Clinical Diagnosis

The diagnosis of Muenke syndrome is suggested by clinical findings and established by the presence of the FGFR3 mutation 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 anterior

    • Deviation of the nasal root

    • Bossing of the forehead

  • Contralateral

    • Bulging of the frontal bone

    • Depression of the eyebrow

• Bilateral coronal craniosynostosis that typically results in brachycephaly (broad 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

  • Reduced anterior-posterior dimension of skull

• Synostosis of other sutures (lambdoid, metopic, sagittal)

• Macrocephaly without craniosynostosis

• Normal skull (no synostosis, no macrocephaly)

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

• Developmental delay

• Intellectual disability

• Learning disorder

• High-arched palate

• Midface hypoplasia

• Ocular hypertelorism

• Ptosis

• Proptosis (rare, but has been reported)

• Strabismus

• Hearing loss (typically mild and sensorineural)

• Brachydactyly (short fingers and toes)

• Cutaneous syndactyly (rarer finding; reported in 13 individuals with Muenke syndrome)

• Broad toes

• Broad thumbs

• Clinodactyly

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:

• Fusion of the carpal bones (commonly the capitate and hamate or trapezoid and trapezium bones) [Muenke et al 1997, Trusen et al 2003]

• Fusion of the tarsal bones (commonly the calcaneus and cuboid bones) [Muenke et al 1997, Trusen et al 2003]

• Thimble-like (short and broad) middle phalanges of the hands and feet

• Epiphyseal coning

Note: (1) Didolkar et al [2009] reported an individual presenting with polyarthralgia and hearing loss who was determined to have Muenke syndrome 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) and bilateral fusion of the calcaneus and cuboid. These cases demonstrate how extracranial findings may serve as a clinical clue to the presence of the p.Pro250Arg mutation, 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 only detected in individuals with Muenke syndrome.

Molecular Genetic Testing

Gene. FGFR3 is the only gene known to be associated with Muenke syndrome.

Clinical testing

• Targeted mutation analysis. By definition all individuals with Muenke syndrome have an FGFR3 c.749C>G point mutation, resulting in a p.Pro250Arg substitution [Bellus et al 1996].
  Note: Additional testing methods are listed for FGFR3-related craniosynostosis in the Gene Tests Laboratory Directory; however, these are not relevant for Muenke syndrome.

Table 1. Summary of Molecular Genetic Testing Used in Muenke Syndrome

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Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency by Test Method 1	Test Availability
FGFR3	Targeted mutation analysis	p.Pro250Arg 2	>99%	Clinical

Test Availability refers to availability in the GeneTests Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. Muenke syndrome is defined by the FGFR3 c.749C>G (p.Pro250Arg) mutation.

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

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) mutation, 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]:

    • Tier 1. Detects most intragenic mutations 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 mutations 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) mutation 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].

• 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 mutation.

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

• For management because of the significantly increased rate of cranial reoperation, hearing impairment, and developmental delay in Muenke syndrome

• For selective screening of related abnormalities

• For genetic counseling

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

The following are clinically distinct disorders and their causative FGFR3 mutations. Note: Amino acid changes are given as in the original publications.

• Thanatophoric dysplasia type 1. p.Arg248Cys, p.Ser249Cys, p.Gly370Cys, p.Ser371Cys, p.Tyr373Cys, p.Lys650Glu and several types of codon 807 substitutions [Rousseau et al 1994, Bellus et al 1995, Tavormina et al 1995]

• Achondroplasia. Point mutations at codon 380, p.Gly380Arg [Rousseau et al 1994, Shiang et al 1994]

• Hypochondroplasia. Mutations dispersed in FGFR3; p.Asn540Lys accounts for 60%-65% of affected persons [Bellus et al 1995, Prinos et al 1995, Prinster et al 1998].

• Lacrimo-auriculo-dento-digital syndrome (OMIM 149730). p.Asp513Asn [Rohmann et al 2006]

• Camptodactyly, tall stature, and hearing loss (CATSHL) syndrome (OMIM 610474). p.Arg621His [Toydemir et al 2006]

• Crouzon syndrome with acanthosis nigricans/Crouzonodermoskeletal syndrome (see FGFR-Related Craniosynostosis Syndromes). p.Ala391Glu [Meyers et al 1995, Wilkes et al 1996]

Note: An individual with isolated unilateral coronal synostosis and her mildly affected mother were found to be heterozygous for a point mutation in FGFR3 resulting in p.Pro250Leu [Schindler et al 2002]. Although Schindler et al [2002] considered this family to have Muenke syndrome, it is not clear if these individuals (who have a different mutation at the same position as the defining p.Pro250Arg mutation) actually have Muenke syndrome because no additional individuals with a phenotype resembling Muenke syndrome have been reported to have missense mutations at codon 250 encoding a substitution other than proline to arginine.

Natural History

Craniosynostosis. Coronal synostosis may be bilateral or unilateral. Bilateral coronal synostosis results in brachycephaly (broad 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, pansynostosis occurs. In one report, one of ten family members with the p.Pro250Arg mutation had pansynostosis [Golla et al 1997]. This individual, the most severely affected family member, also had ocular proptosis.

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.

Craniosynostosis is not always present in individuals with Muenke syndrome:

• In 72 individuals from 24 families, nine (12.5%) persons known to be heterozygous for the FGFR3 p.Pro250Arg mutation 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].

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 malar hypoplasia, a short upturned nose, a “hook-shaped” nasal tip, deviation of the nasal septum, a short nose with a flat nasal bridge, dental malocclusion, mild retrognathia, hypoplastic auricles, and low-set ears.

Extracranial findings

Hearing loss. Although 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].

