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

Abstract

The study of inborn genetic errors can lend insight into mechanisms of normal human development and congenital malformations. Here, we present the first detailed comparison of cranial and neuro pathology in two exceedingly rare human individuals with cyclopia and alobar holoprosencephaly (HPE) in the presence and absence of aberrant chromosome 18 (aCh18). The aCh18 fetus contained one normal Ch18 and one with a pseudo-isodicentric duplication of chromosome 18q and partial deletion of 18p from 18p11.31 where the HPE gene, TGIF, resides, to the p terminus. In addition to synophthalmia, the aCh18 cyclopic malformations included a failure of induction of most of the telencephalon – closely approximating anencephaly, unchecked development of brain stem structures, near absence of the sphenoid bone and a malformed neurocranium and viscerocranium that constitute the median face. Although there was complete erasure of the olfactory and superior nasal structures, rudiments of nasal structures derived from the maxillary bone were evident, but with absent pharyngeal structures. The second non-aCh18 cyclopic fetus was initially classified as a true Cyclops, as it appeared to have a proboscis and one median eye with a single iris, but further analysis revealed two eye globes as expected for synophthalmic cyclopia. Furthermore, the proboscis was associated with the medial ethmoid ridge, consistent with an incomplete induction of these nasal structures, even as the nasal septum and paranasal sinuses were apparently developed. An important conclusion of this study is that it is the brain that predicts the overall configuration of the face, due to its influence on the development of surrounding skeletal structures. The present data using a combination of macroscopic, computed tomography (CT) and magnetic resonance imaging (MRI) techniques provide an unparalleled analysis on the extent of the effects of median defects, and insight into normal development and patterning of the brain, face and their skeletal support.

Anatomical Network Comparison of Human Upper and Lower, Newborn and Adult, and Normal and Abnormal Limbs, with Notes on Development, Pathology and Limb Serial Homology vs. Homoplasy

“…For this work, we studied the musculoskeletal structures of the ULs and LLs of a 28-week old T18 cyclopic fetus and in karyotypically normal newborn and adult humans. Details about the dissections of the T18 fetus were recently provided in detail by Reid et al [ 76 ], Gondré-Lewis et al [ 77 ], and Smith et al [ 49 ]. The descriptions and network matrices done for the normal newborn and adult configuration are based those dissections of human newborns and our own review of the literature, which allowed us to carefully establish the normal (i.e.…”

Cellular identities in an unusual presentation of cyclopia in a chick embryo

“…A remarkable series of studies have allowed for the description of human cases of cyclopia, which are often regarded as a part of the spectrum of holoprosencephaly (HPE; Gondré‐Lewis et al, ; Howard, ; Orioli et al, ; Pachajoa, Tabares, Quintero, Saldarriaga, & Isaza, ). In Figure , we have compared different malformations described in the literature, which are associated with embryonic failure to form normal eyes and nose (Figure c–h).…”

Holoprosencefalia Semilobar y Malformaciones Asociadas: Reporte de Caso y Algunas Consideraciones

“…La HPE semilobar, en los estadios de Carnegie (CS) 10-14, en modelos murinos, ocurre por una interrupción en los centros de moldeado telencefálicos rostral y ventral, determinando alteraciones del cerebro anterior y del desarrollo de la línea media (Geng & Oliver; Lacbawan et al). Asimismo, existe el antecedente de consumo de alcohol de la madre durante los primeros dos meses de gestación como un posible factor etiológico (Ronen & Andrews, 1991) relacionado al deterioro en la expresión de SHH y la apoptosis en las célulasdel PrCP por lo que se altera la formación de la cara, la división del prosencéfalo y la separación del campo óptico primario (Gondré-Lewis et al, 2015;Goswami & Kusre, 2015).…”