Muenke Syndrome

Excerpt

Clinical characteristics: Muenke syndrome is characterized by considerable phenotypic variability; features may include coronal synostosis (more often bilateral than unilateral); synostosis of other sutures, all sutures (pan synostosis), or no sutures; or macrocephaly. Bilateral coronal synostosis typically results in brachycephaly, although turribrachycephaly (a "tower-shaped" skull) or a cloverleaf skull can be observed. Unilateral coronal synostosis results in anterior plagiocephaly. Other craniofacial findings typically include temporal bossing, widely spaced eyes, ptosis or mild proptosis, mild midface retrusion, and highly arched palate or cleft lip and palate. Strabismus is common. Other findings can include hearing loss, developmental delay, intellectual disability, behavioral issues, intracranial anomalies, epilepsy, ocular anomalies, brachydactyly, carpal and/or tarsal bone fusions, broad thumbs and great toes, clinodactyly, and radiographic findings of short and broad middle phalanges and/or cone-shaped epiphyses. Of note, some individuals who have the p.Pro250Arg pathogenic variant may have no signs of Muenke syndrome on physical or radiographic examination.

Diagnosis/testing: The diagnosis of Muenke syndrome is established by the identification of the FGFR3 pathogenic variant c.749C>G (p.Pro250Arg) by molecular genetic testing.

Management: Treatment of manifestations: Children with Muenke syndrome and craniosynostosis are best managed by a pediatric craniofacial clinic, which typically includes a craniofacial surgeon and neurosurgeon, clinical geneticist, ophthalmologist, otolaryngologist, pediatrician, radiologist, psychologist, dentist, audiologist, speech therapist, and social worker. Depending on severity, the first craniosynostosis repair (fronto-orbital advancement and cranial vault remodeling) is typically performed between ages three and six months. An alternative approach is endoscopic strip craniectomy, which is a less invasive procedure and is typically performed prior to age three months. Postoperative increased intracranial pressure and/or the need for secondary or tertiary extracranial contouring may occur. Standard treatments for hearing loss; early speech therapy and intervention programs for those with developmental delay, intellectual impairment, behavioral issues, and/or hearing loss; surgical correction for strabismus; lubrication for exposure keratopathy.

Surveillance: Affected individuals benefit from integrated multidisciplinary care and protocol-driven management from birth to maturity that includes audiograms to screen for acquired or progressive hearing loss; developmental and behavioral assessments; neurologic assessment for seizures; ophthalmology assessment for strabismus; and social work assessment.

Evaluation of relatives at risk: It is appropriate to evaluate relatives at risk in order to identify as early as possible those who would benefit from institution of treatment and preventive measures.

Genetic counseling: Muenke syndrome is inherited in an autosomal dominant manner. Each child of an individual with Muenke syndrome has a 50% chance of inheriting the pathogenic variant. Because penetrance is reduced and the phenotype is variable within families, the manifestations in a child who inherits the pathogenic variant cannot be predicted based on the phenotypes of other heterozygous family members. Once the FGFR3 p.Pro250Arg pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing for Muenke syndrome are possible.