The exact cause of the hearing loss is unknown. 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.

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 mutation 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 mutation was found in the individuals with DFNA6.

Developmental delay. 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.

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

Reardon et al [1997] found that four of nine persons evaluated had intellectual impairment: two had mild to moderate mental handicap 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 mutation [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. Additionally, 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.

Strabismus. The most common ocular finding in Muenke syndrome is strabismus.

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].

Minor clinical signs/asymptomatic heterozygotes

Some individuals heterozygous for the FGFR3 p.Pro250Arg mutation 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 mutation 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 mutation 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 mutation were female and 100% of individuals with unicoronal synostosis and an FGFR3 mutation 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, etc). 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 mutation; 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 mutation (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].

Evaluations Following Initial Diagnosis

To establish the extent of disease 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

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), medical 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). For a more thorough discussion, see FGFR-Related Craniosynostosis Syndromes.

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

• Severe initial clinical presentation requiring a staged transcranial repair

• Recurrent deformity requiring a second transcranial repair The need for a surgical revision for aesthetic reasons (typically temporal bulging) is increased 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 mutation 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 mutation.

• 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

In the study of Thomas et al [2005], seven of 29 individuals (24.1%) with the p.Pro250Arg mutation underwent a second surgery (6/7 had increased ICP) as compared to two of 47 (4.3%) without the mutation. This difference in reoperation rate was statistically significant (p=0.048).

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.

In Muenke syndrome a discrepancy between severity of the craniofacial findings (e.g., severe midface hypoplasia, hypertelorism) 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 of craniosynostosis may reduce the risk for secondary complications such as those related to increased ICP.

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]

• Part of protocol-driven care and management includes 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].

Testing of Relatives at Risk

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

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

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 new gene mutation. The proportion of cases caused by de novo mutations is unknown.

• As in achondroplasia, de novo mutations 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 mutation include: physical examination, radiographs of the skull, hands, and feet, and testing for the FGFR3 p.Pro250Arg mutation. Evaluation of the parents may determine that one is heterozygous for the p.Pro250Arg mutation 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 mutation, the risk to the sibs of inheriting this mutation is 50%. Because penetrance is reduced and the phenotype variable within a family, some individuals who inherit the FGFR3 p.Pro250Arg mutation have no (or extremely mild) signs of Muenke syndrome.

• When the parents are clinically unaffected and do not have the FGFR3 p.Pro250Arg mutation, the risks to the sibs are low.

• If the defining mutation cannot be detected in either parent, two possible explanations are: (a) germline mosaicism in a parent or (b) a de novo mutation 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 mutation.

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 mutation, his or her family members are at risk.

Related Genetic Counseling Issues

Children who inherit the FGFR3 p.Pro250Arg mutation 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 mutation

• When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation or clinical evidence of the disorder, it is likely that the proband has a de novo mutation. However, germline mosaicism as well as possible non-medical explanations, including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption should 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, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering DNA banking.

Prenatal Testing

Molecular genetic testing. Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at about 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at about ten to 12 weeks' gestation. The molecular genetic diagnosis must be established in the family before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Ultrasound examination. Craniosynostosis should be suspected when the cephalic index, cranial shape, or fetal face shape is abnormal [Tonni et al 2010]. 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.

In a family known to have the disease-causing mutation, 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.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutation has been identified. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Molecular Genetic Pathogenesis

The c.749C>G transversion 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].

Normal allelic variants. Human FGFR3 is 16.7 kb long and is composed of 17 coding exons [Perez-Castro et al 1997].

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

Figure

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 (more...)

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 mutation results in enhanced FGF binding [Ibrahimi et al 2004]. This mutation 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 mutations demonstrate that the mutation 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 mutations are hypermorphic, causing the mutated gene product to over-perform its normal function.

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Suggested Reading

1. Almeida M, Campos-Xavier A, Medeira A, Cordeiro I, Sousa A, Lima M, Soares G, Rocha M, Saraiva J, Ramos L, Sousa S, Marcelino J, Correia A, Santos H. Clinical and molecular diagnosis of the skeletal dysplasias associated with mutations in the gene encoding fibroblast growth factor receptor 3 (FGFR3) in Portugal. Clin Genet. 2009;75:150–6. [PubMed: 19215249]
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4. Macintosh C, Wall S, Leach C. Strabismus in unicoronal synostosis: ipsilateral or contralateral? J Craniofac Surg. 2007;18:465–9. [PubMed: 17538304]
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6. Muenke M, Kress W, Collmann H, Solomon BD, eds. Monographs in Human Genetics: Craniosynostoses: Molecular Genetics, Principles of Diagnosis and Treatment. Basel, Switzerland: Karger Publishing. Vol 19. 2010.
7. Muenke M, Wilkie AOM. Craniosynostosis syndromes. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B, eds. The Metabolic and Molecular Bases of Inherited Disease (OMMBID). New York: McGraw-Hill. Chap 245. Available at www.ommbid.com. Accessed 12-1-10.
8. Passos-Bueno MR, Sertié AE, Jehee FS, Fanganiello R, Yeh E. Genetics of craniosynostosis: genes, syndromes, mutations and genotype-phenotype correlations. Front Oral Biol. 2008;12:107–43. [PubMed: 18391498]
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12. Wilkie AO. Bad bones, absent smell, selfish testes: the pleiotropic consequences of human FGF receptor mutations. Cytokine Growth Factor Rev. 2005;16:187–203. [PubMed: 15863034]

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

• 7 December 2010 (me) Comprehensive update posted live

• 10 May 2006 (me) Review posted to live Web site

• 30 January 2006 (mm) Original submission