Muenke Syndrome

Agochukwu NB, Doherty ES, Muenke M.

Publication Details

Summary

Clinical characteristics.

Muenke syndrome is defined by the presence of the specific FGFR3 pathogenic variant, c.749C>G, that results in the protein change p.Pro250Arg. 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 (reduced anteroposterior dimension of the skull), although turribrachycephaly (a "tower-shaped" skull) or a cloverleaf skull can be observed. Unilateral coronal synostosis results in anterior plagiocephaly (asymmetry of the skull and face). Other craniofacial findings typically include: temporal bossing; widely spaced eyes, ptosis or proptosis (usually mild); midface retrusion; and highly arched palate or cleft lip and palate. Strabismus is common. Other findings can include: hearing loss (in 33%-100% of affected individuals); developmental delay (~33%); epilepsy; intracranial anomalies; intellectual disability; carpal bone and/or tarsal bone fusions; brachydactyly, broad toes, broad thumbs, and/or clinodactyly; and radiographic findings of thimble-like (short and broad) middle phalanges and/or cone-shaped epiphyses. Phenotypic variability is considerable even within the same family. 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 suggested by clinical findings and is established by the presence of the FGFR3 pathogenic variant c.749C>G (p.Pro250Arg).

Management.

Treatment of manifestations: Children with Muenke syndrome and craniosynostosis are best managed by a pediatric craniofacial clinic that 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. The need for secondary revision procedures is inversely related to the age of the affected individual at the time of initial repair. The location of the fused/synostotic suture, type of fixation, and the use of bone grafting do not have a significant effect on the need for revision.

Prevention of secondary complications: Early surgical reconstruction for craniosynostosis may reduce the risk for complications including sequelae related to increased intracranial pressure (e.g., behavioral changes).

Surveillance: Affected individuals benefit from integrated multidisciplinary care and protocol-driven management from birth to maturity that includes: annual multidisciplinary reviews and periodic review by a social work team; regular developmental assessments; periodic repeat audiograms to screen for acquired or progressive hearing loss; and early speech therapy or intervention programs for those with developmental delay, intellectual impairment, or hearing loss.

Genetic counseling.

Muenke syndrome is inherited in an autosomal dominant manner with incomplete penetrance and variable expressivity. If the defining FGFR3 pathogenic variant cannot be detected in either parent of a proband, germline mosaicism in a parent or a de novo pathogenic variant in the proband are possible. Each child of an individual with Muenke syndrome has a 50% chance of inheriting the pathogenic variant. Prenatal diagnosis for pregnancies at increased risk is possible if the pathogenic variant has been identified in the family. Prenatal ultrasound examination may be used as an adjunct to prenatal genetic testing.

Diagnosis

Clinical Diagnosis

The diagnosis of Muenke syndrome is suggested by clinical findings and established by the presence of the FGFR3 pathogenic variant c.749C>G (p.Pro250Arg).

Phenotypic variability in individuals with Muenke syndrome is considerable.

Skull phenotype, as determined by radiographs and/or CT scan of the skull can include the following:

  • Unilateral coronal craniosynostosis with anterior plagiocephaly (asymmetry of the skull and face) with the following physical findings:
    • Facial asymmetry
    • Ipsilateral
      • Flattening of the forehead
      • Elevation of the superior orbital rim
      • Elevation of the eyebrow
      • Anterior placement of the ear
      • Deviation of the nasal root
    • Contralateral
      • Frontal bossing of the forehead
      • Depression of the eyebrow
  • Bilateral coronal craniosynostosis that typically results in brachycephaly (reduced anteroposterior dimension of the skull), although turribrachycephaly (a "tower-shaped" skull) or a cloverleaf skull can be observed. Physical findings:
    • Temporal bossing (which is a helpful diagnostic sign)
    • Facial symmetry
  • Synostosis of other sutures (lambdoid, metopic, sagittal, squamosal)
  • Macrocephaly without craniosynostosis
  • Normal skull (no synostosis, no macrocephaly)

Variable features similar to other FGFR-related craniosynostosis syndromes (e.g., Apert syndrome, Pfeiffer syndrome, and/or Crouzon syndrome) and Saethre-Chotzen syndrome include:

  • Developmental delay, intellectual disability, or learning disorder
  • Epilepsy
  • Intracranial anomalies
  • Widely spaced eyes, ptosis, or proptosis (rare, but has been reported)
  • Strabismus
  • Midface retrusion
  • High-arched palate or cleft lip and palate
  • Hearing loss (typically mild and sensorineural)
  • Cervical vertebral fusion
  • Ankylosis
  • Brachydactyly (short fingers and toes)
  • Broad thumbs and broad toes
  • Clinodactyly
  • Cutaneous syndactyly (rarer finding; reported in 13 individuals with Muenke syndrome) or polydactyly

Note: Absence of minor clinical signs of Muenke syndrome may lead to misdiagnosis of an affected individual. For example, an individual with craniosynostosis who does not have extracranial findings may be misdiagnosed with "isolated" craniosynostosis.

