CraniosynostosisNCT03025763
Network Of Clinical Research Studies On Craniosynostosis, Skull Malformations With Premature Fusion Of Skull Bones
An observational study of Craniosynostosis, run by Icahn School of Medicine at Mount Sinai at 20 sites in 5 countries.
Trial summary
Craniosynostosis (CS) is a common malformation occurring in ~4 per 10,000 live births in which the sutures between skull bones close too early, causing long-term problems with brain and skull growth. Read more about this study
- Who is it for?
- Ages Up to 80 yearsHealthy volunteers can take part
- Conditions the study is for
- Craniosynostosis
- What is being tested?
- Craniosynostosis Network Environmental Survey, 2D/3D Photography and Buccal Swab Cell Sampling
- Type of treatment
- Surgery or procedure
- How many people
- 2,145 participants
- Where
- 20 sitesin 5 countries
- Study dates
- 13 Jan 2015to 31 Jan 2028
- Phase
- Observational
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 Up to 80 years
- All sexes
- Healthy volunteers accepted
- Child, Adult, Older adult
Study population: Individuals with coronal nonsyndromic craniosynostosis (cNSC) and their relatives and controls (including noncraniosynostosis patients having neurosurgery for another surgical indication) will be included in this study. Approximately 4,000 individuals will participate of either gender and all ages, ethnicities, and race. All research subjects will be consented through approved IRB protocols at Icahn School of Medicine at Mount Sinai or respective collaborating institutions which will be governed by their own institutional IRB committees. Only de-identified medical information, CT scans, and samples from collaborating institutions will be shared with Mount Sinai.
Who may be able to join
- Cases with diagnosis of coronal
- Unaffected relatives of cases
- Unaffected controls including those who may have undergone clinically indicated craniofacial surgery for trauma or conditions other than craniosynostosis or bone disease. These individuals will be recruited at some of the other collaborating institutions, but not at Mount Sinai.
- Individuals of any racial or ethnic group with the established or suspected clinical diagnosis of coronal, nonsyndromic craniosynostosis will be included in this study. Unaffected relatives, such as their biological parents and/or sibs, will also be included to contribute medical information and samples as negative controls for our study.
Who cannot join
- Those who fit the criteria, but who choose not to participate
- Those who do not meet the criteria.
- Other than children, no vulnerable individuals will be recruited, such as intellectual impaired individuals or prisoners.
Trial locations and contacts
20 sites in 5 countries.
20 sites in 5 countries
United States15 sites
Birth Defect Registries of New York State
Albany, New York, 12237
Seton Family of Hospitals
Austin, Texas, 78723
Johns Hopkins University
Baltimore, Maryland, 21218
Boston Children's Hospital
Boston, Massachusetts, 02115
Ann & Robert H. Lurie Children's Hospital of Chicago
Chicago, Illinois, 60611
Medical City Children's Hospital
Dallas, Texas, 75230
University of Texas at Southwestern
Dallas, Texas, 75390
The International Craniosynostosis Consortium at University of California at Davis
Davis, California, 95616
Yale University
Hartford, Connecticut, 06520
Pennsylvania State Milton S. Hershey Medical Center
Hershey, Pennsylvania, 17033
National Birth Defects Prevention Study at University of Iowa
Iowa City, Iowa, 52242
New York University
New York, New York, 10016
Icahn School of Medicine at Mount Sinai
New York, New York, 10029
University of Utah
Salt Lake City, Utah, 84158
Pennsylvania State University
University Park, Pennsylvania, 16802
France2 sites
INSERM/ Hospital Necker-Enfants Malades
Paris, Cedex 14, 75993
University of Bordeaux
Talence, Aquitaine, 33405
About this study
Official title: Craniosynostosis Network
Craniosynostosis (CS) is a common malformation occurring in ~4 per 10,000 live births in which the sutures between skull bones close too early, causing long-term problems with brain and skull growth. Infants with CS typically require extensive surgical treatment and may experience many perioperative complications, including hemorrhage and re-synostosis. Even with successful surgery, children can experience developmental and learning disabilities or vision problems. Most often, CS appears as isolated nonsyndromic CS (NSC). Of the several subtypes of CS, unilateral or bilateral fusion of the coronal suture is the second most common form of CS accounting for 20-30% of all NSC cases. The etiology of coronal NSC (cNSC) is not well understood, although the published literature suggests that it is a multifactorial condition. About 5-14% of coronal craniosynostosis patients have a positive family history, with a specific genetic etiology identified in >25% of cNSC cases, suggesting a strong genetic component in the pathogenesis of this birth defect. The causes for cNSC and its phenotypic heterogeneity remain largely unknown. An international team of investigators will generate large genomic and gene expression datasets on samples from patients with cNSC. State-of-the-art imaging, genetic, and developmental and systems biology approaches will be used to quantitatively model novel pathways and networks involved in the development of cNSC. Novel variant-, gene- and network-level analyses will be performed on the genomic data obtained from cNSC cases, their relatives, and controls to identify novel variants and genetic regions associated with cNCS. Quantitative, analytical, and functional validations of these predictions will provide insights into the etiology and possible therapeutic targets for CS and potentially other bone-related disorders.
