Clinical features that commonly occur in conjunction with the molecular diagnosis of Muenke syndrome are often brought to the attention of clinicians when a proband with a more severe phenotype is born in a family. Therefore, it is important to note that the statistics described in the literature may be susceptible to ascertainment bias for the rate of occurrence of the aforementioned clinical features. In other words, more severe phenotypes may be less prevalent than indicated in the literature.
Lastly, Saethre–Chotzen syndrome is characterized by a high penetrance of pathogenic mutations in the TWIST gene (Gallagher et al., 2012). As with the aforementioned syndromes, Saethre–Chotzen syndrome is characterized by the classic finding of bicoronalsynostosis and also includes unicoronalsynsotosis and mid-face hypoplasia (Gallagher et al., 2012). Features that may help distinguish Saethre–Chotzen syndrome from Muenke syndrome include the presence of a small ear pinna with prominent crus and syndactyly of fingers 2 and 3.
Overall, phenotypes of the above syndromes tend to overlap, sometimes making it difficult to clinically distinguish Muenke syndrome from other common craniosynostosis syndromes. In addition, it may be difficult to clinically distinguish Muenke syndrome from nonsyndromic craniosynostosis. For example, in one study, 52% of a group of patients who were originally described as having nonspecific brachycephaly were found to have Muenke syndrome (Mulliken et al., 1999). In other cases, the p.Pro250Arg pathogenic variant was found in patients who had craniosynostosis with nonspecific phenotypes (Moloney et al., 1997; Reardon et al., 1997; Gripp et al., 1998; Renier et al., 2000; Mulliken et al., 2004). The difficulty of accurate clinical diagnosis highlights the importance of including genetic testing in addition to clinical assessments.
As in many Mendelian disorders, incomplete penetrance and variable expressivity provide evidence for multiple interacting genetic and environmental factors. These factors likely affect the degree of severity and the presence or the absence of specific findings (Ming and Muenke, 2002). For example, monozygotic twins, both with Muenke syndrome but with significant phenotypic variability, have been reported, and animal models show variable phenotypes depending on the breed’s genetic background (Escobar et al., 2009; Twigg et al., 2009).
FGFR3 regulates bone growth negatively, and a number of chondrodysplasias (including hypochondroplasia, achondroplasia, and thanatophoric dysplasia) with varying severity result from constitutively activating mutations in FGFR3 (Webster and Donoghue, 1997; L’Hôte and Knowles, 2005; Schibler et al., 2009). Although the mechanism has not been defined precisely, the current model as related to these conditions involves at least partial ligand-independent FGFR3 activation, leading to reduced chondrocyte proliferation and differentiation, and the resultant decreased bone growth, due to the inhibitory effect of increased FGFR3 signaling in chondrocytes (Schibler et al., 2009; Twigg et al., 2009). In Muenke syndrome, however, long bones are not affected, suggesting a different, but still poorly understood, pathogenetic mechanism. Animal models do not recapitulate the human spectrum well, but suggest a different mechanism from that underlying allelic chondrodysplasias (Twigg et al., 2009).
The defining proline-to-arginine mutation in amino acid 250 of FGFR3, located in a linker region between the second and the third extracellular immunoglobulin-like FGF-binding domains (Fig. 4), results in enhanced ligand binding through the presence of additional hydrogen bonds (Ibrahimi et al., 2004). A similar process underlies the pathogenesis of the analogous mutations in FGFR1 and FGFR2 (Ibrahimi et al., 2004). Unlike allelic chondrodysplasias, this enhanced ligand binding appears to remain ligand-dependent (Twigg et al., 2009). Further, the effect of very specific FGF ligand-binding activity to mutant FGFR3 may explain differences in limb phenotypes in Muenke syndrome as opposed to other FGFR-related craniosynostoses (Ibrahimi et al., 2004).
The knowledge of FGFR3’s role in sutural development is less robust than that of other craniosynostosis-related genes. Clinically, Muenke syndrome has some similarities to Saethre–Chotzen syndrome (which is due to mutations in TWIST1) and to nonsyndromic craniosynostosis; scalp fibroblasts in patients with the three disorders have been reported to have shared expression profiles (Funato et al., 2001; Bochukova et al., 2010).