The extracranial radiographic features of Muenke syndrome are variable and may include the following:

Note: (1) Didolkar et al [2009] reported an individual presenting with polyarthralgia and hearing loss in whom the diagnosis of Muenke syndrome was determined when hand and foot radiographs revealed bilateral non-osseous calcaneo-navicular fusions, osseous cuboid-lateral cuneiform fusions, bilateral capitate and hamate osseous fusions, cone-shaped epiphysis of the middle phalanges, and brachydactyly. Barbosa et al [2009] reported an individual with intellectual disability whose hand and foot radiographs showed an osteochondroma (a previously unreported finding in Muenke syndrome prior to that time) and bilateral fusion of the calcaneus and cuboid. Since then there has been an additional report of an affected individual with multiple osteochondromas of the upper and lower extremities by Talbot et al [2012]. Additionally, Agochukwu et al [2013] reported an affected individual with symptomatic bilateral talocalcaneal fusions involving the middle facet. This was the first reported case of Muenke syndrome involving tarsal fusions of these particular tarsal bones, as the most commonly observed tarsal fusion in Muenke syndrome is of the calcaneus and cuboid bones. These cases demonstrate how extracranial findings may serve as a clinical clue to the presence of the p.Pro250Arg pathogenic variant, particularly in individuals who do not have craniosynostosis. (2) Some fusions are not seen on radiographs until skeletal maturity is reached. Trusen et al [2003] studied the radiographs of persons with Muenke syndrome and Saethre-Chotzen syndrome. He found that five of eight individuals with Muenke syndrome had partial syndactyly and that two of eight had calcaneo-cuboid fusion. In this series, calcaneo-cuboid fusion was detected only in individuals with Muenke syndrome.

Molecular Genetic Testing

Gene. The FGFR3 c.749C>G pathogenic variant is the defining pathogenic variant associated with Muenke syndrome.

Clinical testing

Table 1.

Table 1.

Summary of Molecular Genetic Testing Used in Muenke syndrome

Testing Strategy

To confirm/establish the diagnosis in a proband. Findings on the initial evaluation (complete medical history, physical examination, review of systems, and family history) should help direct selection of the most appropriate molecular study.

Note: At this stage, radiographs may be useful in providing clues to the presence of Muenke syndrome, particularly in individuals with a family history and/or subtle physical signs of Muenke syndrome including mild hearing loss, intellectual disability, and/or macrocephaly.

  • Syndromic bilateral coronal synostosis. It is customary to perform a "craniosynostosis panel" that typically consists of molecular genetic testing of FGFR1, FGFR2, FGFR3 (including the defining FGFR3 c.749C>G [p.Pro250Arg] pathogenic variant), and TWIST (see Differential Diagnosis).
    • An algorithm for molecular genetic testing based on clinical findings proposes to improve the efficiency and cost effectiveness of molecular testing [Chun et al 2003].
    • An additional three-tiered algorithm has been suggested [Wilkie et al 2006, Agochukwu et al 2012b]:
      • Tier 1. Detects most intragenic pathogenic variants causing Apert syndrome, Crouzon syndrome, Pfeiffer syndrome, Muenke syndrome, and Saethre-Chotzen syndrome (FGFR1 exon 7 [IIa]; FGFR2 exons 8 [IIIa] and 10 [IIIc]; FGFR3 exons 7 [IIIa] and 10 [TM]; and TWIST1 [exon 1]).
      • Tier 2. Detects rarer pathogenic variants associated with Crouzon syndrome and Pfeiffer syndrome (FGFR2 exons 3, 5, 11, and 14-17).
      • Tier 3. Detects heterozygous gene deletions in TWIST1 (Saethre-Chotzen syndrome) and EFNB1 (craniofrontonasal syndrome).
  • Apparently isolated coronal synostosis. Some experts recommend that all probands with apparently isolated coronal synostosis be tested for the defining FGFR3 c.749C>G (p.Pro250Arg) pathogenic variant because it is difficult to differentiate Muenke syndrome from true coronal nonsyndromic craniosynostosis based on clinical evaluation alone [Renier et al 2000, Tsai et al 2000, Thomas et al 2005, Boyadjiev 2007, Kimonis et al 2007, Seto et al 2007, Agochukwu et al 2012b].
  • In the first cohort-based analysis of the genetic basis of craniosynostosis, Wilkie et al [2010] found that 24% of identified genetic causes of syndromic and nonsyndromic synostosis resulted from the defining Muenke syndrome FGFR3 pathogenic variant.

