Subtypes of frontonasal dysplasia are useful in determining clinical prognosis

Abstract

Frontonasal dysplasia [FND; OMIM 136760] results from abnormal morphogenesis of the frontonasal process with disruption of the formation of the facial midline. Craniofacial anomalies in FND include anterior cranium bifidum, ocular hypertelorism, orofacial clefting and notching or clefting of the alae nasi. The majority of FND cases are sporadic and discordance has been demonstrated in monozygotic twin pairs, arguing against a strong inherited component in pathogenesis. However, pedigrees with Mendelian inheritance and non-recurrent chromosome aberrations in FND patients demonstrate that gene mutations or cytogenetic imbalance can also be important in the etiology of this phenotype. We classified 101 reported cases of FND from the medical literature and three new cases into seven separate FND phenotypic subtypes in addition to isolated FND. Our aim was to evaluate FND patients for distinct phenotypes within the FND spectrum and to determine the evidence for a genetic etiology in each of the different subtypes. Our analysis showed significant differences in the severity of the accompanying malformations and the rates of learning disabilities in the FND subtypes, although the small patient numbers and method of patient ascertainment may have influenced the data. The results suggest that cases with FND should be evaluated for additional anomalies, as these may help to determine prognosis.

Zebrafish zic2 controls formation of periocular neural crest and choroid fissure morphogenesis

“…There is emerging evidence for a reciprocal interaction, whereby NC cells signal back to the eye and brain (reviewed in (Bazin-Lopez et al, 2015; Gestri et al, 2012; Le Douarin et al, 2007). In humans, significant comorbidity has been reported between frontonasal dysplasia and coloboma (Wu et al, 2007), suggesting that NC plays a specific role in choroid fissure morphogenesis. The importance of this mechanism has only recently come to light and needs robust genetic models to be fully understood.…”

Craniofacial features resembling frontonasal dysplasia with a tubulonodular interhemispheric lipoma in the adult 3H1 tuft mouse

“…Tubulonodular lipomas are likely brought about by the delay or failure in resorption of the meninx primitiva along the dorsal midline of the developing telencephalon near the primitive lamina terminalis (Truwit and Barkovich 1990), but the exact cause is unknown. There have been a number of reports where craniofacial defects such as hypertelorism and median facial cleft, two characteristic features of frontonasal dysplasia (FND), have been observed together with tubulonodular lipomas (Pascual-Castroviejo et al, 1985; de Villiers et al, 1991; Tart et al, 1991; Demaerel et al, 1996, Wu et al, 2007). …”

Brain Commissural Anomalies

“…Because the development of the corpus callosum itself is associated with the dorsalization of the hemispheres, other disorders of the dorsalization may be observed, primarily at the level of the cerebellum: a Dandy-Walker malformation (or related defect) is commonly associated with an agenesis of the corpus callosum (Johnston, 1943;Raybaud, 1982). The rare rhombencephalon synapsis is often found in association with septal defects/ septo-optic dysplasia (Michaud et al, 1982;Jellinger, 2002) and obviously the midline skull defects commonly include commissural agenesis or dysgenesis, especially the frontonasal dysplasia (Guion-Almeida et al, 1996;Wu et al, 2007) and the basal, notably sphenoidal cephaloceles (Koenig et al, 1982).…”