An X-linked syndrome, strangely more severe in females, combining frontonasal dysplasia, coronal craniosynostosis, various other skeletal and soft tissue abnormalities, and mild mental deficiency.
Craniofrontonasal Syndrome; Frontofacionasal Dysostosis/Dysplasia.
Unknown. Females are approximately four to six times more often affected than males.
X-linked (dominant). The disease is usually much more severe in females, a highly unusual feature for an X-linked (dominant) disorder, a phenomenon referred to as cellular interference where random X-chromosome inactivation in heterozygous females with Craniofrontonasal Dysplasia (CFNS) results in mosaicism for the expression of EFNB1, the gene whose mutations are responsible for the disorder. The EFNB1 (Ephrin B1) gene has been mapped to chromosome Xp13.1. Ephrin-B1 protein is a member of the ephrin family of transmembrane ligands for Eph receptors with tyrosine kinase activity and plays an important role in cell signaling and cell migration, adhesion, midline fusion, neural plasticity, synaptogenesis, and pattern formation during embryonic development. No genotype-phenotype correlation could be detected and inter- and intrafamilial variability of the clinical features can be significant.
Based on the clinical and radiological findings.
Almost all symptoms (except the urogenital findings) are either more severe in females or only present in females. Males often show only mild symptoms (eg, hypertelorism). Multiple head and neck malformations have been described including craniosynostosis (in 78% of patients) with uni- or bilateral coronal synostosis, (mild to severe) facial asymmetry (in almost 90% and often secondary to unicoronal craniosynostosis), anterior bifid cranium, brachycephaly, frontal bossing, low-set ears (in 52%) downslanting (in 35%) or mild upslanting (in 48%) of the palpebral fissures, hypertelorism (in almost all patients), epicanthic folds, strabismus, nystagmus (both in 40%), broad and flattened nasal bridge (in 70%), bifid nose tip and columellar indentation (both in >90%), maxillary hypoplasia, high-arched palate, cleft lip and/or palate, and short neck with mild webbing. Musculoskeletal features may include growth retardation, abnormal clavicular curvature or pseudarthrosis, Sprengel deformity (defined as one shoulder blade that placed more cranial on the back than the other), restricted range of motion of the arms with limited elevation above the head or abduction (in the majority of patients) most likely due to clavicular and Sprengel deformity, pectus excavatum (in 64%), mild-to-moderate scoliosis, limb anomalies such as leg length difference, brachy-, syn-, and/or clinodactyly of fingers and toes, broad or duplicated thumbs and halluces, muscular hypotonia, and joint laxity. Other findings can include developmental delay (in constant finding, some patients have normal intelligence), partial or complete agenesis of the corpus callosum, diaphragmatic hernia, unilateral breast hypoplasia, low implantation of breasts (in 90%) and asymmetry of the nipples, axillary pterygia, hypospadias, shawl scrotum, widows peak (in 65%) and low-anterior hairline, dry, thick and frizzy hair, and ...