Muenke syndrome

• Muenke syndrome is a rare genetic disorder characterized by craniosynostosis, or premature closure of certain bones in the skull. This affects the shape of the face and head. Muenke syndrome is typically detected during infancy.
• Other distinctive features of Muenke syndrome include wide-set eyes, flattened cheekbones, and a large, abnormally shaped head. Some people with Muenke syndrome also have hearing loss and deformities of the hands and feet.
• Muenke syndrome is caused by a mutation or defect in the FGFR3 gene. This gene provides instructions for making the fibroblast growth factor receptor 3 protein, which is essential to normal development and maintenance of the brain and bones. In Muenke syndrome, this protein is overactive, causing abnormal bone growth and development.
• Muenke syndrome is inherited, or passed down from parent to child, as an autosomal dominant trait. This means that only one copy of the defective gene must be inherited for the disease to appear. In some cases, Muenke syndrome is present in individuals with no family history of the disorder. In these cases, the disease occurs as a result of a spontaneous genetic mutation in the sperm or eggs cells or in the developing embryo. The worldwide incidence of Muenke syndrome is about one in 30,000 newborn infants. No gender, race, or ethnic group appears to be affected more than another.
• While there is currently no known cure for Muenke syndrome, surgical repair of craniosynostosis can decrease the risk of complications such as hydrocephalus or fluid surrounding the brain. If managed appropriately, patients with Muenke syndrome may have a normal life span.

• Because Muenke syndrome is inherited, the only known risk factor is a family history of the disorder. Muenke syndrome is inherited, or passed down from parent to child, as a dominant trait. Individuals receive two copies of most genes, one from the mother and one from the father. For a dominant disorder to appear, only one copy of the disease-causing
  gene is necessary. If one parent has the disorder, there is a 50% chance that his or her child will have the disorder. If both parents have the disorder, there is a 75% chance that their child will have the disorder.

• Genetic mutations: Muenke syndrome is caused by a mutation or defect in the FGFR3 gene. This gene provides instructions for making the fibroblast growth factor receptor 3 protein, which is essential to normal development and maintenance of the brain and bones. In Muenke syndrome, this protein is overactive, causing abnormal bone growth and development.
• Autosomal dominant inheritance: Muenke syndrome is inherited, or passed down from parent to child, as a dominant trait. Individuals receive two copies of most genes, one from the mother and one from the father. For a dominant disorder to appear, only one defective copy of the FGFR3 gene is necessary. If one parent has the disorder, there is a 50% chance that his or her child will have the disorder. If both parents have the disorder, there is a 75% chance that their child will have the disorder.
• Random occurrence: In some cases, Muenke syndrome is present in individuals with no family history of the disorder. This occurs as the result of a spontaneous genetic mutation in the egg or sperm cells or in the developing embryo.

• General: Symptoms of Muenke syndrome may vary among individuals, even among members of the same family. About 6%-7% of people with the genetic mutation that causes Muenke syndrome do not show the classic symptoms described below.
• Face: Abnormal bone growth may cause people with Muenke syndrome to have distinctive facial features. These may include wide-set eyes and flattened cheekbones. Other facial features may include droopy eyelids, an underdeveloped mid-face, and a high, arched palate.
• Skull: An infant's skull is made of several bones connected by growth areas called sutures. In an adult skull these sutures are nothing more than wiggly lines, but in a child they permit bone growth along their borders and allow the skull to enlarge normally. Most people with Muenke syndrome have premature fusing of these skull bones, which is called craniosynostosis. In particular, this affects the growth line or suture extending over the head from ear to ear. This can cause the skull to be broad or tower-shaped. The two sides of the skull may or may not be symmetrical. Other growth lines of the skull may also be affected. About 5% of people with Muenke syndrome also have an abnormally large head. Females may be more likely to have skull involvement than males.
• Other: Some people with Muenke syndrome may have problems with the hands and feet such as short fingers and toes, fusion of the bones in the wrists and ankles, and short or abnormally shaped bones in the fingers and toes. About one third of people with the condition experience hearing loss of unknown origin. Intellectual disability and developmental delays have been reported in about one third of people with Muenke syndrome. Intellectual disability may be affected by or related to hearing loss. It is not clear whether intellectual ability is related to structural skull abnormalities.

