Years published: 2023
NORD gratefully acknowledges Kate Richardson, MS, CGC, UTHealth Houston, Chaya Murali, MD, Assistant Professor, Molecular and Human Genetics, Baylor College of Medicine and Danielle DeMarzo-Burdsall, MD, FACMG, Assistant Professor, Department of Pediatrics, Section of Genetics, University of Oklahoma, Health Sciences Center, for the preparation of this report.
Muenke syndrome is a genetic condition characterized by an early closure of certain bones of the skull (craniosynostosis). The main signs and symptoms of Muenke syndrome include craniosynostosis and other bone defects on x-rays, different head shapes and distinct facial features. Other characteristics include hearing loss, developmental delay, intellectual disability, behavioral issues, epilepsy, eyes drifting inward or outward (strabismus), repetitive, uncontrolled eye movements (nystagmus), vision loss and interrupted breathing during sleep (obstructive sleep apnea). Craniosynostosis is typically diagnosed in newborns.
Muenke syndrome is caused by changes (pathogenic variants) in the FGFR3 gene.
The best outcomes are observed if the affected children receive early surgical procedures as well as early and continued medical management of the other signs and symptoms of the disorder.
Dr. Maximilian Muenke, a medical geneticist, first identified this disorder in 1997 making this diagnosis distinct from other previously defined craniosynostosis syndromes. Muenke syndrome may also be known as FGFR3-related craniosynostosis. Notably, Muenke syndrome is estimated to account for 25%-30% of all genetic causes of craniosynostosis.
The signs and symptoms of Muenke syndrome vary among affected people, and a few people with Muenke syndrome do not have any of the characteristic features of the disorder. For example, some patients may not have craniosynostosis. The symptoms and signs may include:
• Craniosynostosis, especially coronal craniosynostosis (present in about 85% of patients) which is the early horizontal fusion of the skull between the ears
• Hearing loss (70% of patients)
• Recurrent ear infections, which if not treated effectively can lead to hearing loss
• Large head (macrocephaly)
• Developmental delay (60% of patients), most commonly speech delay
• Intellectual disability (40% of patients)
• Behavioral issues which may include hyperactivity, attention deficit and hyperactivity disorder (ADHD) or autism
• Crossed eyes (strabismus)
• Differences in the structure or shape of the hands and toes (50% of patients), but these typically do not cause medical problems or difficulty in daily life
• Seizures, which are rare, but can occur at any time
• Distinctive face, such as down-slanting eyes, eyes that are spaced widely (hypertelorism), forehead that is more rounded (frontal bossing), an opening in the lip or roof of the mouth (cleft lip or palate), flattening of the middle part of face (midface hypoplasia) and a small jaw (retrognathia)
Muenke syndrome is caused by a specific disease causing (pathogenic) change (variant) in the fibroblast growth factor receptor-3 (FGFR3) gene. Genes are the body’s instruction manual for creating proteins that play critical roles in the body. When a pathogenic variant in a gene occurs, it causes the protein to stop working or to not work properly. Depending on the function of the protein, it can affect different parts of the body. More than half (>50%) of the people affected with Muenke syndrome inherit a pathogenic variant from a parent. When not inherited from either parent, the genetic change in FGFR3 is new in the patient (de novo).
The name of the specific genetic change that causes Muenke syndrome is known as p.Pro250Arg. It may also be written as p.P250R. This means that at position 250 in the FGFR3 gene, a building block (amino acid) of the protein was changed to a different amino acid and this causes the gene to stop working properly. The FGFR3 gene provides instructions for making a protein called fibroblast growth factor receptor 3. This protein is needed for the normal development of many parts of the body, including the brain and bone. The specific genetic change that causes Muenke syndrome makes the process of normal development occur too fast and leads to the signs and symptoms of the disease. Different changes in the FGFR3 gene are associated with different syndromes.
Muenke syndrome is an autosomal dominant disorder. This means that a change (pathogenic variant) in only one of the two copies of the FGFR3 gene is necessary to cause the disease. The genetic change can be inherited from either parent or can be the result of a changed gene in the affected individual. The risk of passing the pathogenic variant from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females.
Muenke syndrome is reported to have variable expressivity and reduced penetrance. Variable expressivity means that there is a range of symptoms that can occur in people affected with the same genetic condition. Reduced penetrance is when not all people with a disease-causing genetic change will have symptoms. It is possible for someone to have Muenke syndrome and not have medical problems but have children with Muenke syndrome who have many medical problems.
Muenke syndrome occurs in approximately one in 30,000 livebirths. Muenke syndrome occurs equally in males and females and does not occur more frequently in any specific ethnic group. About one third of individuals with Muenke syndrome are the first to be diagnosed in their families and two-thirds of individuals have a family history of the diagnosis.
Doctors may suspect of Muenke syndrome in people with:
• An abnormal shape of the skull, especially a “tower-shaped” skull, known as turribrachycephaly or cloverleaf skull
• Craniosynostosis with sensorineural hearing loss
• A head computerized tomography (CT) scan demonstrating unilateral or bilateral coronal craniosynostosis or synostosis of other skull sutures
• Fusion of the bones in the wrist (carpal bones) or the bones of the ankles (tarsal bones)
• A short and broad middle finger of the hands and feet
• A cone-shaped end of the long bones of the body (epiphyseal coning)
The diagnosis of Muenke syndrome is established by the identification of the FGFR3 pathogenic variant c.749C>G (p.Pro250Arg) by molecular genetic testing.