Read the detailed description
The long-term goal of the Program Project, Craniosynostosis Network, is to elucidate normal and abnormal craniofacial biology to ultimately improve the treatment of craniofacial disorders. Craniosynostosis and other skull abnormalities are among the most common human malformations usually requiring surgical and medical intervention. The Network will integrate three projects and two cores. Scientists with diverse expertise including anthropology, morphometry, imaging, birth defects, developmental biology, genetics, genomics, epidemiology, statistics, and systems biology will explore the determinants of the fate of the relevant mesenchymal progenitor cells, abnormalities in osteogenesis that contribute to global skull growth abnormality and premature closure of cranial sutures, especially the coronal suture. High quality genomic data will be obtained from patients with coronal nonsyndromic craniosynostosis (cNSC) and their available parents. Novel genome-wide variant-, gene- and network-level analyses will be performed on these families to identify novel variants and genetic regions associated with coronal craniosynostosis.
This study is a multi-center, open-enrollment, retrospective study, employing both family-based and case-control study designs.
Approximately 4000 cNSC patients, their family members, and controls will be recruited by Icahn School of Medicine at Mount Sinai and the majority will be recruited from the more than 10 collaborating institutions worldwide.
- Conditions
- Craniosynostosis
- Being tested
- Craniosynostosis Network Environmental Survey, 2D/3D Photography, Buccal Swab Cell Sampling, Blood sampling, Skin Biopsy
- Keywords
- Craniosynostosis, Bone, Birth Defect, Congenital Anomaly, Malformation, Genetics, Genomics, Skull, Human, Mouse, Imaging, Cell Biology, Induced Pluripotent Stem Cells, System Biology
- Medical subject headings
- Craniosynostoses, Congenital Abnormalities
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Craniosynostosis Network Environmental SurveyOther
Questionnaire is administered to the mothers of affected participants regarding medical history and environmental exposures during pregnancy, delivery, and neonatal period. Optional.
2D/3D PhotographyOther
Full frontal and lateral face and other parts of the body may be taken for dysmorphic assessment. There is the risk of identification and loss of confidentiality. Optional.
Buccal Swab Cell SamplingProcedure or surgery
One or more swabs, like a Q-tip (for children), or saliva collection kit (for adults) will be used to collect buccal cells. With a swab, they will brush the inside of the mouth several times. With saliva collection kit, they will collect their saliva by spitting into a container several times using a commercially available saliva collection kit. Required.
Blood samplingProcedure or surgery
Venipuncture so that one teaspoon to tablespoons (1-20 ml.) of blood is collected. The volume drawn will be dependent on the age and size of the child. Minimal amounts may be required for DNA, but to establish a lymphoblastoid or iPS cell line at least 3 to 10 ml will be required independent of age. In the case of an infant, if 3 to 10 ml cannot be obtained, then a lymphoblastoid or iPS cell line will not be created. Optional.
Skin BiopsyProcedure or surgery
For those who do not undergo surgery or the skin removal is not considered part of the surgical procedure. After proper cleaning, a piece of skin the size of a pencil eraser (about 4 mm or 1/8 inch in diameter) will be removed (using a circular blade or scalpel) from the arm (inside of arm or forearm in a spot that is as unnoticeable as possible). This area will be covered with a Band-Aid. No stitches are usually required. A crust will form and eventually fall off. Optional.
Tissues from a Clinically Indicated ProcedureProcedure or surgery
In some instances when there is discarded tissues and specimens (including skin and bone at the time of reconstructive craniofacial surgery), they will be collected by making arrangements with their physicians. Some of these tissues will be used to generate cell lines. Optional.