Optimal management of affected patients and families involves a multidisciplinary approach through a team experienced with the disorder (Flapper et al., 2009;De Jong et al., 2010). Patients with Muenke syndrome may require treatment for a number of medical issues, but three areas are especially important: neurological development, management of hearing loss, and surgical treatment of craniosynostosis. Many large pediatric centers have a dedicated craniofacial team to allow the streamlining of care, which can be beneficial for both patients and caregivers. In addition to a dedicated primary care doctor or medical home, required specialists may include experts in audiology, clinical genetics, dentists, development, neurology and neuroradiology, ophthalmology, and surgery (neurosurgery, craniofacial surgery, and plastic surgery).
Diagnosed patients should be tested for hearing loss, and monitoring should continue even if the initial evaluation (including on neonatal screening) is normal. Similarly, patients should have initial and subsequent regular developmental evaluations in childhood (Doherty et al., 2010). Surgical management algorithms for patients with Muenke syndrome and other syndromic craniosynostoses have been proposed. These algorithms include initial surgery in the first year of life and at least annual multidisciplinary evaluations (Honnebier et al., 2008; Flapper et al., 2009). Fronto-orbital advancement and reshaping is typically the initial surgery. Patients may require a secondary additional revision, and most patients require secondary (and sometimes tertiary) extracranial contouring procedures (Honnebier et al., 2008).
Given the range of possibilities of phenotypic manifestations, and complexities regarding the inheritance of mutations, genetic counseling for the affected patients and families can be intricate, and is therefore best handled by clinicians familiar with the nuances of Muenke syndrome and other craniosynostosis syndromes. As some patients may have a degree of neurocognitive impairment, and because hearing loss is common, counseling must also take into account challenges involving communication with patients and families. In our experience, we have found a number of parents and siblings of probands with Muenke syndrome who were initially not tested for the p.Pro250Arg mutation in FGFR3 and were later found to be unaffected carriers. Despite examination by highly experienced clinicians with considerable familiarity with craniosynostosis in general and Muenke syndrome in particular, mutation carriers may lack even subtle characteristics of disease (Muenke et al., 1997; Robin et al., 1998). Given the recurrence risk in carriers of the p.Pro250Arg mutation and the expanding phenotypes such as hearing loss, it is imperative to test parents and give appropriate genetic counseling.
This work was supported by the Division of Intramural Research, National Human Genome Research Institute, National Institutes of Health, Department of Health and Human Services, USA.
There are no conflicts of interest.
Agochukwu NB, Solomon BD, Gropman AL, Muenke M. (2012). Epilepsy in Muenke syndrome
: FGFR3-related craniosynostosis
. Pediatr Neurol 47:355–361.
Agochukwu NB, Solomon BD, Benson LJ, Muenke M. (2013). Talocalcaneal coalition in Muenke syndrome
: report of a patient, review of the literature in FGFR-related craniosynostoses, and consideration of mechanism. Am J Med Genet A 161A:453–460.
Bellus GA, Hefferon TW, Ortiz de Luna RI, Hecht JT, Horton WA, Machado M. (1995). Achondroplasia is defined by recurrentG380R mutations of FGFR3. Am J Hum Genet 56:368–373.
Bellus GA, Gaudenz K, Zackai EH, Clarke LA, Szabo J, Francomano CA. (1996). Identical mutations in three different fibroblast growth factor receptor genes in autosomal dominant craniosynostosis
syndromes. Nat Genet 14:174–176.
Bochukova EG, Soneji S, Wall SA, Wilkie AO. (2010). Scalp fibroblasts have a shared expression profile in monogenic craniosynostosis
. J Med Genet 47:803–808.
Boulet SL, Rasmussen SA, Honein MA. (2008). A population-based study of craniosynostosis
in metropolitan Atlanta, 1989–2003. Am J Med Genet 146A:984–991.
Chun K, Teebi AS, Jung JH, Kennedy S, Laframboise R, Meschino WS, et al.. (2002). Genetic analysis of patients with the Saethre-Chotzen phenotype. Am J Med Genet 110:136–143.
Cohen MM Jr. (1993). Pfeiffer syndrome update, clinical subtypes, and guidelines for differential diagnosis. Am J Med Genet 45:300–307.
De Jong T, Bannink N, Bredero-Boelhouwer HH, van Veelen ML, Bartels MC, Hoeve LJ, et al.. (2010). Long-term functional outcome in 167 patients with syndromic craniosynostosis
; defining a syndrome-specific risk profile. J Plast Reconstr Aesthet Surg 63:1635–1641.
De Jong T, Maliepaard M, Bannink N, Raat H, Mathijssen IM. (2012). Health-related problems and quality of life in patients with syndromic and complex craniosynostosis
. Childs Nerv Syst 28:879–882.