It is important to establish the molecular diagnosis of Muenke syndrome:

  • For management because of the significantly increased rate of cranial reoperation, hearing impairment, cognitive impairment, and developmental delay in Muenke syndrome;
  • For selective screening of related abnormalities;
  • For genetic counseling.

Clinical Characteristics

Clinical Description

Craniosynostosis

Coronal synostosis may be bilateral or unilateral. Bilateral coronal synostosis results in brachycephaly (reduced anteroposterior dimension of the skull); other head shapes may include turribrachycephaly (a "tower-shaped" skull) or cloverleaf-shaped skull in severe cases. Unilateral coronal synostosis results in anterior plagiocephaly (asymmetry of the skull and face). Occasionally, other sutures may be involved. One individual with Muenke syndrome had trigonocephaly resulting from metopic suture synostosis; his affected mother had bicoronal synostosis [van der Meulen et al 2006]. Rarely, pan synostosis occurs. In one report, one of ten family members with the p.Pro250Arg pathogenic variant had pan synostosis [Golla et al 1997]. This individual, the most severely affected family member, also had ocular proptosis. Squamosal suture synostosis has recently been reported in individuals with Muenke syndrome [Doumit et al 2014].

Craniosynostosis in Muenke syndrome most commonly involves the coronal suture. Bilateral coronal synostosis appears to be more common than unilateral synostosis. Renier et al [2000] determined that 71% of individuals with Muenke syndrome had bilateral coronal synostosis and 29% had unilateral coronal synostosis. Keller et al [2007] reported 66% with bilateral coronal synostosis and 34% with unilateral coronal synostosis. This figure has remained constant in later studies.

Craniosynostosis is not always present in individuals with Muenke syndrome:

  • In 72 individuals from 24 families, nine persons (12.5%) known to be heterozygous for the FGFR3 p.Pro250Arg pathogenic variant had no evidence of craniosynostosis [Renier et al 2000].
  • In a family of seven, five had coronal synostosis and two were phenotypically normal [Moko & Blandin de Chalain 2001]. All seven individuals were heterozygous for the FGFR3 p.Pro250Arg pathogenic variant.

In these cases, extracranial findings (i.e., radiographic findings of carpal and tarsal fusions, short and broad middle phalanges, cone-shaped epiphysis, or hearing loss), when present, helped support the diagnosis of Muenke syndrome.

Craniofacial features that may result from craniosynostosis are summarized in Diagnosis. 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.

Extracranial Findings

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]; more recent studies indicate 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]. The exact cause of the hearing loss is unknown (see Therapies Under Investigation).

Additionally, some individuals with Muenke syndrome have had recurrent episodes of otitis media treated with multiple myringotomy tube placements [Didolkar et al 2009].

In a large family several individuals who were heterozygous for the FGFR3 p.Pro250Arg pathogenic variant had moderate, bilateral sensorineural hearing loss but no craniosynostosis [Hollway et al 1998]; the sensorineural hearing loss was similar to the autosomal dominant form of deafness (DFNA6), which has been mapped to 4p16.3, the same region as FGFR3 [Lowry et al 2001]. In a subsequent study by Bespalova et al [1999], no evidence for the p.Pro250Arg pathogenic variant was found in the individuals with DFNA6.

Developmental delay and/or intellectual disability, usually mild, have been reported in approximately one third of individuals [Muenke et al 1997, Kress et al 2006].

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.

Honnebier et al [2008] did not find gross mental delays in 15/16 individuals with Muenke syndrome; however, no formal neurocognitive evaluation was performed. One individual had autism.

Reardon et al [1997] found that four of nine persons with Muenke syndrome who were evaluated had intellectual impairment: two had mild to moderate intellectual disability requiring special education; one had developmental delay requiring special education; one was described as having severe developmental delay.

In twins with Muenke syndrome and bicoronal suture synostosis reported by Escobar et al [2009], one twin had generalized anxiety disorder (GAD) and attention-deficit-hyperactivity disorder (ADHD) at age seven years; the other twin had pervasive developmental disorder (PDD), developmental delay (DD), ADHD, and structural brain anomalies on MRI including a large porencephalic cyst of the occipital horn of the left ventricle, hydrocephalus, and absence of the corpus callosum. Of note, both twins developed bilateral sensorineural hearing loss requiring hearing aids.

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].

The etiology of the developmental delay, intellectual disability, and behavioral problems reported in individuals with Muenke syndrome is yet to be elucidated. It is not yet known whether hearing loss plays a role in the developmental delay or whether individuals without craniosynostosis have a better intellectual/functional outcome as adults.

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. Some of these abnormalities may not be reported because of the lack of central nervous system imaging in individuals with Muenke syndrome, or because microscopic anomalies may not be detectable on routine magnetic resonance or computed tomography imaging. FGFR3 mRNA is abundantly expressed in the glial cells of the brain. To date, six individuals with Muenke syndrome and intracranial anomalies have been reported; epilepsy has been reported in thirteen individuals with Muenke syndrome [Agochukwu et al 2012b].

