Clinical Study of Muenke Syndrome (FGFR3-Related Craniosynostosis)

NCT00106977 | Completed

• 2 other identifiers: 05013105-HG-0131
• Study Type: observational
• Target: 137
• Locations: 1 country
• Sites: 2

Brief Summary

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

Conditions

Craniosynostosis; Muenke Syndrome

Keywords

Coronal Craniosynostosis; Hearing Loss; Pro250 Arg Mutation; Tarsal Coalition; Carpal Coalition; Muenke Syndrome; Craniosynostosis

Outcome Measures

Primary Outcomes (1)

• Understanding

  The objective of this study is primarily to increase our understanding of the genetics and clinical characteristics of Muenke syndrome.

  Ongoing

Study Arms (2)

Family

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

Patient

Subjects who have had confirmation of a p. Pro250Arg mutation in FGFR3 by a CLIA-certified laboratory.

Eligibility Criteria

• Age: 1 Month+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

Subjects who have had confirmation of a p.Pro250Arg mutation in FGFR3 by a CLIA-certified laboratory. Family members (typically parents or siblings) of probands with Muenke syndrome are also eligible to participate.@@@@@@

You may qualify if:

• 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 study. Individuals who do not carry the mutation but that have an affected first degree family member will be invited to participate in the
• genomic and/or survey arm of the study.

You may not qualify if:

• 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.
• 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.
• 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.

Sponsors & Collaborators

• National Human Genome Research Institute (NHGRI): lead

Study Sites (2)

Childrens National Medical Center

Washington D.C., District of Columbia, United States

Location

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (3)

• Bellus GA, Gaudenz K, Zackai EH, Clarke LA, Szabo J, Francomano CA, Muenke M. Identical mutations in three different fibroblast growth factor receptor genes in autosomal dominant craniosynostosis syndromes. Nat Genet. 1996 Oct;14(2):174-6. doi: 10.1038/ng1096-174.

  PMID: 8841188 BACKGROUND

• 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, Ades 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 BACKGROUND

• Moloney DM, Wall SA, Ashworth GJ, Oldridge M, Glass IA, Francomano CA, Muenke M, Wilkie AO. Prevalence of Pro250Arg mutation of fibroblast growth factor receptor 3 in coronal craniosynostosis. Lancet. 1997 Apr 12;349(9058):1059-62. doi: 10.1016/s0140-6736(96)09082-4.

  PMID: 9107244 BACKGROUND

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Craniosynostoses; Muenke Syndrome; Hearing Loss; Tarsal Coalition

Condition Hierarchy (Ancestors)

Synostosis; Dysostoses; Bone Diseases, Developmental; Bone Diseases; Musculoskeletal Diseases; Craniofacial Abnormalities; Musculoskeletal Abnormalities; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Hearing Disorders; Ear Diseases; Otorhinolaryngologic Diseases; Sensation Disorders; Neurologic Manifestations; Nervous System Diseases; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Foot Deformities, Congenital; Foot Deformities; Lower Extremity Deformities, Congenital; Limb Deformities, Congenital

Study Officials

• Paul S Kruszka, M.D.

  National Human Genome Research Institute (NHGRI)

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 1, 2005
• First Posted: April 4, 2005
• Study Start: March 31, 2005
• Primary Completion: March 23, 2020
• Study Completion: March 23, 2020
• Last Updated: March 26, 2020

Record last verified: 2020-03

Locations

US (2)