• General: Muenke syndrome is generally detected during infancy. A clinician should complete a thorough physical exam and obtain a complete family history. In particular, a clinician should look for characteristic symptoms that affect the face, skull, hands, and feet.
• Hearing test: A hearing test, or audiogram, may help diagnose the condition. During an audiogram, the patient wears headphones and is exposed to various sounds that have different pitches and frequencies. The patient is asked to indicate each time a sound is heard. The audiologist may also say various words to evaluate the patient's hearing ability.
• Imaging: X-rays or computed tomography (CT) can reveal abnormalities of the skull, including premature fusion of the growth lines or sutures extending over the head from ear to ear (craniosynostosis). Magnetic resonance imaging (MRI) or CT of the brain can also reveal whether fluid has accumulated around the brain. In addition, X-ray can be used to view the bones of the wrists, ankles, fingers, and toes. Some of these changes may not be visible until an individual is older. CT is an X-ray technique that allows clinicians to see internal body structures in cross-sectional images rather than in the overlapping images usually produced by X-rays. MRI uses a magnetic field, radio waves, and a computer to produce pictures of internal structures of the body, which can be printed or observed on a computer screen.
• Genetic testing: If Muenke syndrome is suspected, a genetic test may be performed to confirm a diagnosis. A sample of the patient's blood is taken and analyzed in a laboratory for the defect in the FGFR3 gene. If this defect is detected, a positive diagnosis is made.
• Prenatal DNA testing: If there is a family history of Muenke syndrome, prenatal testing may be performed to determine whether the fetus has the disorder. Amniocentesis and chorionic villus sampling (CVS) can diagnose Muenke syndrome. However, because there are serious risks associated with these tests, patients should discuss the potential health benefits and risks with a medical professional.
• During amniocentesis, a long, thin needle is inserted through the abdominal wall and into the uterus, and a small amount of amniotic fluid is removed from the sac surrounding the fetus. Cells in the fluid are then analyzed for normal and abnormal chromosomes. This test is performed after 15 weeks of pregnancy. The risk of miscarriage is about one in 200-400 patients. Some patients may experience minor complications, such as cramping, leaking fluid, or irritation where the needle was inserted.
• During CVS, a small piece of tissue (chorionic villi) is removed from the placenta between the ninth and 14th weeks of pregnancy. CVS may be performed through the cervix or through the abdomen. The cells in the tissue sample are then analyzed for the mutation in the FGFR3 gene. Miscarriage occurs in about 0.5-1% of women who undergo this procedure.

• Hearing loss: Some individuals with Muenke syndrome develop mild to moderate hearing loss. The exact cause of this hearing loss is not known.
• Hydrocephalus: Hydrocephalus literally translates to "water on the brain." The structural problems with the bones of the skull in Muenke syndrome can cause fluid to collect around the brain. This can increase the pressure on the brain and cause intellectual or developmental disabilities, seizures, and additional skull deformities.
• Speech impairment: Some individuals, particularly those who experience hearing loss, may have delayed or impaired speech development.

• General: There is currently no known cure for Muenke syndrome. Treatment aims to reduce symptoms and prevent complications. Individuals with Muenke syndrome should be referred to a craniofacial clinic, preferably one that specializes in pediatrics. In addition, these individuals should be seen regularly by a geneticist, surgeon, ophthalmologist, audiologist, speech therapist, and social worker.
• Hearing aids: People with Muenke syndrome who experience hearing loss may benefit from hearing aids. These battery-operated devices are available in three basic styles: behind-the-ear, in-the-ear, and in the canal. Patients should talk to their healthcare provider to determine the type of hearing aid that is best for them. A behind-the-ear device is used for mild to profound hearing loss. The device is worn behind the ear and is attached to a plastic ear mold inside the outer ear. In-the-ear hearing aids are worn inside the outer ear, and are used for mild to severe hearing loss. Canal hearing aids are smaller hearing aids that fit inside the patient's ear canal. They are used for mild to moderately severe hearing loss. If hearing loss is severe, patients may benefit from cochlear implants, which are electronic devices surgically implanted inside the ears. Unlike a hearing aid, which amplifies sound, a cochlear implant compensates for damaged parts of the inner ear.
• Surgery: Depending on the severity of skull abnormalities and the age of the individual at diagnosis, surgery may be used to repair the premature fusion of the growth lines or sutures that extend over the head from ear to ear (craniosynostosis). Surgeries may have to be performed repeatedly, and people who undergo surgery are at risk for swelling and increased pressure on the brain.

