Frontonasal dysplasia

Frontonasal dysplasia (FND) concerns a rare malformation of the face characterized by the association of hypertelorism, a median facial cleft and nasal anomalies (bifid tip, cleft nostrils).

Intellectual deficiency, cerebral malformation, notably of the corpus callosum, and visceral malformations may also be associated. There is considerable clinical and genetic heterogeneity, linked on the one hand to the rarity of these syndromes, which means they are little known to clinicians, and on the other hand to lack of knowledge about the molecular bases in most of the entities described. Mutations of genes of the ALX family cause FND with an autosomal recessive (ALX1, ALX3, ALX4) or dominant pattern (ALX4). Cranio-fronto-nasal syndrome (CFN), which has an X-linked dominant pattern of inheritance, is caused by mutations of the EFNB1 gene. More recently, heterozygous mutations in the genes ZSWIM6 and SPECC1L have been described in acromelic FND syndromes for the first, and Opitz G/BBB and Teebi for the second. Finally, oculo-auriculo-frontonasal (OAFN), oculo-cerebro-cutaneous (OCC) and Pai syndromes, frequently revealed by FND at first, have no known molecular bases so far.

dysplasies frontonasales

From The American Journal of Human Genetics 2010: 86, 789-796

The Molecular Biology team of Dijon University Hospital carried out targeted sequencing of the ALX genes in the setting of FND. The results from negative patients were exploited in a context of research. First, phenotyping was done so as to classify patients according to one of the clinical presentations cited above. The strategy then consisted in sequencing the exome/genome in trio. These results will lead to a better clinical description of these rare entities and probably to a broader phenotype spectrum of known syndromes.