Craniofrontonasal dysplasia (ORPHA:1520)
A rare X-linked malformation syndrome characterized by craniofacial abnormalities such as uni- or bicoronal synostosis, hypertelorism and a bifid nose, grooved or split nails, frizzy hair, abnormalities of the shoulder girdle, hands and feet.
Epidemiology
It occurs in fewer than 1/100,000 newborns. Detailed phenotypic analysis shows that females are more severely affected than males, a highly unusual characteristic for an X-linked disorder.
Clinical description
Female patients have hypertelorism, and a broad nose with a vertical groove on the top of the nose or a bifid nose, uni or bicoronal craniosynostosis. The following facial abnormalities may be seen: facial asymmetry, downslanting palpebral fissures, dry, curly and frizzy hair, widow's peak, low posterior hairline, webbed neck, highly arched palate, cleft lip and palate, a narrow and V-shaped maxilla. Ophthalmologic abnormalities, abnormal auditory ossicles, and both conductive and sensorineural deafness can be seen. Skeletal deformities may include sloping shoulders with dysplastic clavicles, broad or duplicated thumbs and halluces, short thumbs, brachydactyly, clinodactyly, gaps between the first and second toes, syndactyly, camptodactyly, scoliosis and hyperextensible joints. Longitudinal splits or grooves in the finger- and toe- nails are frequent and characteristic. Diaphragmatic hernia, pectus excavatum or carinatum, breast hypoplasia, cardiac abnormalities, bicornuate uterus, shawl scrotum, hypospadias and agenesis of the corpus callosum occur occasionally. Mild developmental delay can occur. Variable difficulties with speech and language development can be associated. Most of the male patients are mildly affected with hypertelorism only but can occasionally present with a severe female-like phenotype. The cause for this severe phenotype in males is probably mosaic pathogenic variants in EFNB1.
Etiology
The syndrome is caused by variants in the EFNB1 gene. This gene encodes ephrin-B1 and maps to Xq13.1. Random X-inactivation explains the more severe outcome in heterozygous females, as this leads to functional mosaicism for cells with differing expression of ephrin-B1, generating abnormal tissue boundaries.
Diagnostic methods
In case of a low-level of mosaicism for EFNB1 variants, extensive analysis of several types of tissues might be required to detect variants. Variation in EFNB1 is detected from DNA isolated from blood, fibroblast cell lines, saliva and hair roots by a combination of PCR/Sanger sequencing, or by next-generation sequencing and multiplex ligation-dependent probe amplification (MPLA; for the detection of deletions in females).
Differential diagnosis
Isolated hypertelorism can mimic the mild presentation of craniofrontonasal syndrome. The disease needs to be distinguished from other syndromes associated with hypertelorism such as SPECC1L-related hypertelorism syndrome and Baraitser-Winter cerebrofrontofacial syndrome.
Antenatal diagnosis
In case of an established EFNB1 mutation in a parent, prenatal diagnosis is possible.
Genetic counseling
The risk that an affected female will pass the disease on her daughter or son is 50%. An affected male will pass the disease on to all of his daughters but none of his sons.
Management and treatment
Multistage surgery is the general treatment plan for craniosynostosis. The synostotic sutures of the skull are released in the first year of life. The aim of this surgery is decompression of the brain and remodeling of the skull. Correction of the facial anomalies is usually delayed until the age of 5 or later, depending on the severity of hypertelorism, orbital dystopia and shape of the maxilla. Surgical correction of strabismus can be indicated and timing should be discussed within the craniofacial team. Multidisciplinary treatment is mandatory with the input of plastic surgeons, maxillofacial surgeons, ophthalmologists, orthoptists, otolaryngotologists, speech therapists, psychologists and social workers, and orthodontists.
Prognosis
Life expectancy in general is similar to the normal population. Quality of life may be affected because of a different facial appearance and the consequences of other congenital abnormalities.

                            Last update: 
                            February 2024


                            - Expert reviewer(s): 
                            Pr Irene MATHIJSSEN | ERN CRANIO* - Pr Andrew WILKIE | ERN CRANIO*


                                * European Reference Network