Strabismus is the most common ocular finding in Muenke syndrome. In one family with six members with Muenke syndrome, all six had strabismus [Yu et al 2010].

A study of the ocular phenotype of Muenke syndrome showed that compared to the average pediatric population, children with Muenke syndrome have a higher incidence of strabismus (66%), anisometropia, epicanthal fold changes, ocular hypertelorism, downward lateral canthal dystopia, and amblyopia [Jadico et al 2006].

In a larger series, the incidence of strabismus was 14/36 (39%) [de Jong et al 2010].

One individual had paralytic strabismus secondary to a cranial nerve VI deficit [Lowry et al 2001].

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 work-up 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].

Table 2.

Table 2.

Rare Findings in Persons with Muenke Syndrome

Minor Clinical Signs / Asymptomatic Heterozygotes

Some individuals heterozygous for the FGFR3 p.Pro250Arg pathogenic variant have no clinical or radiographic features of Muenke syndrome [Robin et al 1998, Moko & Blandin de Chalain 2001].

Some individuals with Muenke syndrome have minor clinical signs such as macrocephaly [Gripp et al 1998] and subtle facial findings without craniosynostosis [Gripp et al 1998, Robin et al 1998, Moko & Blandin de Chalain 2001, Sabatino et al 2004, Didolkar et al 2009]; some appear clinically unaffected until their radiographs are examined [Muenke et al 1997]. These individuals may not come to medical attention until the birth of a more severely affected child.

Genotype-Phenotype Correlations

No genotype-phenotype correlations are observed because all individuals with Muenke syndrome have the same pathogenic variant in FGFR3.

Penetrance

Penetrance is reduced. In a familial study of seven affected individuals, six of eight individuals had coronal synostosis and two of eight were phenotypically normal [Moko & Blandin de Chalain 2001], yielding a penetrance of approximately 75% for that family.

Penetrance is higher in females (87%) than in males (76%) [Solomon & Muenke 2010].

  • Gender-specific differences in the suture involved in craniosynostosis have been noted [Doherty et al 2007]. Females heterozygous for the p.Pro250Arg pathogenic variant may be more likely to have craniosynostosis than heterozygous males; when craniosynostosis is present, females have a more severe phenotype [Lajeunie et al 1999].
  • Honnebier et al [2008] also noted female preponderance for bicoronal synostosis: 56% of individuals with bicoronal synostosis and an FGFR3 pathogenic variant were female and 100% of individuals with unicoronal synostosis and an FGFR3 pathogenic variant were male. The findings of Moloney et al [1997] supported this observation: five of six persons with Muenke syndrome and bicoronal synostosis were female.

Anticipation

Anticipation has not been described in Muenke syndrome.

Nomenclature

Several terms in the literature may be confusing to the reader.

  • The term "nonsyndromic" means that a condition does not fit the pattern of a recognizable genetic syndrome [Mulliken 2002]. The term "nonsyndromic craniosynostosis" is variably used either:
    • As a synonym for single-suture craniosynostosis because most instances of single-suture craniosynostosis are of unknown etiology. However, the two terms are not identical in meaning.
      OR
    • To describe bilateral coronal suture synostosis that is not identifiable as a classic syndrome (e.g., Pfeiffer syndrome, Crouzon syndrome). When appropriate, the authors suggest the alternate terms "nonspecific craniosynostosis" or "unclassified brachycephaly."
  • The phrase "Muenke nonsyndromic coronal craniosynostosis" is occasionally used to mean Muenke syndrome. The authors discourage the use of this phrase because it inaccurately implies a "non-genetic" cause of Muenke syndrome.
  • An individual with "isolated craniosynostosis" has no extracranial manifestations [Cohen & MacLean 2000]. However, some authors use the term "isolated craniosynostosis" to mean that only one type of suture (e.g., coronal, sagittal) is fused. The correct term for uni- or bilateral premature fusion of one suture is "simple craniosynostosis." "Complex craniosynostosis" is correctly used to describe the involvement of two or more sutures.
  • In the field of genetics, the term "sporadic" has been used to describe a variety of disparate phenomena. The term "sporadic craniosynostosis" is used by some authors to mean a case without a family history. However, "sporadic craniosynostosis" may incorrectly imply a low recurrence risk. The correct term for a single occurrence of Muenke syndrome in a family is "simplex."
  • The term "Adelaide-type craniosynostosis" is no longer used to describe Muenke syndrome.

Prevalence

The birth prevalence of Muenke syndrome is approximately one in 30,000.

