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Network Of Clinical Research Studies On Craniosynostosis, Skull Malformations With Premature Fusion Of Skull Bones

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ClinicalTrials.gov Identifier: NCT03025763
Recruitment Status : Recruiting
First Posted : January 20, 2017
Last Update Posted : January 23, 2018
Sponsor:
Collaborator:
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Information provided by (Responsible Party):
Icahn School of Medicine at Mount Sinai

Brief 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. 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.

Condition or disease Intervention/treatment
Craniosynostosis 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.

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 Mount Sinai and the majority will be recruited from the more than 10 collaborating institutions worldwide.


Study Type : Observational
Estimated Enrollment : 4000 participants
Observational Model: Other
Time Perspective: Other
Official Title: Craniosynostosis Network
Study Start Date : November 2014
Estimated Primary Completion Date : June 2019
Estimated Study Completion Date : June 2029


Group/Cohort Intervention/treatment
Coronal Nonsyndromic Craniosynostosis, trios
Participants with diagnosis of coronal, nonsyndromic craniosynostosis including affected and unaffected biological parents
Other: Craniosynostosis Network Environmental Survey
Questionnaire is administered to the mothers of affected participants regarding medical history and environmental exposures during pregnancy, delivery, and neonatal period. Optional.

Other: 2D/3D Photography
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.

Procedure: Buccal Swab Cell Sampling
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.

Procedure: Blood sampling
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.

Procedure: Skin Biopsy
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). This area will be covered with a Band-Aid. No stitches are usually required. A crust will form and eventually fall off. Optional.

Procedure: Tissues from a Clinically Indicated Procedure
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.

Procedure: Pre-operative CT Scan Image Files.
Optional for those who had a previous CT scan for a prior traumatic event.

Coronal, nonsyndromic craniosynostosis
Participants with coronal, nonsyndromic craniosynostosis when biological parents are not available
Other: Craniosynostosis Network Environmental Survey
Questionnaire is administered to the mothers of affected participants regarding medical history and environmental exposures during pregnancy, delivery, and neonatal period. Optional.

Other: 2D/3D Photography
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.

Procedure: Buccal Swab Cell Sampling
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.

Procedure: Blood sampling
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.

Procedure: Skin Biopsy
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). This area will be covered with a Band-Aid. No stitches are usually required. A crust will form and eventually fall off. Optional.

Procedure: Tissues from a Clinically Indicated Procedure
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.

Procedure: Pre-operative CT Scan Image Files.
Optional for those who had a previous CT scan for a prior traumatic event.

Unaffected controls
Unaffected controls who may have undergone clinically indicated craniofacial surgery for trauma or conditions other than craniosynostosis or bone disease
Other: Craniosynostosis Network Environmental Survey
Questionnaire is administered to the mothers of affected participants regarding medical history and environmental exposures during pregnancy, delivery, and neonatal period. Optional.

Other: 2D/3D Photography
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.

Procedure: Buccal Swab Cell Sampling
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.

Procedure: Blood sampling
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.

Procedure: Skin Biopsy
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). This area will be covered with a Band-Aid. No stitches are usually required. A crust will form and eventually fall off. Optional.

Procedure: Tissues from a Clinically Indicated Procedure
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.

Procedure: Pre-operative CT Scan Image Files.
Optional for those who had a previous CT scan for a prior traumatic event.




Primary Outcome Measures :
  1. Phenotype-genotype gene expression correlations [ Time Frame: up to 5 years ]
    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.


Secondary Outcome Measures :
  1. Incidence of gene mutations [ Time Frame: up to 5 years ]
    gene mutations and variants may be found that are significantly associated with coronal nonsyndromic craniosynostosis


Biospecimen Retention:   Samples With DNA
Saliva, blood, white blood cells, DNA, RNA, and generated induced pluripotent stem cells


Information from the National Library of Medicine

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Ages Eligible for Study:   up to 80 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Sampling Method:   Non-Probability Sample
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 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.
Criteria

Inclusion Criteria:

  • 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.

Exclusion Criteria:

  • 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03025763


Contacts
Contact: Ethylin Wang Jabs, MD 212-241-3504 ethylin.jabs@mssm.edu

Locations
United States, California
The International Craniosynostosis Consortium at University of California at Davis Recruiting
Davis, California, United States, 95616
United States, Connecticut
Yale University Recruiting
Hartford, Connecticut, United States, 06520
United States, Iowa
National Birth Defects Prevention Study at University of Iowa Recruiting
Iowa City, Iowa, United States, 52242
United States, Maryland
Johns Hopkins University Recruiting
Baltimore, Maryland, United States, 21218
United States, Massachusetts
Boston Children's Hospital Recruiting
Boston, Massachusetts, United States, 02115
United States, New York
Birth Defect Registries of New York State Recruiting
Albany, New York, United States, 12237
Principal Investigator: Paul Romitti         
New York University Recruiting
New York, New York, United States, 10016
Icahn School of Medicine at Mount Sinai Recruiting
New York, New York, United States, 10029
Principal Investigator: Ethylin Jabs, MD         
United States, Pennsylvania
Pennsylvania State Milton S. Hershey Medical Center Recruiting
Hershey, Pennsylvania, United States, 17033
Pennsylvania State University Active, not recruiting
University Park, Pennsylvania, United States, 16802
United States, Texas
Univ. of Texas at Southwestern Recruiting
Dallas, Texas, United States, 75390
France
University of Bordeaux Active, not recruiting
Talence, Aquitaine, France, 33405
INSERM/ Hospital Necker-Enfants Malades Recruiting
Paris, Cedex 14, France, 75993
Germany
University Hospital Heidelberg Recruiting
Heidelberg, Germany, 69120
Spain
Hospital Sant Joan de Deu Recruiting
Barcelona, Esplugues De Llobregat, Spain, 08950
United Kingdom
Oxford University Recruiting
Oxford, Oxfordshire, United Kingdom, OX1 2JD
Sponsors and Collaborators
Icahn School of Medicine at Mount Sinai
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Investigators
Principal Investigator: Ethylin Wang Jabs, MD Icahn School of Medicine at Mount Sinai
Principal Investigator: Inga Peter, PhD Icahn School of Medicine at Mount Sinai

Additional Information:
Publications:

Responsible Party: Icahn School of Medicine at Mount Sinai
ClinicalTrials.gov Identifier: NCT03025763     History of Changes
Other Study ID Numbers: GCO 13-0147
P01HD078233 ( U.S. NIH Grant/Contract )
First Posted: January 20, 2017    Key Record Dates
Last Update Posted: January 23, 2018
Last Verified: January 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: 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.

Keywords provided by Icahn School of Medicine at Mount Sinai:
Craniosynostosis
Bone
Birth Defect
Congenital Anomaly
Malformation
Genetics
Genomics
Skull
Human
Mouse
Imaging
Cell Biology
Induced Pluripotent Stem Cells
System Biology

Additional relevant MeSH terms:
Craniosynostoses
Synostosis
Dysostoses
Bone Diseases, Developmental
Bone Diseases
Musculoskeletal Diseases
Craniofacial Abnormalities
Musculoskeletal Abnormalities
Congenital Abnormalities