This study will explore the range and type of medical and developmental problems in patients with Muenke syndrome, a condition that results when one or more of the suture between the bones of the skull close before birth. Because of the premature closure, the skull is not able to grow in its natural shape; instead, it compensates with growth in areas of the skull where the sutures have not yet closed. This can result in an abnormally shaped head, wide-set eyes, and flattened cheekbones. Patients may also have an enlarged head, abnormalities of the hands or feet, and hearing loss.

The fibroblast growth factor receptor 3 (FGFR3) gene, which is involved in the development and maintenance of bone tissue, plays a role in Muenke syndrome. In some cases, the FGFR3 mutation is inherited from a parent with Muenke syndrome; in other cases, where there is no family history of the disorder, the mutation occurs anew. A better understanding of this gene may lead researchers to develop better treatments and genetic counseling for people affected by Muenke syndrome.

Patients with Muenke syndrome and their blood relatives may be eligible for this study. Family members with confirmed Muenke syndrome will have genetic counseling, and patients undergo the following tests and procedures:

• Review of medical records and test results.
• Questionnaires about the patient's prenatal, birth, newborn, and past medical history; family history; growth and development; medications; and current therapies.
• Physical, neurological, ear, nose and throat, dental, and eye examinations.
• Neuropsychological testing to assess cognitive thinking abilities.
• Hearing evaluation. This includes an audiology test in which the patients listens to soft tones through earphones; a power reflectance test in which a chirping sound is heard through an earpiece placed at the entrance to the ear canal, and possibly an ABR/ASSR test, in which electrodes are attached to the forehead, earlobes, and behind the ears to measure brain waves in response to certain conditions.
• MRI scan of the brain. MRI uses a strong magnetic field and radio waves to produce detailed pictures of the brain. During the scan, the patient lies on a table in a narrow cylinder (the scanner), wearing ear plugs to muffle loud noises that occur with electrical switching of the magnetic fields.
• MRI scan of the middle and inner ear. This test is similar to the MRI, but uses a dye injected in a vein to enhance the images.
• CT scan of the skull. CT uses x-rays to produce 3-dimensional images of the part of the body studied.
• Dental evaluation with x-rays.
• Skeletal survey (x-rays of all bones of the body).
• Developmental assessment of IQ testing.
• Blood tests for research purposes. A cell line may be established for use in future research.
• Medical photographs to demonstrate clinical features, including side and front views of the face, head, and other parts of the body that may be involved in Muenke syndrome, like the hands and feet.
• Other consultations or tests as clinically indicated

Craniosynostosis is a common craniofacial abnormality caused by premature fusion of one or several sutures of the skull. The prevalence of craniosynostosis is approximately 1 in 2100 to 3000 births. Originally described by our group, Muenke syndrome (OMIM #602849) is a specific form of craniosynostosis caused by a single nucleotide transversion in fibroblast growth factor receptor 3 (FGFR3), 749 C> G. This mutation encodes the amino acid substitution Pro250Arg. Individuals carrying the Pro250Arg mutation variably manifest coronal suture craniosynostosis, developmental delay, deafness, and carpal and tarsal bone fusion. The purpose of the present study is to increase our understanding of the clinical manifestations of Muenke Syndrome through detailed physical, developmental, neurologic, dental, ophthalmologic, otolaryngologic, audiologic, and radiologic studies. We also plan to examine the spectrum of clinical characteristics of Muenke syndrome to facilitate early diagnosis and clinical management, including genetic counseling. To accomplish this, we plan to enroll approximately 75-100 probands and family members each year, with an enrollment ceiling of 200. Our study has three arms. The clinical arm is the major focus of our study. Patients and their families will be seen at the NIH Clinical Center and Children's National Medical Center. The second arm is DNA banking of clinically unaffected family members. The third arm is a review of medical records for those individuals with Muenke syndrome who are unable or unwilling to participate in the clinical arm.

• INCLUSION CRITERIA:

Subjects who have had confirmation of a Pro250Arg mutation in FGFR3 by a CLIA-certified laboratory. Our research team must receive a photocopy of the positive test result in order to enroll a patient in the study. All races and genders are known to be at risk for Muenke syndrome. Nationality or place of origin is not a specific barrier to participation.

Family members (typically parents or siblings) of probands with Muenke syndrome are also eligible to participate.

• Pediatric and adult individuals with physical examination findings consistent with Muenke syndrome, and adult individuals who are presumed to be unaffected based on examination findings will be given the option of enrolling in the research study for FGFR3 testing. Those individuals who are found to carry the Pro250Arg mutation may be invited to participate in the clinical and/or medical record review arms of the study.
• Clinically unaffected parents or adult siblings of a proband enrolled in the clinical protocol may choose to provide a blood sample. This sample will be used only for purposes of further research on Muenke syndrome.

Patient of interest cases. Geneticists and genetic counselors may refer individuals who are suspected to have Muenke syndrome, but who have not yet been tested for the FGFR3 Pro250Arg mutation. The purpose of enrolling these subjects is to evaluate a wider spectrum of patients for the mutation causing Muenke syndrome. Testing for the Pro250Arg mutation maybe performed at the discretion of our research group. Those individuals who are found to carry the Pro250 Arg mutation may be invited to participate in the clinical study arm and/or medical record review arm of the study.

EXCLUSION CRITERIA:

Anyone unwilling to provide informed consent (for themselves as adults, or on behalf of their children as minors) or assent.

Medical condition(s) or mental retardation are not per se reason for exclusion. We anticipate that children with mental handicaps would be included in the research population. We will make every effort to explain the study for purpose of assent in a manner that the family feels is both age and developmentally appropriate for that child. The participation of cognitively impaired adults is discussed in Section 14.4, Protection of Vulnerable Populations.

• In the process of recruiting individuals, we will use any of the following methods to evaluate a candidate for enrollment in the study:
• Review a brief clinical description from the referring physician,
• Interview a candidate by telephone, and/or
• Review a candidate's medical records.

We reserve the right to exclude individuals for whom the medical risks of travel and evaluation at NIH appear to outweigh the benefits of study participation.

We will not sponsor or encourage FGFR3 mutation testing of asymptomatic children. Family members below the age of 18 years who do not demonstrate physical examination findings consistent with Muenke syndrome will not be eligible for the study.