Doherty ES, Lacbawan F, Hadley DW, Brewer C, Zalewski C, Kim HJ. (2007). Muenke syndrome
): expansion of the phenotype and review of the literature. Am J Med Genet A 143A:3204–3215.
Escobar LF, Hiett AK, Marnocha A. (2009). Significant phenotypic variability of Muenke syndrome
in identical twins. Am J Med Genet A 149A:1273–1276.
Flapper WJ, Anderson PJ, Roberts RM, David DJ. (2009). Intellectual outcomes following protocol management in Crouzon, Pfeiffer, and Muenke syndromes. J Craniofac Surg 20:1252–1255.
Funato N, Ohtani K, Ohyama K, Kuroda T, Nakamura M. (2001). Common regulation of growth arrest and differentiation of osteoblasts by helix-loop-helix factors. Mol Cell Biol 21:7416–7428.
Gallagher ER, Ratisoontorn C, Cunningham MLPagon RA, Adam MP, Ardinger HH, Bird TD, Dolan CR, Fong CT, Smith RJH, Stephens K. (2012). Saethre-Chotzen syndrome. GeneReviews® Seattle, WA: University of Washington.
Graham JM Jr, Braddock SR, Mortier GR, Lachman R, Van Dop C, Jabs EW. (1998). Syndrome of coronal craniosynostosis
with brachydactyly and carpal/tarsal coalition due to Pro250Arg mutation in FGFR3 gene. Am J Med Genet 77:322–329.
Gripp KW, McDonald-McGinn DM, Gaudenz K, Whitaker LA, Bartlett SP, Glat PM, et al.. (1998). Identification of a genetic cause for isolated unilateral coronal synostosis: a unique mutation in the fibroblast growth factor receptor 3. J Pediatr 132:714–716.
Honnebier MB, Cabiling DS, Hetlinger M, McDonald-McGinn DM, Zackai EH, Bartlett SP. (2008). The natural history of patients treated for FGFR3
. Plast Reconstr Surg 121:919–931.
Hughes J, Nevin NC, Morrison PJ. (2001). Familial craniosynostosis
due to Pro250Arg mutation in the fibroblast growth factor receptor 3 gene. Ulster Med J 70:47–50.
Ibrahimi OA, Zhang F, Eliseenkova AV, Linhardt RJ, Mohammadi M. (2004). Proline toarginine mutations in FGF receptors 1 and 3 result in Pfeiffer and Muenke craniosynostosis
syndromes through enhancement of FGF binding affinity. Hum Mol Genet 13:69–78.
Jadico SK, Huebner A, McDonald-McGinn DM, Zackai EH, Young TL. (2006). Ocular phenotype correlations in patients with TWIST versus FGFR3 genetic mutations. J AAPOS 10:435–444.
Kolar JC, Munro IR, Farkas LG. (1988). Patterns of dysmorphology in Crouzon syndrome: an anthropometric study. Cleft Palate J 25:235–244.
Kress W, Schropp C, Lieb G, Petersen B, Büsse-Ratzka M, Kunz J. (2006). Saethre-Chotzen syndrome caused by TWIST 1 gene mutations: functional differentiation from Muenke coronal synostosis syndrome. Eur J Hum Genet 14:39–48.
Lajeunie E, El Ghouzzi V, Le Merrer M, Munnich A, Bonaventure J, Renier D. (1999). Sex related expressivity of the phenotype in coronal craniosynostosis
caused by the recurrent P250R FGFR3 mutation. J Med Genet 36:9–13.
Lekovic GP, Bristol RE, Rekate HL. (2004). Cognitive impact of craniosynostosis
. Semin Pediatr Neurol l11:305–310.
L’Hôte CG, Knowles MA. (2005). Cell responses to FGFR3 signalling: growth, differentiation and apoptosis. Exp Cell Res 304:417–431.
Lowry RB, Jabs EW, Graham GE, Gerritsen J, Fleming J. (2001). Syndrome of coronalcraniosynostosis, Klippel-Feil anomaly, and sprengel shoulder with and without Pro250Arg mutation in the FGFR3 gene. Am J Med Genet 104:112–119.
Mansour SL, Twigg SR, Freeland RM, Wall SA, Li C, Wilkie AO. (2009). Hearing loss in a mouse model of Muenke syndrome
. Hum Mol Genet 18:43–50.
Mathijssen I, Arnaud E, Lajeunie E, Marchac D, Renier D. (2006). Postoperative cognitive outcome for synostotic frontal plagiocephaly. J Neurosurg 105:16–20.
Ming JE, Muenke M. (2002). Multiple hits during early embryonic development: digenic diseases and holoprosencephaly. Am J Hum Genet 71:1017–1032.
