Craniofacial conditions

Muenke Syndrome

Coronal suture craniosynostosis due to an FGFR3 mutation, with very variable expression and frequent hearing loss.

Summary

Muenke syndrome is caused by one very specific change in the FGFR3 gene (p.Pro250Arg). Characteristic is premature closure of one or both coronal sutures. The expression is very variable: some affected people have clear skull changes, others barely visible signs. A sensorineural hearing loss is common. The diagnosis is confirmed genetically, as the external appearance alone is often not unequivocal.

Cause & genetics

Cause and inheritance

Muenke syndrome arises from a single, always identical change in the FGFR3 gene (c.749C>G, p.Pro250Arg).^[1] Inheritance is autosomal dominant, but with reduced penetrance and variable expressivity: not every carrier shows a synostosis, and the picture can range from severe to barely noticeable. Girls with the mutation develop craniosynostosis more often than boys.^[2] For the children of an affected person, there is a 50 % transmission risk.

Genetic testing is central: because the external appearance can be non-specific, all uni- or bilateral coronal suture synostoses should be tested for the FGFR3 mutation.^[2]

Features

Typical features

Uni- or bilateral coronal suture synostosis (facial asymmetry in the unilateral form)
Broad or slightly tower-shaped skull; sometimes macrocephaly
Sensorineural hearing loss, often in the low frequency range (in studies in a large proportion of affected people)
Possible developmental or learning differences
Fusions of carpal or tarsal bones (carpal/tarsal fusion), often visible only on X-ray
Sometimes normal external appearance despite a proven mutation

The range is wide. Some children need several operations, others hardly any treatment.

Hearing & development

Hearing and development

A sensorineural (inner-ear-related) hearing loss is a frequent, characteristic feature – usually mild to moderate in the low frequency range. In a small case series it was detectable in the majority of those examined; reliable frequency data for all affected people are lacking.^[2] An audiometry is therefore part of the standard work-up. Intellectual development is often normal but can vary; a developmental assessment is useful.

Important: because the hearing loss is easily overlooked, children with Muenke syndrome should receive regular hearing tests – early support aids language development.

Surgery

Craniofacial procedures

In case of relevant coronal synostosis, a fronto-orbital advancement with remodelling of the forehead and orbital rim is usually performed in the first year of life; in the unilateral form the asymmetry is corrected. As in Saethre-Chotzen syndrome, there is an increased risk of a renewed rise in intracranial pressure after the operation, which is why long-term checks are important. A midface operation is only rarely necessary.

Diagnostics

The work-up includes: clinical examination by a craniofacial team, genetic testing (targeted FGFR3 test), 3D imaging of the skull, hearing test (audiometry) as well as developmental assessment. Because of the non-specific picture, genetic confirmation is particularly valuable.

Interdisciplinary

Treatment in an interdisciplinary centre

Ideal is care by a team with craniofacial surgery / oral and maxillofacial surgery, neurosurgery, ENT and audiology, paediatrics, ophthalmology, genetics, speech therapy and developmental support.

Treatment roadmap

Possible treatment roadmap

Newborn period / early infancy

Confirmation of the diagnosis (FGFR3), assessment of skull shape and hearing.

1st year of life

Fronto-orbital advancement in case of relevant synostosis.

Toddler / childhood

Regular hearing tests, monitoring of intracranial pressure, developmental support.

School age / adolescence

Support of hearing, learning and skull shape; psychosocial support.

Prognosis

The prognosis is overall favourable. Many children develop well; decisive are timely management of the hearing loss, control of intracranial pressure and developmental support. The individual course can however – owing to the variable expression – be very different.

Key message: Muenke syndrome is genetically clearly defined (FGFR3 p.Pro250Arg) but very variable in appearance. Genetic testing and regular hearing tests are particularly important.

References

Bellus GA, Gaudenz K, Zackai EH, et al. (1996). Identical mutations in three different fibroblast growth factor receptor genes in autosomal dominant craniosynostosis syndromes. Nat Genet, 14(2):174–6. DOI
Doherty ES, Lacbawan F, Hadley DW, et al. (2007). Muenke syndrome (FGFR3-related craniosynostosis): expansion of the phenotype and review of the literature. Am J Med Genet A, 143A(24):3204–15. DOI
Renier D, Lajeunie E, Arnaud E, Marchac D (2000). Management of craniosynostoses. Childs Nerv Syst, 16(10–11):645–58. DOI