Clinical Testing and Work-Up
Management focuses on the treatment of symptoms. This is best achieved in a pediatric craniofacial clinic, which typically includes a craniofacial surgeon and neurosurgeon, clinical geneticist, eye doctor (ophthalmologist), ear, nose and throat doctor (otolaryngologist), pediatrician, radiologist, psychologist, dentist, hearing specialist (audiologist), speech therapist and social worker.
Cranyosisnostosis can be treated with surgery. Depending on severity, the first surgery for 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 the need for additional surgeries (including secondary or tertiary extracranial contouring) may occur.
Standard interventions for hearing loss including hearing aids are usually needed. Affected people may have recurrent episodes of ear infections (otitis media) that can be treated with myringotomy tube placement.
Early speech therapy and intervention programs (including physical, speech and occupational therapy) for those with developmental delay, intellectual impairment and behavioral issues has been shown to be helpful. Parents should work with their local early intervention centers and school systems on individualized educational plans (IEPs) to ensure appropriate accommodations. Social work and parent support systems are particularly important.
Strabismus may require surgical correction. Since surgical correction of craniosynostosis is the priority, the strabismus repair can be delayed in the first two years of life. However, early repair can help the brain to fuse two independent images, one from each eye, into one (binocularity) and it should be considered as soon as feasible. In people with bulging eyes (proptosis), lubrication is needed to avoid damage to the corneas (exposure keratopathy).
In addition to a neurologic exam and EEG to assess for the possibility of seizure, a detailed eye (ophthalmologic) assessment is important.
Surveillance by multiple specialists is required to monitor for the multiple health issues that may arise in children with Muenke syndrome.
Recommendations may include:
• Hearing evaluations annually
• Eye evaluations at least annually or more frequently, if indicated
• Periodic developmental re-evaluations to monitor development in children, including a behavioral/developmental assessment
• Neurologic evaluations for seizures and any new movement disorders
Genetic counseling is advised for families of a child with Muenke Syndrome. The absence of symptoms does not mean that a person is not affected with this condition. More than half of the people diagnosed with Muenke syndrome inherited their FGFR3 pathogenic variant from a parent. This could have implications for the risk to siblings, future pregnancies and other family members. A genetic counselor can help facilitate testing for family members and provide access to additional resources.
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Murali CN, McDonald-McGinn DM, Wenger TL, McDougall C, Stroup BM, Sheppard SE, Taylor J, Bartlett SP, Bhoj EJ, Zackai EH, Santani A. Muenke syndrome: Medical and surgical comorbidities and long-term management. Am J Med Genet A. 2019 Aug;179(8):1442-1450. doi: 10.1002/ajmg.a.61199. Epub 2019 May 20. PMID: 31111620; PMCID: PMC6959001
Kruszka P, Addissie YA, Yarnell CM, Hadley DW, Guillen Sacoto MJ, Platte P, Paelecke Y, Collmann H, Snow N, Schweitzer T, Boyadjiev SA, Aravidis C, Hall SE, Mulliken JB, Roscioli T, Muenke M. Muenke syndrome: An international multicenter natural history study. Am J Med Genet A. 2016;170A:918–29
Wilkie AO, Byren JC, Hurst JA, Jayamohan J, Johnson D, Knight SJ, Lester T, Richards PG, Twigg SR, Wall SA. Prevalence and complications of single gene and chromosomal disorders in craniosynostosis. Pediatrics. 2010;126:e391–400.
Wilkie AO, Byren JC, Hurst JA, Jayamohan J, Johnson D, Knight SJ, Lester T, Richards PG, Twigg SR, Wall SA. Prevalence and complications of single-gene and chromosomal disorders in craniosynostosis. Pediatrics. 2010 Aug;126(2):e391-400. doi: 10.1542/peds.2009-3491. Epub 2010 Jul 19. PMID: 20643727; PMCID: PMC3535761.
Morriss-Kay GM, Wilkie AO. Growth of the normal skull vault and its alteration in craniosynostosis: insights from human genetics and experimental studies. J Anat. 2005 Nov;207(5):637-53. doi: 10.1111/j.1469-7580.2005.00475.x. PMID: 16313397; PMCID: PMC1571561.
Muenke M, Gripp KW, McDonald-McGinn DM, Gaudenz K, Whitaker LA, Bartlett SP, Markowitz RI, Robin NH, Nwokoro N, Mulvihill JJ, Losken HW, Mulliken JB, Guttmacher AE, Wilroy RS, Clarke LA, Hollway G, Adès LC, Haan EA, Mulley JC, Cohen MM Jr, Bellus GA, Francomano CA, Moloney DM, Wall SA, Wilkie AO, et al. A unique point mutation in the fibroblast growth factor receptor 3 gene (FGFR3) defines a new craniosynostosis syndrome. Am J Hum Genet. 1997 Mar;60(3):555-64. PMID: 9042914; PMCID: PMC1712518.
Kruszka P, Rolle M, Kahle KT, et al. Muenke Syndrome. 2006 May 10 [Updated 2023 Mar 30]. In: Adam MP, Mirzaa GM, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1415/ Accessed Sept 18, 2023.
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