Clinical Study of Muenke Syndrome (FGFR3-Related Craniosynostosis)

Conditions:Other Indications, Neurology
Therapuetic Areas:Neurology, Other
Age Range:Any - 100
Start Date:March 31, 2005
Contact:Paul S Kruszka, M.D.
Phone:(301) 402-9654

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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

- 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 2,100
to 3,000 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), c.749C>G, resulting in p.Pro250Arg. Individuals carrying
the defining 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,
radiologic, and genetic/genomic 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 10-20
probands, as well as their family members each year, with an enrollment ceiling of 200
probands. 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. Individuals with Muenke syndrome who are unable or unwilling to come to the
NIH, can submit their medical records, including a copy of the molecular testing, for review.
The second arm is genetic/genomic studies with the goal of investigating modifying factors
that relate to disease severity and expression. The third arm consists of a cognitive
function, development and hearing questionnaire to be completed by patients online, via phone
or mail.


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.

- Since the penetrance of Muenke syndrome is incomplete, any at risk individual will be
given the option of enrolling in the research study for FGFR3 testing. Those
individuals who are found to carry the p.Pro250Arg mutation may benefit from
interventions like hearing screening or speech evaluations that would alter their
medical management. Variable expressivity is another characteristic of Muenke syndrome
and carrier status and adequate genetic counseling are important. Individuals with the
mutation will be invited to participate in the clinical and/or medical record review
arms of the study

- Unaffected family members of a proband enrolled in the clinical protocol may choose to
provide a blood sample and/or participate in the behavioral arm of the study. These
information 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. While we do not incomplete penetrance, children who
are not eligible for enrollment due to lack of physical findings consistent with Muenke
Syndrome will be referred for hearing testing, and further testing if indicated.


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

- 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.

Description and justification of inclusion/exclusion of participants. (age, gender,
ethnicity, prisoners, pregnant women, fetuses, decisionally-impaired, healthy volunteers,
lab personnel)

It is our intention to remove as many economic, cultural, geographic, racial, and gender
barriers as we reasonably can to promote participation of individuals with Muenke syndrome
and their families for research purposes. The study will include pediatric and
decisionally-impaired individuals, because these characteristics are possible with Muenke
syndrome. Pregnant or nursing women may be limited in their participation in some aspects
of the study (e.g. ionizing radiation exposure).

As described above, Muenke syndrome has been demonstrated to occur in persons of different
ethnic backgrounds. We would make every reasonable effort to encourage the enrollment and
participation of a wide spectrum of individuals.

-Pregnant women will not be excluded.
We found this trial at
9000 Rockville Pike
Bethesda, Maryland 20892
Phone: 800-411-1222
Bethesda, MD
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111 Michigan Ave NW
Washington, District of Columbia
(202) 476-5000
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