Note
: Currently there is limited scientific evidence on the use of integrative therapies for the treatment or prevention of Muenke syndrome. The following therapies have been studied for their effect on related conditions such as hearing loss, should be used only under the supervision of a qualified healthcare provider, and should not be used in replacement of other proven therapies.

C

Unclear or conflicting scientific evidence

• Acupuncture
  : Early evidence suggests that deep needling acupuncture may be more effective in treating sudden deafness than shallow needling acupuncture. Better-designed trials are needed to reach a firm conclusion. Needles must be sterile in order to avoid disease transmission. Avoid acupuncture in patients with valvular heart disease, infections, bleeding disorders, medical conditions of unknown origin, neurological disorders, or pregnancy, or in those taking drugs that increase the risk of bleeding (e.g., anticoagulants). Avoid acupuncture on areas that have received radiation therapy. Acupuncture should be used cautiously in patients with pulmonary disease such as asthma or emphysema. Use cautiously in elderly or medically compromised patients, people with diabetes, or those with a history of seizures. Avoid electroacupuncture in patients with arrhythmias (i.e., irregular heartbeats) and in patients with pacemakers.
• Ginkgo
  : Early clinical study has been conducted on the effect of ginkgo in chronic cochleovestibular disorders. Further research is needed before a recommendation can be made. Avoid ginkgo if allergic or hypersensitive to members of the Ginkgoaceae family.
  If a person is allergic to mango rind, sumac, poison ivy or oak, or cashews, then allergy to ginkgo is possible. Avoid ginkgo with blood thinners such as aspirin or warfarin (Coumadin®) because of an increased risk of bleeding. Ginkgo should be stopped two weeks before surgical procedures. Ginkgo seeds are dangerous and should be avoided. Skin irritation and itching may also occur if allergic to ginkgo. Do not use ginkgo in supplemental doses if pregnant or breastfeeding.
• Kudzu
  : Kudzu has been used in limited clinical study to treat sudden nerve deafness. Additional evidence is needed to confirm these results. Use caution with anticoagulants or antiplatelet and blood-pressure lowering agents, hormones, antiarrhythmics, benzodiazepines, bisphosphonates, diabetes medications, drugs that are metabolized by the liver's cytochrome P450 enzymes, mecamylamine, neurologic agents, and methotrexate. Well-designed studies on the long-term effects of kudzu are currently unavailable. Avoid if allergic or hypersensitive to Pueraria lobata or members of the Fabaceae/Leguminosae family. Avoid if pregnant or breastfeeding.
• Noni
  : Noni juice has been used for many years for a wide variety of conditions in Southeast Asia, and noni juice may improve hearing in people with auditory dysfunction. Although results are promising, additional research is warranted in this area. Avoid if allergic or hypersensitive to noni, its constituents, or any plants in the Rubiaceae family. Use cautiously if taking oral agents, warfarin, or other anticoagulants, antivirals, antihypertensives, or immunosuppressants. Use cautiously with injuries or post-surgery, low blood pressure, HIV/AIDS, compromised liver function, gastrointestinal disorders and obstructions, or compromised kidney function. Avoid if pregnant or breastfeeding.

• General: Because Muenke syndrome is an inherited condition, there is currently no known way to prevent the disease. However, a number of options are available for prospective parents with family histories of Muenke syndrome.
• Genetic testing and counseling: Individuals who have Muenke syndrome may meet with a genetic counselor to discuss the risks of having children with the disease. Individuals with family histories of Muenke syndrome may meet with a genetic counselor to determine whether they carry the defective FGFR3 gene. Carriers can be determined through detailed family histories or genetic testing.
• Known carriers of Muenke syndrome may undergo genetic counseling before they conceive a child. Genetic counselors can explain the options and the associated risks of various tests, including pre-implantation genetic diagnosis (PGD), amniocentesis, and chorionic villus sampling (CVS).
• Pre-implantation genetic diagnosis (PGD) may be used with in vitro (artificial) fertilization. In PGD, embryos are tested for the defective gene, and only the embryos that are not affected may be selected for implantation. Because Muenke syndrome can be detected in a fetus, parents may choose whether or not to continue the pregnancy. Genetic counselors may assist parents with these difficult decisions.