural development in these disorders. Here we present the first in-depth analysis of malformations of the basicranium of a holoprosencephalic (HPE) trisomy 18 (T18; Edwards' syndrome) fetus with synophthalmic cyclopia and alobar HPE. With a combination of traditional gross dissection and state-of-the-art computed tomography, we demonstrate the deleterious effects of T18 caused by a translocation at 18p11.31. Bony features included a single developmentally unseparated frontal bone, and complete dual absence of the anterior cranial fossa and ethmoid bone. From a superior view with the calvarium plates removed, there was direct visual access to the orbital foramen and hard palate. Both the eyes and the pituitary gland, normally protected by bony structures, were exposed in the cranial cavity and in direct contact with the brain. The middle cranial fossa was shifted anteriorly, and foramina were either missing or displaced to an abnormal location due to the absence or misplacement of its respective cranial nerve (CN). When CN development was conserved in its induction and placement, the respective foramen developed in its normal location albeit with abnormal gross anatomical features, as seen in the facial nerve (CNVII) and the internal acoustic meatus. More anteriorly localized CNs and their foramina were absent or heavily disrupted compared with posterior ones. The severe malformations exhibited in the cranial fossae, orbital region, pituitary gland and sella turcica highlight the crucial involvement of transcription factors such as TGIF, which is located on chromosome 18 and contributes to neural patterning, in the proper development of neural and cranial structures. Our study of a T18 specimen emphasizes the intricate interplay between bone and brain development in midline craniofacial abnormalities in general.

The human brain and face: mechanisms of cranial, neurological and facial development revealed through malformations of holoprosencephaly, cyclopia and aberrations in chromosome 18

“…These results are consistent with the previously reported enlarged petrous portion of the temporal bone and its foramen in the interior of the cranium (Reid et al. ), indicating that sensory processing of sound may have been impaired.…”

“…B), and the sphenoid bone was underdeveloped and it, along with the entire middle cranial fossa, was shifted anteriorly as previously shown for the a Ch18 cranial fossa (Reid et al. ). Lateral perspectives (Fig.…”

“…B); thus, unlike the a Ch18 cyclops, there was no direct contact between neural structures in the cranial cavity and the underlying eye (Reid et al. ). At the point of the base of the proboscis (Fig.…”

“…A prime example is the tightly regulated physical and functional relationship of the brain and neurocranium (Richtsmeier & Flaherty, ; Reid et al. ). The brain develops in synchrony with both the neurocranium and the viscerocranium, but less directly with the muscles of the face.…”

Cranial Nerves: Mind Your Head

“…This is relevant because several diseases that occur with cerebral malformation, also develop problems of facial development and, consequently, problems of shape and function of the face. It is revealing that several of these diseases occur with severe impairments of cranial nerve development, like human trisomy (Reid et al ., ). In the same way, DiGeorge syndrome occurs with craniofacial and cardiovascular malformation, probably due to their coordinated development and to share stem cell populations with overlapping roles (reviewed by Diogo et al ., ).…”