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Muenke syndrome is a syndromic craniosynostosis with significant phenotypic variability, usually characterized by coronal synostosis, midfacial retrusion, strabismus, hearing loss and developmental delay.
ORPHA:53271Classification level: Disorder
Birth prevalence is estimated at approximately 1/30,000, accounting for about 8% of all craniosynostoses and over 25% of cases with an identified genetic cause.
Muenke syndrome (MS) patients show a wide range of clinical findings, even within a single family. Most have coronal synostosis (more frequently bilateral), however, synostosis of other sutures, all sutures, macrocephaly without craniosynostosis, or a normal skull may be observed. Bilateral coronal synostosis usually results in brachycephaly (turribrachycephaly/cloverleaf skull are also possible) with temporal bossing and facial symmetry. Unilateral coronal synostosis results in plagiocephaly with facial asymmetry, frontal bossing, eyebrow elevation, anterior placement of the ear, and midface retrusion. Over 15% of mutation-positive individuals do not have premature fusion of the skull, but may or may not have other associated clinical findings. Craniofacial findings include: widely spaced eyes, ptosis or proptosis, strabismus, and high arched palate or cleft lip/palate. Over 70% of patients have some form of, usually mild, hearing loss (sensorineural being the most common, followed by conductive and mixed). Neurologic complications such as elevated intracranial pressure and hydrocephalus can occur, especially when two or more sutures are prematurely fused. Additional extracranial manifestations include: otitis media, brachydactyly, broad toes, broad thumbs, clinodactyly, developmental delay, intellectual disability (often mild), epilepsy, and/or increased risk for behavioral problems, including adaptive behavior.
MS is due to a mutation in the FGFR3 gene (4p16.3), encoding fibroblast growth factor receptor 3, which is required for normal skeleton development.
Molecular genetic testing identifying a p.Pro250Arg mutation in FGFR3 confirms diagnosis. Suture involvement and the presence of hydrocephalus can be visualized by radiography, 3D computed tomography, and MRI. Characteristic extracranial radiographic features include: fusion of the carpal and tarsal bones, short and broad (''thimble-like'') middle phalanges of the hands and feet, and epiphyseal coning.
Differential diagnoses include other types of syndromic craniosynostosis such as Crouzon and Saethre-Chotzen syndromes and Pfeiffer syndrome type 1.
Prenatal diagnosis is possible in families with a known disease-causing mutation. Prenatal ultrasound examination may be used as an adjunct to prenatal genetic testing.
Inheritance is autosomal dominant and genetic counseling can inform a parent with MS of their 50% risk of passing on the pathogenic variant to future offspring.
Management and treatment
Management of MS should be multidisciplinary. Patients should be tested for hearing loss and be subsequently monitored, even if initial evaluation is normal. Developmental and behavioral assessments, eye exams, speech therapy and/or special education should be evaluated on a case-by-case basis. Surgical management is offered based on craniosynostosis severity. Typically, an initial craniosynostosis repair (usually at 3-6 months of age), that consists of fronto-orbital advancement and cranial vault remodeling, is performed. A secondary (or tertiary) transcranial repair, with or without extracranial contouring, may be needed. Endoscopic strip craniectomy is a newer and less invasive procedure, usually performed before the age of 3 months.
The prognosis is variable. Good outcomes are observed if patients receive early surgical reconstruction (based on severity), as well as early and continued medical management of the neurologic, auditory, ocular, developmental and behavioral manifestations. Life-expectancy is normal.
- Clinical genetics review
- English (2016)