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Muenke syndrome

Addissie, Yonit A.; Yarnell, Colin M.P.; Kruszka, Paul; Muenke, Maximilian

Middle East Journal of Medical Genetics: January 2015 - Volume 4 - Issue 1 - p 1–6
doi: 10.1097/01.MXE.0000456629.07295.8e
Review article
Free

Muenke syndrome is an autosomal dominant disorder characterized by coronal suture craniosynostosis, hearing loss, developmental delay, and carpal and tarsal fusions. Reduced penetrance and variable expressivity contribute to the wide spectrum of clinical findings in Muenke syndrome. Muenke syndrome constitutes the most common syndromic form of craniosynostosis, with an incidence of one in 30 000 births and is defined by the presence of the p.Pro250Arg mutation in FGFR3. Clinical diagnosis is difficult because of phenotypic overlap with other craniosynostosis syndromes, and diagnosis is always made by molecular testing. Optimal management of patients involves a coordinated, multidisciplinary team familiar with the condition.

Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA

Correspondence to Maximilian Muenke, MD, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, 35 Convent Drive, Room 1B203, Bethesda, MD 20892, USA Tel: +301 402 8167; fax: +301 480 7876; e-mail: mamuenke@mail.nih.gov

Received October 18, 2014

Accepted November 17, 2014

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Introduction

Craniosynostosis occurs in approximately one in 3000 live births and is characterized by the premature fusion of one or more cranial sutures resulting in the malformation of the skull. Potential consequences of abnormal skull growth include increased intracranial pressure, problems with hearing and vision, impaired blood flow in the cerebrum, and developmental delay (Wilkie, 2000). Craniosynostosis usually occurs as an isolated and sporadic anomaly in an otherwise normal child; however, craniosynostosis is a component feature in over 150 described syndromes (Boulet et al., 2008). Relatively common craniosynostosis syndromes include Apert syndrome, Crouzon syndrome, Pfeiffer syndrome, Saethre–Chotzen syndrome, and Muenke syndrome.

Muenke syndrome constitutes the most common syndromic form of craniosynostosis, with an incidence of one in 30 000 births; of all the patients with craniosynostosis, 8% manifest Muenke syndrome. Further, of those patients with craniosynostosis and an identified genetic cause, 24% have Muenke syndrome (Wilkie et al., 2010). Muenke syndrome is defined by the c.749 C>G mutation encoding a Pro250Arg substitution in the fibroblast growth factor receptor 3 (FGFR3) gene encoding the FGFR3 protein (Bellus et al., 1996; Muenke et al., 1997). The classic presentation of the syndrome includes unilateral or bilateral coronal suture craniosynostosis, broad toes, and carpal and tarsal fusions. However, the phenotype is quite variable and ranges from no detectable clinical manifestations to ‘isolated’ craniosynostosis to more complex findings that overlap other classic craniosynostosis syndromes (e.g. Crouzon, Pfeiffer, or Saethre–Chotzen syndrome).

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Clinical description

Patients with the defining FGFR3 p.Pro250Arg mutation demonstrate a wide range of findings, even within a single family (Muenke et al., 1997; Escobar et al., 2009). Table 1 lists common clinical features found in Muenke syndrome and their prevalence. The majority of the patients have craniosynostosis, with 55% presenting with bilateral coronal craniosynostosis and 26% presenting with unilateral coronal craniosynostosis (Doherty et al., 2007). Premature fusion involving other noncoronal sutures (e.g. lamboid, sagittal, metopic, multiple, and pan-sutures) is less prevalent in Muenke syndrome (5%). Trigonocephaly has been observed in one instance, whereas turricephaly (‘tower-shaped’ skull) and cloverleaf-like deformity have been observed in some more severe cases (Lajeunie et al., 1999; Van der Meulen et al., 2006). Most patients with Muenke syndrome exhibit craniofacial findings, including brachycephaly, plagiocephaly, mild mid-face hypoplasia, hypertelorism, ptosis, or a high palate (Muenke et al., 1997; Van der Meulen et al., 2006; Doherty et al., 2007). Fig. 1 demonstrates some of the facial features seen in Muenke syndrome.

Table 1

Table 1

Figure 1

Figure 1

In addition to craniosynostosis, common phenotypic findings in affected patients may include macrocephaly, low-frequency sensorineural hearing loss, and developmental delay/mental retardation (Table 1). It is important to note that these manifestations may be present in mutation-positive patients who do not have craniosynostosis. Hydrocephalus may also be present (Muenke et al., 1997; Doherty et al., 2007; Mansour et al., 2009).

As noted above, a significant finding in Muenke syndrome is mild to moderate sensorineural hearing loss, which is present in at least one-third of the individuals with the syndrome (Muenke et al., 1997; Kress et al., 2006; De Jong et al., 2010). Some studies suggest that all affected individuals with the pathogenic mutation are at risk of having mild hearing loss (Doherty et al., 2007; Honnebier et al., 2008; Mansour et al., 2009; De Jong et al., 2010).

Developmental delay and/or intellectual disability may be prevalent in as much as one-third of the patients with Muenke syndrome (Muenke et al., 1997; Kress et al., 2006). In a study on syndromic craniosynostosis, De Jong et al. (2012) found that Muenke syndrome has a relatively high prevalence of speech delay and cognitive delay. It is unclear whether cognitive dysfunction in patients is a primary part of the disease or whether there is an additional contribution by deformational forces; some have reported that early neurosurgical intervention is associated with a more positive neurological outcome (Lekovic et al., 2004; Mathijssen et al., 2006). Patients with Muenke syndrome may be more likely to have intellectual impairment than patients with other FGFR-related craniosynostoses (Doherty et al., 2007; Flapper et al., 2009).