Pre-operative CT Scan Image Files.Procedure or surgery
Optional for those who had a previous CT scan for a prior traumatic event.
| Study group | Role | What they receive |
|---|---|---|
| Coronal Nonsyndromic Craniosynostosis, trios | Participants with diagnosis of coronal, nonsyndromic craniosynostosis including affected and unaffected biological parents Receives: Other: Craniosynostosis Network Environmental Survey; Other: 2D/3D Photography; Procedure: Buccal Swab Cell Sampling; Procedure: Blood sampling; Procedure: Skin Biopsy; Procedure: Tissues from a Clinically Indicated Procedure; Procedure: Pre-operative CT Scan Image Files. | |
| Coronal, nonsyndromic craniosynostosis | Participants with coronal, nonsyndromic craniosynostosis when biological parents are not available Receives: Other: Craniosynostosis Network Environmental Survey; Other: 2D/3D Photography; Procedure: Buccal Swab Cell Sampling; Procedure: Blood sampling; Procedure: Skin Biopsy; Procedure: Tissues from a Clinically Indicated Procedure; Procedure: Pre-operative CT Scan Image Files. | |
| Unaffected controls | Unaffected controls who may have undergone clinically indicated craniofacial surgery for trauma or conditions other than craniosynostosis or bone disease Receives: Other: Craniosynostosis Network Environmental Survey; Other: 2D/3D Photography; Procedure: Buccal Swab Cell Sampling; Procedure: Blood sampling; Procedure: Skin Biopsy; Procedure: Tissues from a Clinically Indicated Procedure; Procedure: Pre-operative CT Scan Image Files. |
What is being measured
The primary outcome is the main question the study is designed to answer.
Phenotype-genotype gene expression correlations
Phenotype-genotype-gene expression correlations among cohorts of cases of coronal nonsyndromic craniosynostosis and genotype-gene expression correlations among controls will be analyzed and compared.
Measured: up to 5 years
Secondary outcomes (1)
Incidence of gene mutations
gene mutations and variants may be found that are significantly associated with coronal nonsyndromic craniosynostosis
Measured: up to 5 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted20 Jan 2017 (estimated)
- Study start13 Jan 2015
- Primary completion31 Jan 2028 (estimated)
- Study completion31 Jan 2028 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (50)Papers the sponsor has linked to this study.
- Other trials for CraniosynostosisStudies of the same condition, open and under way.
- More trials run by Icahn School of Medicine at Mount SinaiThe sponsor's other registered studies.
- 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
- Other
- Time perspective
- Other
- Enrolment
- 2,145 participants (actual)
Sponsor and investigators
- Lead sponsor
- Icahn School of Medicine at Mount Sinai
- Sponsor type
- University, hospital or other
- Collaborators
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
- Responsible party
- Principal investigator, Ethylin Wang Jabs, Icahn School of Medicine at Mount Sinai
- Investigators
- Ethylin Wang Jabs, MD, Principal investigator, Icahn School of Medicine at Mount SinaiInga Peter, PhD, Principal investigator, Icahn School of Medicine at Mount Sinai
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03025763
- Sponsor's protocol ID
- GCO 13-0147
- Other IDs
- P01HD078233
- Status last verified
- Dec 2024
- First submitted
- 17 Jan 2017
- Last updated
- 2 Jan 2025
- Results posted
- No
- Data monitoring committee
- No
- Individual data sharing
- Yes: Clinical results from chromosomal analysis and DNA mutation analysis performed in CLIA approved laboratories with standard clinical genetic counseling will be given to the patient upon request. Individual research results will be made available to the individual from the PI or their primary care physician (PCP) who has obtained preliminary results from the PI from our non-CLIA laboratory, as long as the PCP can confirm and validate the lab results through a CLIA approved lab before the results are given to the subjects.
Publications
Heuze Y, Holmes G, Peter I, Richtsmeier JT, Jabs EW. Closing the Gap: Genetic and Genomic Continuum from Syndromic to Nonsyndromic Craniosynostoses. Curr Genet Med Rep. 2014 Sep 1;2(3):135-145. doi: 10.1007/s40142-014-0042-x.
PubMed 26146596Heuze Y, Singh N, Basilico C, Jabs EW, Holmes G, Richtsmeier JT. Morphological comparison of the craniofacial phenotypes of mouse models expressing the Apert FGFR2 S252W mutation in neural crest- or mesoderm-derived tissues. Bone. 2014 Jun;63:101-9. doi: 10.1016/j.bone.2014.03.003. Epub 2014 Mar 13.
PubMed 24632501Heuze Y, Martinez-Abadias N, Stella JM, Arnaud E, Collet C, Garcia Fructuoso G, Alamar M, Lo LJ, Boyadjiev SA, Di Rocco F, Richtsmeier JT. Quantification of facial skeletal shape variation in fibroblast growth factor receptor-related craniosynostosis syndromes. Birth Defects Res A Clin Mol Teratol. 2014 Apr;100(4):250-9. doi: 10.1002/bdra.23228. Epub 2014 Feb 27.
