Clinical Description
Craniosynostosis and craniofacial features. Coronal synostosis may be bilateral (~2/3 of affected individuals) or unilateral (~1/3 of affected individuals) [Renier et al 2000, Keller et al 2007, Kruszka et al 2016]. Occasionally, other sutures may be involved, including the metopic suture (leading to trigonocephaly), the sagittal suture, the squamosal suture, or, rarely, all sutures (pan synostosis) [Golla et al 1997, van der Meulen et al 2006, Doumit et al 2014, Kruszka et al 2016].
Craniosynostosis is not always present in individuals with Muenke syndrome:
In a large international cohort of individuals with Muenke syndrome, 16 (15.5%) of 103 did not have craniosynostosis [
Kruszka et al 2016].
In these cases, extracranial findings (i.e., hearing loss [often mild to moderate], radiographic findings of carpal and tarsal fusions, short and broad middle phalanges, and cone-shaped epiphysis), when present, helped support the diagnosis of Muenke syndrome.
Craniofacial features that may result from craniosynostosis are summarized in Suggestive Findings. Rarer craniofacial features include ptosis, malar flattening, a short nose with anteverted nares, an overhanging nasal tip, deviation of the nasal septum, a short nose with a depressed nasal bridge, high-arched palate and cleft lip and/or palate, dental malocclusion, mild retrognathia, hypoplastic auricles, and low-set ears.
Hearing loss. Initial studies revealed that at least one third of individuals with Muenke syndrome have mild to moderate sensorineural hearing loss [Muenke et al 1997, Kress et al 2006, de Jong et al 2010], with some even suggesting that all individuals with Muenke syndrome are likely to have some degree of hearing loss, usually mild [Doherty et al 2007, Honnebier et al 2008, Mansour et al 2009, de Jong et al 2011b]. There is evidence that sensorineural hearing loss (usually mild and mid-to-low frequency) is specific to Muenke syndrome compared to other FGFR-related craniosynostosis syndromes [Agochukwu et al 2014a], sometimes occurring in individuals with Muenke syndrome who do not have craniosynostosis [Hollway et al 1998].
In a large-cohort international study, more than 70% of individuals with Muenke syndrome had hearing loss, with a majority (70.8%) having bilateral sensorineural hearing loss and the remainder having conductive (22%) and mixed forms (8.6%).
Overall, a majority of hearing loss observed in craniosynostosis syndromes is conductive, except in Muenke syndrome, where sensorineural hearing loss is more likely [
de Jong et al 2010,
Agochukwu et al 2014b].
Some children with Muenke syndrome and craniosynostosis develop hearing loss despite passing their newborn hearing screens [Doherty & Muenke, personal observation]. Additionally, some affected individuals may have hearing loss that progresses or becomes more severe as they age.
Some individuals with Muenke syndrome have recurrent episodes of otitis media treated with myringotomy tube placement [
Didolkar et al 2009,
Kruszka et al 2016], which may explain the occurrence of conductive hearing loss in some affected individuals.
Developmental delay and behavioral functioning. Developmental delay and/or intellectual disability, usually mild, has been reported in approximately one third of individuals [Muenke et al 1997, Kress et al 2006]. Compared to normative populations, individuals with Muenke syndrome have also been reported to be at increased risk for developing some behavioral and emotional problems [Maliepaard et al 2014, Yarnell et al 2015].
In a large international study of Muenke syndrome, 40.8% were reported to have intellectual disability and 66.3% had developmental delay, with speech delay the most common type (61.1%) [Kruszka et al 2016]. Approximately 24% had a diagnosis of ADHD.
In a study of intellectual outcomes following protocol management in four persons with Muenke syndrome followed from birth to skeletal maturity compared to persons with Crouzon syndrome and Pfeiffer syndrome,
Flapper et al [2009] found that individuals with Muenke syndrome and Pfeiffer syndrome were more likely to be intellectually impaired than were individuals with Crouzon syndrome. One of the four with Muenke syndrome had moderate intellectual disability (IQ <70) and a history of behavioral problems; two had borderline intellectual disability (IQ 70-80) and required special education; and one was of average intelligence (IQ 90-110), completed high school without difficulty, and is currently training to be a pilot.
In a study by
de Jong et al [2012] of individuals with
syndromic craniosynostosis, it was found that all of the studied syndromes had a high prevalence of speech delay. In this study, cognitive delay was mainly reported in Apert, Crouzon, and Muenke syndromes. A study of syndromic craniosynostosis by
Bannink et al [2011] found behavioral problems to be more common in boys with Apert and Muenke syndromes, with a prevalence of 67% and 50%, respectively.
One study found a slightly lower IQ in individuals with craniosynostosis with Muenke syndrome compared to individuals with craniosynostosis who do not have the defining
pathogenic variant [
Arnaud et al 2002].
After evaluating 13 children with Muenke syndrome, a study by
Maliepaard et al [2014] found that children with Muenke syndrome had more social, attention, and inattention problems compared to a normative population and children with other craniosynostosis syndromes.
In a cohort on 44 affected persons,
Yarnell et al [2015] found that individuals with Muenke syndrome were at increased risk for developing adaptive and executive functioning problems compared to their unaffected (mutation negative) sibs and the normative population. Interestingly, the change in behavior in the affected cohort was not dependent on the presence or absence of craniosynostosis or hearing loss, raising the question of an intrinsic brain effect of the pathogenic
FGFR3 p.Pro250Arg variant that is distinct from the change in skull shape.
Neurologic abnormalities. Differences in patterns of the expression, formation, and structure of the central nervous system may be partly responsible for the developmental delay and intellectual disability observed in Muenke syndrome.
Ocular anomalies. Strabismus is the most common ocular finding in Muenke syndrome [Yu et al 2010], with one large study reporting an incidence of 31/69 (45%) [Kruszka et al 2016] and another study finding strabismus in 14 (39%) of 26 individuals [de Jong et al 2010].
Compared to the average pediatric population, children with Muenke syndrome have a higher incidence of strabismus (66%), anisometropia, epicanthal fold changes, widely spaced eyes, downward lateral canthal dystopia, and amblyopia [
Jadico et al 2006].
Limb findings. Most individuals with Muenke syndrome have normal-appearing hands and feet with normal range of motion of all joints; therefore, many of the limb findings in Muenke syndrome are identified during the diagnostic evaluation when radiographs reveal findings such as short, broad middle phalanges of the fingers, absent or hypoplastic middle phalanges of the toes, carpal and/or tarsal fusion, and cone-shaped epiphyses [Hughes et al 2001, Kruszka et al 2016]. Broad toes and great thumbs have also been described in individuals with Muenke syndrome.
Cutaneous syndactyly has been described in 13 affected individuals [Golla et al 1997, Passos-Bueno et al 1999, Chun et al 2002, Trusen et al 2003, Shah et al 2006, Baynam & Goldblatt 2010, de Jong et al 2011a].
Obstructive sleep apnea (OSA), a common finding in craniosynostosis syndromes in general, is less prevalent in those with Muenke syndrome [Bannink et al 2011, Dentino et al 2015].
Minor clinical signs / asymptomatic heterozygotes