Swallowing and feeding difficulties have also been reported (Doherty et al., 2007). Ocular findings indicate that strabismus is the most common eye condition occurring in Muenke syndrome (39–66% of cases), although amblyopia, anisometropia, epicanthal fold changes, and downward lateral canthal dystopia are also possible (Lowry et al., 2001; Jadico et al., 2006).

Skeletal anomalies other than craniosynostosis in Muenke syndrome are clinodactyly and brachydactyly, which occur in about one-third of the patients (Muenke et al., 1997). Other frequent findings include carpal and/or tarsal fusions, absent or hypoplastic middle phalanges, short and broad/thimble-like middle phalanges, cone-shaped epiphyses, and broad great toes (Muenke et al., 1997; Hughes et al., 2001). Figure 2 shows some of these common extremity anomalies. It is important to note that because limb anomalies tend to have mild presentations, they are usually identified using radiographs during diagnostic workups. Tarsal coalition is a term used to describe a fibrous, cartilaginous, or bony connection between two or more tarsal bones and is a distinct feature of Muenke syndrome, as evidenced by its occasional description as ‘coronal craniosynostosis with brachydactyly and carpal/tarsal coalition’ (Graham et al., 1998). Tarsal bone coalition has been reported since the initial description of the disorder in the 1990s, and in our review of the literature, it was found to have an incidence of 25% in Muenke syndrome (Agochukwu et al., 2013). The coalition usually involves calcaneus and cuboid bones, a coalition that is actually quite rare in the general population. Interestingly, although talocalcaneal coalition is the most common tarsal coalition in the general population, it has never been reported previously in a patient with Muenke syndrome (Fig. 3).

Figure 2

Figure 2

Figure 3

Figure 3

The occurrence of epilepsy in Muenke syndrome has been reported in the literature, with Agochukwu et al. (2012) reporting a prevalence of 12%. Therefore, the impact of Muenke syndrome on the central nervous system may be greater than previously thought, and there is now evidence that there may be behavioral changes in those with Muenke syndrome (Kruszka P, Yarnell CMP, Addissie YA, Hadley DW, Muenke M, unpublished data).

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.

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Differential diagnosis

Certain relatively common craniosynostosis syndromes have mild and/or overlapping features with Muenke syndrome. These classic syndromes are all inherited in an autosomal dominant manner and include (but are not limited to) Pfeiffer syndrome, Crouzon syndrome (which are all linked to the FGFR genes), and Saethre–Chotzen syndrome. Some individuals who were clinically described as having one of these conditions have later been found to test positive for the p.Pro250Arg variant (Chun et al., 2002; Sahlin et al., 2009); therefore, molecular testing is instrumental in differentiating between these syndromes.

Pfeiffer syndrome has been linked to mutations in the FGFR1 and the FGFR2 genes (Muenke et al., 1994; Robin et al., 2011). Some reoccurring features include bicoronalsynostosis, broad thumbs, mid-face hypoplasia, and hypertelorism (Cohen, 1993). The distinguishing features include medial and lateral deviation of the thumbs and toes and malformed and fused phalanges.

Crouzon syndrome has been linked to mutations in the FGFR2 gene (Wilkie et al., 1995). This condition has features found in Muenke syndrome, such as bicoronal craniosynostosis and mid-face hypoplasia. Crouzon syndrome is associated with ocular proptosis and has a lower incidence of limb anomalies than in Muenke syndrome (Kolar et al., 1988).

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.

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Inheritance

Muenke syndrome is a classic autosomal dominant disorder with incomplete penetrance and a highly variable expressivity (Muenke et al., 1997). Penetrance is higher in female (87%) than in male patients (76%), and there are additional sex-specific differences in manifestations, such as the suture involved in craniosynostosis (Lajeunie et al., 1999; Doherty et al., 2007). In one comprehensive review of patients, 58% of the female patients had bilateral craniosynostosis, compared with only 37% of the male patients (Doherty et al., 2007).

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).

De-novo mutations in FGFR3 are of paternal origin, and are associated with an increased paternal age (Rannan-Eliya et al., 2004). The majority of the mutations are de novo, although the exact proportion of de-novo mutations is not known in probands with Muenke syndrome (Moloney et al., 1997). The mutation rate at the disease-causing nucleotide, the highest of any tranversion in the human genome, is estimated to occur at up to 8×10−6 per haploid genome (compared with the highest rate in the human genome, the c.1138G>A transition resulting in the common achondroplasia mutation, which occurs at a rate of 5–28×10−6) (Bellus et al., 1995).

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Molecular pathogenesis

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).

Figure 4

Figure 4

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).

Mouse models of Muenke syndrome have revealed some insights, but animal systems do not recapitulate all aspects of the human disease. Twigg et al. (2009) showed that coronal craniosysnostosis is not reliably reproduced in the mouse, although the mouse model may be nonetheless informative with regard to more general bone development. In addition, the mouse model does provide a good system for the study of hearing loss in Muenke syndrome, which could be important in the development of molecular therapies (Lowry et al., 2001).

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Management

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.

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Conclusion

Patients with Muenke syndrome present a complex picture to the both the research scientist and the managing clinician. Although impressive progress has been made in the laboratory, the clinic, and the operating theatre, much work remains. Future questions that demand more complete answers include improved understanding of the molecular pathogenesis, elucidating factors that affect penetrance and expressivity, unraveling gender-specific differences observed in patients, both in terms of inheritance and clinical manifestations, and optimization of management algorithms for affected patients and families, and exploring a behavioral phenotype.

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Acknowledgements

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.

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Conflicts of interest

There are no conflicts of interest.

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    Keywords:

    craniosynostosis; FGFR3-related craniosynostosis; Muenke syndrome

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