PubMed 24578066Di Rocco F, Biosse Duplan M, Heuze Y, Kaci N, Komla-Ebri D, Munnich A, Mugniery E, Benoist-Lasselin C, Legeai-Mallet L. FGFR3 mutation causes abnormal membranous ossification in achondroplasia. Hum Mol Genet. 2014 Jun 1;23(11):2914-25. doi: 10.1093/hmg/ddu004. Epub 2014 Jan 12.
PubMed 24419316Justice CM, Yagnik G, Kim Y, Peter I, Jabs EW, Erazo M, Ye X, Ainehsazan E, Shi L, Cunningham ML, Kimonis V, Roscioli T, Wall SA, Wilkie AO, Stoler J, Richtsmeier JT, Heuze Y, Sanchez-Lara PA, Buckley MF, Druschel CM, Mills JL, Caggana M, Romitti PA, Kay DM, Senders C, Taub PJ, Klein OD, Boggan J, Zwienenberg-Lee M, Naydenov C, Kim J, Wilson AF, Boyadjiev SA. A genome-wide association study identifies susceptibility loci for nonsyndromic sagittal craniosynostosis near BMP2 and within BBS9. Nat Genet. 2012 Dec;44(12):1360-4. doi: 10.1038/ng.2463. Epub 2012 Nov 18.
PubMed 23160099Heuze Y, Martinez-Abadias N, Stella JM, Senders CW, Boyadjiev SA, Lo LJ, Richtsmeier JT. Unilateral and bilateral expression of a quantitative trait: asymmetry and symmetry in coronal craniosynostosis. J Exp Zool B Mol Dev Evol. 2012 Mar;318(2):109-22. doi: 10.1002/jezb.21449.
PubMed 22532473Martinez-Abadias N, Heuze Y, Wang Y, Jabs EW, Aldridge K, Richtsmeier JT. FGF/FGFR signaling coordinates skull development by modulating magnitude of morphological integration: evidence from Apert syndrome mouse models. PLoS One. 2011;6(10):e26425. doi: 10.1371/journal.pone.0026425. Epub 2011 Oct 28.
PubMed 22053191Heuze Y, Boyadjiev SA, Marsh JL, Kane AA, Cherkez E, Boggan JE, Richtsmeier JT. New insights into the relationship between suture closure and craniofacial dysmorphology in sagittal nonsyndromic craniosynostosis. J Anat. 2010 Aug;217(2):85-96. doi: 10.1111/j.1469-7580.2010.01258.x. Epub 2010 Jun 22.
PubMed 20572900Wang Y, Sun M, Uhlhorn VL, Zhou X, Peter I, Martinez-Abadias N, Hill CA, Percival CJ, Richtsmeier JT, Huso DL, Jabs EW. Activation of p38 MAPK pathway in the skull abnormalities of Apert syndrome Fgfr2(+P253R) mice. BMC Dev Biol. 2010 Feb 22;10:22. doi: 10.1186/1471-213X-10-22.
PubMed 20175913Percival CJ, Kawasaki K, Huang Y, Weiss KM, Jabs EW, Li R, Richtsmeier JT. Building Bones. Percival CJ, Richtsmeier JT, editors. Cambridge. Cambridge University Press; 2017. Chapter 2, The contribution of angiogenesis to variation in bone development and evolution; 26-51p.
Kawasaki K, Richtsmeier JT. Building Bones. Percival CJ, Richtsmeier JT, editors. Cambridge. Cambridge University Press; 2017. Chapter 3, Association of the chondrocranium and dermatocranium in early skull development; 52-78p.
Kawasaki K, Richtsmeier J. Building Bones. Percival CJ, Richtsmeier JT, editors. Cambridge. Cambridge University Press; 2017. Chapter Appendix, Appendix to Chapter 3 ; 303-315p.
Singh N, Dutka T, Reeves RH, Richtsmeier JT. Chronic up-regulation of sonic hedgehog has little effect on postnatal craniofacial morphology of euploid and trisomic mice. Dev Dyn. 2016 Feb;245(2):114-22. doi: 10.1002/dvdy.24361. Epub 2015 Dec 6.
PubMed 26509735Trainor PA, Richtsmeier JT. Facing up to the challenges of advancing Craniofacial Research. Am J Med Genet A. 2015 Jul;167(7):1451-4. doi: 10.1002/ajmg.a.37065. Epub 2015 Mar 28.
PubMed 25820983Wilkie AOM, Johnson D, Wall SA. Clinical genetics of craniosynostosis. Curr Opin Pediatr. 2017 Dec;29(6):622-628. doi: 10.1097/MOP.0000000000000542.
PubMed 28914635