In a prospective study of 214 individuals with craniosynostosis born between 1993 and 2005, Morriss-Kay & Wilkie [2005] reported that of the 60 who had a specific molecular diagnosis, 28.5% had the p.Pro250Arg pathogenic variant; thus, 8% of the 214 had Muenke syndrome.

Muenke syndrome is estimated to account for 25%-30% of all genetic causes of craniosynostosis [Morriss-Kay & Wilkie 2005, Wilkie et al 2010].

The c.749C>G pathogenic variant (p.Pro250Arg) in FGFR3 is estimated to occur at a rate of 7.6-8x10-6 per haploid genome, one of the highest known rates for a human transversion [Moloney et al 1997, Rannan-Eliya et al 2004].

Differential Diagnosis

Unclassified brachycephaly refers to bilateral coronal synostosis in individuals who do not have any of the classic craniosynostosis syndromes (e.g., Pfeiffer syndrome, Crouzon syndrome). Following discovery of the FGFR3 p.Pro250Arg pathogenic variant, one survey of a group with unclassified brachycephaly found that 52% had Muenke syndrome [Mulliken et al 1999].

Syndromic craniosynostosis. Table 3 compares and contrasts Muenke syndrome with similar craniosynostosis syndromes. Because of phenotypic overlap and/or mild phenotypes, clinical differentiation of these syndromes may be difficult.

Phenotypic variation in Muenke syndrome includes the following:

  • A distinct "Muenke" syndrome phenotype includes: uni- or bilateral coronal synostosis, midface hypoplasia, broad toes, and brachydactyly.
  • Some individuals clinically diagnosed with Crouzon syndrome, Pfeiffer syndrome, or Saethre-Chotzen syndrome are ultimately found to have Muenke syndrome when molecular genetic testing is performed.
    • Chun et al [2002] examined individuals clinically identified as having the Saethre-Chotzen syndrome phenotype. Of 11 individuals identified as having the Saethre-Chotzen phenotype, four (44%) were found to have the p.Pro250Arg pathogenic variant.
    • Sahlin et al [2009] describes a family with the Saethre-Chotzen syndrome (SCS) phenotype. The proband’s father was diagnosed with Saethre-Chotzen syndrome, in addition to the proband and her son. Sequence analysis showed the p.Pro250Arg pathogenic variant in exon 7 of FGFR3.
  • In another case, a mother and a daughter were diagnosed with Muenke syndrome following the sudden unexpected death of the daughter [Shah et al 2006]. The mother had been diagnosed in infancy with Treacher Collins syndrome.
  • A proband with craniosynostosis and her father both had epidermal hyperplasia (Beare-Stevenson-like anomalies) [Roscioli et al 2001]. (See FGFR-Related Craniosynostosis Syndromes.)
  • Additional, less common extracranial findings reported in Muenke syndrome are listed in Table 2. It is not clear whether some of these findings are a consequence of the p.Pro250Arg pathogenic variant or whether they are coincidental.
Table 3.

Table 3.

A Comparison of Muenke Syndrome with Other FGFR-Related Craniosynostosis Syndromes and Saethre-Chotzen Syndrome

An identical proline-to-arginine pathogenic variant occurs at analogous positions in FGFR1, FGFR2, and FGFR3 (Figure 1):

Figure 1.

Figure 1.

Diagram of the C>G pathogenic missense variants that result in a proline-to-arginine substitution at analogous positions in the protein products of FGFR1, FGFR2, and FGFR3

For an excellent overview of other primary and secondary forms of craniosynostosis, see FGFR-Related Craniosynostosis Syndromes.

Nonspecific craniosynostosis. Table 4 summarizes the detection rate for the p.Pro250Arg pathogenic variant among large craniosynostosis populations with nonspecific phenotypes.

Table 4. . Craniosynostosis Clinic Populations with a Nonspecific Phenotype Tested for the p.

Table 4.

Craniosynostosis Clinic Populations with a Nonspecific Phenotype Tested for the p.Pro250Arg FGFR3 Pathogenic Variant

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Muenke syndrome, the following evaluations are recommended:

  • Assessment of suture involvement by skull radiographs or preferably 3D skull CT
  • Assessment for hydrocephalus with brain CT or MRI
  • Assessment for exposure keratopathy
  • Hearing assessment
  • Developmental assessment in children
  • Ophthalmologic assessment including screening for strabismus and vision. Additionally, this assessment should include fundoscopy to assess for papilledema, a finding that is present when intracranial pressure (ICP) is increased.
  • Radiographic assessment of hands and feet
  • Clinical genetics consultation

Treatment of Manifestations

Children with Muenke syndrome and craniosynostosis should be referred to a craniofacial clinic with pediatric experience. These individuals benefit most from a multidisciplinary approach to care. A craniofacial clinic associated with a major pediatric medical center usually includes: a surgical team (craniofacial surgeon and neurosurgeon), clinical geneticist, ophthalmologist, otolaryngologist, pediatrician, radiologist, psychologist, dentist, audiologist, speech therapist, and social worker. Other disciplines are involved as needed.

