Craniofacial conditions

Craniofrontonasal Dysplasia

X-linked condition in which – paradoxically – girls and women are more severely affected than boys and men.

Summary

Craniofrontonasal dysplasia (CFND, also craniofrontonasal syndrome) is a rare congenital condition caused by a change in the EFNB1 gene. A particularity is the paradoxical sex expression: girls and women are usually more severely affected than boys and men. Typical features are wide eye spacing (hypertelorism), involvement of the fronto-nasal region and – in girls – a coronal suture synostosis. Intellectual development is usually normal.

Cause & genetics

Cause and inheritance

The cause is changes in the EFNB1 gene on the X chromosome, which encodes the messenger ephrin-B1 – important for the demarcation of tissue boundaries during skull development.^[1] Inheritance is X-linked with paradoxical expression: heterozygous girls/women show the full picture, while boys/men with the change usually only have wide eye spacing. This is explained by a cellular coexistence of healthy and altered cells (X-inactivation mosaic), which particularly disturbs the tissue boundaries.^[2]

Genetic counselling is important to discuss the unusual inheritance pattern, the recurrence risk and the different expression in daughters and sons.

Features

Typical features

In girls and women (usually more severely affected):

Uni- or bilateral coronal suture synostosis, often with facial asymmetry
Marked hypertelorism (wide eye spacing)
Broad nasal root, notched or split nasal tip (frontonasal dysplasia)
High, broad forehead
Longitudinally grooved finger and toe nails, wiry hair
Skeletal particularities (e.g. collarbone, shoulder girdle), occasionally cleft palate

In boys and men, usually only wide eye spacing is recognisable; other signs are often absent.

Surgery

Craniofacial procedures

1. Skull surgery in infancy / early childhood

In case of coronal suture synostosis, a fronto-orbital advancement with remodelling of the forehead and orbital rim is usually performed, to give the brain room and improve the forehead/orbit shape. In the unilateral form the asymmetry is corrected.

2. Correction of the hypertelorism

The enlarged eye spacing can be corrected by an orbital translocation (surgical bringing-together of the eye sockets) – a demanding procedure that combines craniofacial surgery, neurosurgery and ophthalmology. It is usually planned in later childhood, when the skull and eye sockets have grown sufficiently.

3. Nose and soft-tissue corrections

The shape and symmetry of the nose and midface can be improved in further steps, often only in adolescence or early adulthood.

Eyes & hearing

Eyes, development and hearing

Because of the wide eye spacing and possible squint, ophthalmological checks are important. Intellectual development is usually normal. Hearing losses are rarer but should be checked.

Diagnostics

The work-up includes: clinical examination by a craniofacial team, genetic testing of the EFNB1 gene, 3D imaging of the skull and eye sockets as well as ophthalmological examination. Genetic confirmation is also important for family counselling.

Interdisciplinary

Treatment in an interdisciplinary centre

Ideal is care by a team with craniofacial surgery / oral and maxillofacial surgery, neurosurgery, ophthalmology, orthodontics, genetics, ENT and psychology.

Treatment roadmap

Possible treatment roadmap

Newborn period

Confirmation of the diagnosis, assessment of skull shape, eye spacing and – if present – palate.

Infancy / early childhood

Fronto-orbital advancement in case of coronal synostosis; correction of the asymmetry.

Childhood

Planning and performance of the hypertelorism correction (orbital translocation).

Adolescence

Nose and soft-tissue corrections, fine orthodontic adjustment, psychosocial support.

Prognosis

The prognosis is overall favourable: intellectual development is usually normal, and the malformations can be well treated with staged procedures. Severity and individual course are however – especially in girls – very variable. Decisive are careful planning of the operation timing and long-term interdisciplinary support.

Key message: craniofrontonasal dysplasia (EFNB1) shows an unusual X-linked inheritance with stronger expression in girls. Hypertelorism and fronto-nasal involvement are in the foreground; treatment is carried out in stages at a specialised centre.

References

Twigg SRF, Kan R, Babbs C, et al. (2004). Mutations of ephrin-B1 (EFNB1), a marker of tissue boundary formation, cause craniofrontonasal syndrome. Proc Natl Acad Sci USA, 101(23):8652–7. DOI
Wieland I, Jakubiczka S, Muschke P, et al. (2004). Mutations of the ephrin-B1 gene cause craniofrontonasal syndrome. Am J Hum Genet, 74(6):1209–15. DOI
Renier D, Lajeunie E, Arnaud E, Marchac D (2000). Management of craniosynostoses. Childs Nerv Syst, 16(10–11):645–58. DOI