Frontonasal dysplasia (FND) is a heterogeneous group of disorders characterized by hypertelorism, broad nasal tip and root, bifid nose and oral, palatal and facial clefting. Additional findings include microphthalmia, coloboma, and low-set, posteriorly rotated ears. FND1 (MIM 136760), FND2 (MIM 613451) and FND3 (MIM 613456) are autosomal recessive disorders caused by mutations in the ALX3, ALX4 and ALX1 genes. Patients with FND2 can also have skull defects, coronal craniosynostosis, cryptorchidism, agenesis of corpus callosum, total alopecia and mental retardation. Mutations in ALX4 also cause parietal foramina 2 (PFM2; MIM 609597), an autosomal dominant disorder characterized by symmetrical, oval parietal bone defects, cranium bifidum and scalp defect. Parietal foramina also occurs as part of the Potocki-Shaffer syndrome (PSS; MIM 601224), a rare contiguous gene deletion syndrome due to haploinsufficiency of the 11p12-p11.2 region, encompassing the ALX4 gene.  ALX1, ALX3 and ALX4 code for transcription regulators, homeobox protein aristaless-like 1, 3 and 4. Autosomal dominant FND is also recognized. This form is caused by mutations in the SIX2 gene (frontonasal dysplasia, SIX2 related).
Craniofrontonasal syndrome (CFNS; MIM 304110) shares clinical features with FND such as hypertelorism, broad nasal tip root, bifid nose, cleft lip and cleft palate. Other prominent features include longitudinal splitting of nails, clinodactyly, abnormal facial proportions, craniosynostosis, low implant of breasts, narrow shoulders, and frizzy and curly hair. CFNS is an X-linked dominant disorder caused by loss-of-function mutations is EFNB1. Paradoxically, CFNS displays greater severity in heterozygous females than in hemizygous males, who typically only have hypertelorism or no clear features at all. EFNB1 codes for ephrin-B1, a transmembrane ligand for Eph receptor tyrosine kinases. Because heterozygous females are uniquely mosaic due to random X-inactivation, individual cells either produce or do not produce functional protein. This random pattern of expression and non-expression causes abnormal sorting of cells. The cells of the hemizygous males are not able to produce a functional protein and thus the phenomenon cannot occur. A possible explanation for a few severely affected males can be mosaicism.