Depending on the severity, the first craniosynostosis repair is typically performed between age three and six months. This procedure is usually transcranial (i.e., the skull is opened down to the dura so that the bones can be physically repositioned during a procedure such as a midface advancement). A new approach currently being performed with long-term overall better symmetry compared to traditional cranial vault remodeling and fronto-orbital advancement is endoscopic strip craniectomy. This is typically performed earlier, before the affected child reaches age three months.

Following craniosynostosis repair, the need for a second procedure is increased in those with Muenke syndrome compared to those with craniosynostosis without the defining pathogenic variant. The reasons for a second procedure vary by individual and can include:

  • Severe initial clinical presentation requiring a staged repair
  • Cranial vault abnormalities including temporal bulging and recurrent supraorbital retrusion requiring extracranial contouring (i.e., use of a cement such as calcium phosphate to contour the surface of the skull)
  • Postoperative increased ICP
  • Recurrent deformity requiring a second transcranial repair
    • The need for a surgical revision for aesthetic reasons (typically temporal bulging) has been reported in multiple series [Renier et al 2000, Cassileth et al 2001, Arnaud et al 2002, Thomas et al 2005, Honnebier et al 2008].
    • According to Thomas et al [2005], individuals with craniosynostosis and the defining pathogenic variant for Muenke syndrome were more likely to require early intervention with a posterior release operation (at age ~6 months) to prevent excess frontal bulging than were those without the defining pathogenic variant.

      Seven of 29 individuals (24.1%) with the p.Pro250Arg pathogenic variant underwent a second surgery (6/7 had increased ICP) as compared to two of 47 (4.3%) without the pathogenic variant. This difference in reoperation rate was statistically significant (p=0.048) [Thomas et al 2005].
    • In the report of Honnebier et al [2008], 16 individuals with Muenke syndrome required a second procedure: seven required a second transcranial procedure; 15 were expected to undergo extracranial contouring. Note that none had increased ICP.
    • However, a study by Ridgway et al [2011] challenges the above findings, reporting a frequency of frontal revision in individuals with Muenke syndrome who had fronto-orbital advancements that was lower than previously reported. This study found that the need for secondary revision procedures was inversely related to the age of the affected individual at the time of the initial repair. The location of the fused/synostotic suture, type of fixation, and the use of bone grafting do not have a significant effect on the need for revision.

In Muenke syndrome a discrepancy between severity of the craniofacial findings (e.g., severe midface retrusion, widely spaced eyes) and neurologic findings (e.g., increased ICP, hydrocephalus, structural brain anomalies, severe developmental delay or severe intellectual disability) has been noted [Lajeunie et al 1999, Arnaud et al 2002, Honnebier et al 2008]: severe early clinical findings such as recurrent deformity and the need for a second major procedure did not correlate with postoperative risk for increased ICP.

Prevention of Secondary Complications

Early surgical reconstruction for craniosynostosis may reduce the risk for complications including sequelae related to increased intracranial pressure (e.g., behavioral changes).

Surveillance

The following are appropriate:

  • Regular developmental assessments of affected children
  • Periodic repeat audiograms because 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.
  • Early speech therapy and intervention for children with Muenke syndrome who have developmental delay, intellectual disability, or hearing loss, even if mild
  • As part of protocol-driven care and management: annual multidisciplinary reviews and periodic review by a social work team. Protocol-driven approaches to surveillance currently in use include those of Flapper et al [2009] and de Jong et al [2010].

Agents/Circumstances to Avoid

No activities, treatments, or medications that exacerbate the disease manifestations of Muenke syndrome have been identified.

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 (particularly in individuals affected with craniosynostosis, hearing loss, developmental delay and/or cognitive disability).

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Mansour et al [2009] determined that in the mouse model of Muenke syndrome all mice had low-frequency sensorineural hearing loss with relative high-frequency sparing and histologic changes in the organ of Corti and cochlear duct. A further study by the same group, Mansour et al [2013], revealed that the rescue of cochlear function and hearing loss phenotype of these mice is possible with a reduction in Fgf10, which normally activates Fgfr2b or Fgfr1b.

Animal models indicated that FGFR3, the gene mutated in Muenke syndrome, is expressed at its highest levels in the developing central nervous system.

