CraniosynostosisNCT00106977
Clinical Study of Muenke Syndrome (FGFR3-Related Craniosynostosis)
An observational study of Craniosynostosis and Muenke Syndrome, run by National Human Genome Research Institute (NHGRI) at 2 sites in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 1 month and older
- Conditions the study is for
- Craniosynostosis, Muenke Syndrome
- How many people
- 137 participants
- Where
- 2 sitesUnited States
- Study dates
- 31 Mar 2005to 23 Mar 2020
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 1 month and older
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
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.@@@@@@
Who may be able to join
- 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.
Who cannot join
- 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.
- 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.
Trial locations and contacts
2 sites in 1 country.
United States2 sites
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, 20892
Childrens National Medical Center
Washington D.C., District of Columbia
About this study
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.
Read more
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
Read the detailed description
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.
- Conditions
- Craniosynostosis, Muenke Syndrome
- Keywords
- Coronal Craniosynostosis, Hearing Loss, Pro250 Arg Mutation, Tarsal Coalition, Carpal Coalition, Muenke Syndrome, Craniosynostosis
- Medical subject headings
- Craniosynostoses, Muenke Syndrome, Hearing Loss, Tarsal Coalition
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
| Study group | Role | What they receive |
|---|---|---|
| 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. |
What is being measured
The primary outcome is the main question the study is designed to answer.
Understanding
The objective of this study is primarily to increase our understanding of the genetics and clinical characteristics of Muenke syndrome.
Measured: Ongoing
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted4 Apr 2005 (estimated)
- Study start31 Mar 2005
- Primary completion23 Mar 2020
- Study completion23 Mar 2020
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for CraniosynostosisStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Cohort
- Time perspective
- Prospective
- Enrolment
- 137 participants (actual)
Sponsor and investigators
- Lead sponsor
- National Human Genome Research Institute (NHGRI)
- Sponsor type
- US National Institutes of Health
- Responsible party
- Sponsor
- Investigators
- Paul S Kruszka, M.D., Principal investigator, National Human Genome Research Institute (NHGRI)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00106977
- Sponsor's protocol ID
- 050131
- Other IDs
- 05-HG-0131
- Status last verified
- Mar 2020
- First submitted
- 1 Apr 2005
- Last updated
- 26 Mar 2020
- Results posted
- No
Publications
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.
PubMed 8841188Muenke 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.
PubMed 9042914Moloney 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.
PubMed 9107244
Study at a glance
From the registry record, last updated by the sponsor on 26 Mar 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Clinical Study of Muenke Syndrome (FGFR3-Related Craniosynostosis)
- ClinicalTrials.gov ID
- NCT00106977
- Acronym / sponsor ID
- 050131
- Conditions
- Craniosynostosis, Muenke Syndrome
- Keywords
- Coronal Craniosynostosis, Hearing Loss, Pro250 Arg Mutation, Tarsal Coalition, Carpal Coalition, Muenke Syndrome, Craniosynostosis
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 137 participants (actual)
- Lead sponsor
- National Human Genome Research Institute (NHGRI)US National Institutes of Health
- Study start
- 31 Mar 2005 (actual)
- Primary completion
- 23 Mar 2020 (actual)
- Study completion
- 23 Mar 2020 (actual)
- First posted
- 4 Apr 2005 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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
Detailed description
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.
Study design
- Observational model
- Cohort
- Time perspective
- Prospective
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| 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. |
Who may qualify
- Ages
- 1 month and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
- 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.@@@@@@
Key inclusion criteria (6 listed)
- 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
Key exclusion criteria (6 listed)
- 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.
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Primary outcome
Understanding
Time frame: Ongoing
The objective of this study is primarily to increase our understanding of the genetics and clinical characteristics of Muenke syndrome.
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 26 Mar 2020.
- Background: PubMed 8841188Bellus 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.
- Background: PubMed 9042914Muenke 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.
- Background: PubMed 9107244Moloney 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.
- NIH Clinical Center Detailed Web PageLink provided by the sponsor.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Paul S Kruszka, M.D. principal investigator
National Human Genome Research Institute (NHGRI)
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Craniosynostosis and Muenke Syndrome, run by National Human Genome Research Institute (NHGRI) at 2 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 6 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 26 Mar 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Understanding (time frame: Ongoing). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00106977, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 26 Mar 2020.