Moloney DM, Wall SA, Ashworth GJ, Oldridge M, Glass IA, Francomano CA. (1997). Prevalence of Pro250Arg mutation of fibroblast growth factor receptor 3 in coronal craniosynostosis
. Lancet 349:1059–1062.
Muenke M, Schell U, Hehr A, Robin NH, Losken HW, Schinzel A, et al.. (1994). A common mutation in the fibroblast growth factor receptor 1 gene in Pfeiffer syndrome. Nat Genet 8:269–274.
Muenke M, Gripp KW, McDonald-McGinn DM, Gaudenz K, Whitaker LA, Bartlett SP, et al.. (1997). A unique point mutation in the fibroblast growth factor receptor 3 gene (FGFR3) defines a new craniosynostosis
syndrome. Am J Hum Genet 60:555–564.
Mulliken JB, Steinberger D, Kunze S, Müller U. (1999). Molecular diagnosis of bilateral coronal synostosis. Plast Reconstr Surg 104:1603–15.
Mulliken JB, Gripp KW, Stolle CA, Steinberger D, Müller U. (2004). Molecular analysis of patients with synostotic frontal plagiocephaly (unilateral coronalsynostosis). Plast Reconstr Surg 113:1899–1909.
Nah HD, Koyama E, Agochukwu NB, Bartlett SP, Muenke M. (2012). Phenotype profile of a genetic mouse model for Muenke syndrome
. Childs Nerv Syst 28:1483–1493.
Rannan-Eliya SV, Taylor IB, De Heer IM, Van Den Ouweland AM, Wall SA. (2004). Paternal origin of FGFR3
mutations in Muenke-type craniosynostosis
. Hum Genet 115:200–207.
Reardon W, Wilkes D, Rutland P, Pulleyn LJ, Malcolm S, Dean JC. (1997). Craniosynostosis
associated with FGFR3 pro250arg mutation results in a range of clinical presentations including unisutural sporadic craniosynostosis
. J Med Genet 34:632–636.
Renier D, El-Ghouzzi V, Bonaventure J, Le Merrer M, Lajeunie E. (2000). Fibroblast growth factor receptor 3 mutation in nonsyndromic coronal synostosis: clinical spectrum, prevalence, and surgical outcome. J Neurosurg 92:631–636.
Robin NH, Scott JA, Cohen AR, Goldstein JA. (1998). Nonpenetrance in FGFR3
-associated coronal synostosis syndrome. Am J Med Genet 80:296–297.
Robin NH, Falk MJ, Haldeman-Englert CRPagon RA, Adam MP, Ardinger HH, Bird TD, Dolan CR, Fong CT, Smith RJH, Stephens K. (2011). FGFR-related craniosynostosis
syndromes. GeneReviews Seattle, WA: University of Washington.
Sahlin P, Tarnow P, Martinsson T, Stenman G. (2009). Germline mutation in the FGFR3 gene in a TWIST1-negative family with Saethre-Chotzen syndrome and breast cancer. Genes Chromosomes Cancer 48:285–288.
Schibler L, Gibbs L, Benoist-Lasselin C, Decraene C, Martinovic J, Loget P. (2009). New insight on FGFR3
-related chondrodysplasias molecular physiopathology revealed by humanchondrocyte gene expression profiling. PLoS One 4:e7633.
Twigg SR, Healy C, Babbs C, Sharpe JA, Wood WG, Sharpe PT, et al.. (2009). Skeletal analysis of the Fgfr3(P244R) mouse, a genetic model for the Muenke craniosynostosis
syndrome. Dev Dyn 238:331–342.
Van der Meulen J, van den Ouweland A, Hoogeboom J. (2006). Trigonocephaly in Muenke syndrome
. Am J Med Genet A 140:2493–2494.
Webster MK, Donoghue DJ. (1997). FGFR activation in skeletal disorders: too much of a good thing. Trends Genet 13:178–182.
Wilkie AO. (2000). Epidemiology and genetics of craniosynostosis
. Am J Med Genet 90:82–84.
Wilkie AO, Slaney SF, Oldridge M, Poole MD, Ashworth GJ, Hockley AD, et al.. (1995). Apert syndrome results from localized mutations of FGFR2
and is allelic with Crouzon syndrome. Nat Genet 9:165–172.
Wilkie AO, Byren JC, Hurst JA, et al.. (2010). Prevalence and complications of single gene and chromosomal disorders in craniosynostosis
. Pediatrics 126:e391–e400.