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Muenke syndrome is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • Most individuals diagnosed with Muenke syndrome have an affected parent.
  • A proband with Muenke syndrome may have the disorder as the result of a de novo pathogenic variant. The proportion of cases caused by de novo pathogenic variants is unknown.
  • As in achondroplasia, de novo pathogenic variants causing Muenke syndrome appear to be exclusively of paternal origin [Rannan-Eliya et al 2004] and to be associated with advanced paternal age.
  • Recommendations for the evaluation of parents of a proband with an apparent de novo pathogenic variant include: physical examination; radiographs of the skull, hands, and feet; and testing for the FGFR3 p.Pro250Arg pathogenic variant. Evaluation of the parents may determine that one is heterozygous for the p.Pro250Arg pathogenic variant but has a mild phenotype.

Note: Although most individuals diagnosed with Muenke syndrome have an affected parent, the family history may appear to be negative because of subtle/absent clinical findings or failure to recognize the disorder in family members.

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the proband's parents.
  • If a parent of the proband is affected or has the defining FGFR3 p.Pro250Arg pathogenic variant, the risk to the sibs of inheriting this pathogenic variant is 50%. Because penetrance is reduced and the phenotype is variable within a family, some individuals who inherit the FGFR3 p.Pro250Arg pathogenic variant have no (or extremely mild) signs of Muenke syndrome.
  • When the parents are clinically unaffected and do not have the FGFR3 p.Pro250Arg pathogenic variant, the risk to the sibs is low.
  • If the defining pathogenic variant cannot be detected in either parent, two possible explanations are: (a) germline mosaicism in a parent or (b) a de novo pathogenic variant in the proband. Although no instances of germline mosaicism have been reported, it remains a possibility [Rannan-Eliya et al 2004].

Offspring of a proband. Each child of an individual with Muenke syndrome has a 50% chance of inheriting the pathogenic variant.

Other family members of a proband. The risk to other family members depends on the genetic status of the proband's parents. If a parent is affected and/or has the FGFR3 p.Pro250Arg pathogenic variant, his or her family members are at risk.

Related Genetic Counseling Issues

Consideration of molecular genetic testing of young, at-risk family members is appropriate for guiding medical management (see Management, Evaluation of Relatives at Risk). Prior to testing sibs, parents, and extended family members, discussion should be held with a genetic counselor regarding the risks, benefits, and limitations of testing.

Generally, in individuals of school age and older, without any developmental issues, developmental delay, hearing loss, craniosynostosis, or other features of Muenke syndrome, the likelihood of Muenke syndrome is quite low, though the FGFR3 p.Pro250Arg pathogenic variant has been identified in seemingly unaffected individuals [Authors, personal observation]. Children who inherit the FGFR3 p.Pro250Arg pathogenic variant may be more or less severely affected than their parents. Uni- and bilateral coronal synostosis as well as absence of synostosis may be seen in individuals in the same family.

Considerations in families with an apparent de novo pathogenic variant

  • When neither parent of a proband with an autosomal dominant condition has the pathogenic variant, the variant is likely de novo. However, germline mosaicism as well as possible non-medical explanations, including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be considered.
  • Reduced penetrance may lead to misinterpretation of the family history. For example, if a heterozygous parent has minor or no clinical signs, affected offspring may be misdiagnosed as a "simplex" case of Muenke syndrome.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Molecular genetic testing. Once the pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible options.

Ultrasound examination. Craniosynostosis should be suspected when the cephalic index, cranial shape, or fetal face shape is abnormal [Tonni et al 2011]. Although difficult, prenatal diagnosis may be possible by ultrasound examination of the calvarial sutures. When present, additional craniofacial features of Muenke syndrome (i.e., midface hypoplasia, ocular hypertelorism) may also be apparent [Shaw et al 2011].

In a family known to have the pathogenic variant, if craniosynostosis or other craniofacial features (i.e., midface hypoplasia, ocular hypertelorism) are seen on prenatal ultrasound examination, the index of suspicion for Muenke syndrome should be high.

On prenatal ultrasound examination of twins with Muenke syndrome, Escobar et al [2009] found normal anatomy in one twin and congenital anomalies in the other twin. Molecular diagnosis of Muenke syndrome was made after birth in both twins.

Requests for prenatal testing for conditions such as Muenke syndrome are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • National Library of Medicine Genetics Home Reference
  • AboutFace International
    123 Edward Street
    Suite 1003
    Toronto Ontario M5G 1E2
    Canada
    Phone: 800-665-3223 (toll-free); 416-597-2229
    Fax: 416-597-8494
    Email: info@aboutfaceinternational.org
  • Children's Craniofacial Association (CCA)
    13140 Coit Road
    Suite 517
    Dallas TX 75240
    Phone: 800-535-3643 (toll-free); 214-570-9099
    Fax: 214-570-8811
    Email: contactCCA@ccakids.com
  • National Institute of Neurological Disorders and Stroke (NINDS)
    PO Box 5801
    Bethesda MD 20824
    Phone: 800-352-9424 (toll-free); 301-496-5751; 301-468-5981 (TTY)

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Muenke Syndrome: Genes and Databases

GeneChromosome LocusProteinLocus SpecificHGMD
FGFR34p16​.3Fibroblast growth factor receptor 3FGFR3 @ LOVDFGFR3

Data are compiled from the following standard references: gene from HGNC; chromosome locus, locus name, critical region, complementation group from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B.

OMIM Entries for Muenke Syndrome (View All in OMIM)

134934FIBROBLAST GROWTH FACTOR RECEPTOR 3; FGFR3
602849MUENKE SYNDROME; MNKES

Molecular Genetic Pathogenesis

The c.749C>G substitution in FGFR3 is estimated to occur at a rate of 7.6-8x10-6 per haploid genome, one of the highest known mutation rates for a transversion [Moloney et al 1997, Rannan-Eliya et al 2004].

Gene structure. Human FGFR3 is 16.7 kb long and is composed of 17 coding exons [Perez-Castro et al 1997]. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic allelic variants. Figure 2 demonstrates the p.Pro250Arg protein change in FGFR3.

Figure 2. . Schema of the FGFR3 protein

The loops represent the three immunoglobulin domains (left to right: IgI, IgII, IgIII).

Figure 2.

Schema of the FGFR3 protein

The loops represent the three immunoglobulin domains (left to right: IgI, IgII, IgIII). The p.Pro250Arg protein change (indicated with a black dot) is in the linker region between the second and third immunoglobulin (more...)

Table 5.

Table 5.

FGFR3 Pathogenic Variants Discussed in This GeneReview

Normal gene product. The FGFR family is a group of receptor tyrosine kinases. FGFRs 1-4 have an extracellular ligand-binding domain containing three immunoglobulin-like loops, a single-pass transmembrane domain, and a split intracellular kinase domain. FGFRs bind fibroblast growth factors (FGFs) and dimerize in order to effect downstream intracellular signaling [Green et al 1996]. FGFR3 negatively regulates chondrocyte differentiation and proliferation in developing endochondral bone (appendicular skeleton) [Ornitz & Marie 2002].

The genetics of intramembranous bone (skull vault) formation are complex, and the role of FGFR3 is not yet well understood. FGFR3 is detected in coronal suture osteogenic fronts but at lower levels than FGFR1 and FGFR2 [Iseki et al 1999]. FGFR3 is mainly expressed in mature chondrocytes of the cartilage growth plate [Cunningham et al 2007]. FGFR3 mRNA is found in its highest amounts in the developing CNS [Robin 1999]. It is also present in the skeletal precursors for all bones during the period of endochondral ossification and resting cartilage [Robin 1999].

Abnormal gene product. The p.Pro250Arg pathogenic variant results in enhanced FGF binding [Ibrahimi et al 2004]. This pathogenic variant is located in the linker region between the second and third immunoglobulin-like domains (Figure 2) [Park et al 1995, Wilkie et al 1995]. Kinetic ligand binding studies and x-ray crystallography of linker region pathogenic variants demonstrate that the pathogenic variant results in increased ligand affinity (FGF9) and altered specificity [Cunningham et al 2007]. Overactivation of FGFR3 appears to lead to craniosynostosis because bone differentiation is accelerated [Funato et al 2001].

Fgfr3 knockout mice have elongated tails and hind limbs, implying that FGFR3 has a role in slowing skeletal growth [Robin 1999] and indicating that FGFR3 pathogenic variants are hypermorphic, causing the mutated gene product to over-perform its normal function.

References

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Suggested Reading

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Chapter Notes

Author Notes

Cognitive Function, Development, and Hearing in Patients with Muenke Syndrome (FGFR3-Related Craniosynostosis). We have ongoing studies at the National Institutes of Health (NIH) that focus on various aspects of Muenke syndrome, and we hope to improve our understanding of hearing, cognitive function, and development in people with Muenke syndrome.

We are currently conducting research on the relationship between development, cognitive function, and hearing in individuals with Muenke syndrome. The goal of this study is to better understand the development of the central nervous system as well as to understand the causes of developmental delay and intellectual disabilities that can occur in some individuals with Muenke Syndrome. This study will also help us to learn much about the long-term outcomes and functioning of adults with Muenke syndrome. In addition, we also hope to be able to outline factors that may contribute to and predict mental prognosis in individuals with Muenke syndrome. Please note, you do not need to have developmental delay, intellectual disabilities, or hearing loss in order to participate in our study.

Acknowledgments

We are indebted to the affected individuals we work with and their families. This work was supported by the Division of Intramural Research, National Human Genome Research Institute, National Institutes of Health.

Revision History

  • 19 June 2014 (me) Comprehensive update posted live
  • 7 December 2010 (me) Comprehensive update posted live
  • 10 May 2006 (me) Review posted to live Web site
  • 30 January 2006 (mm) Original submission