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


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.

Full Title of Study: “Craniosynostosis Network”

Study Type

  • Study Type: Observational
  • Study Design
    • Time Perspective: Other
  • Study Primary Completion Date: January 31, 2022

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.


  • 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 possible). 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.

Arms, Groups and Cohorts

  • Coronal Nonsyndromic Craniosynostosis, trios
    • Participants with diagnosis of coronal, nonsyndromic craniosynostosis including affected and unaffected biological parents
  • Coronal, nonsyndromic craniosynostosis
    • Participants with coronal, nonsyndromic craniosynostosis when biological parents are not available
  • Unaffected controls
    • Unaffected controls who may have undergone clinically indicated craniofacial surgery for trauma or conditions other than craniosynostosis or bone disease

Clinical Trial Outcome Measures

Primary Measures

  • 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 Measures

  • 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

Participating in This Clinical Trial

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.

Gender Eligibility: All

Minimum Age: N/A

Maximum Age: 80 Years

Are Healthy Volunteers Accepted: Accepts Healthy Volunteers

Investigator Details

  • Lead Sponsor
    • Icahn School of Medicine at Mount Sinai
  • Collaborator
    • Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
  • Provider of Information About this Clinical Study
    • Principal Investigator: Ethylin Wangs Jabs, Professor – Icahn School of Medicine at Mount Sinai
  • Overall Official(s)
    • Ethylin Wang Jabs, MD, Principal Investigator, Icahn School of Medicine at Mount Sinai
    • Inga Peter, PhD, Principal Investigator, Icahn School of Medicine at Mount Sinai
  • Overall Contact(s)
    • Ethylin Wang Jabs, MD, 212-241-3504,


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Lee C, Richtsmeier JT, Kraft RH. A COMPUTATIONAL ANALYSIS OF BONE FORMATION IN THE CRANIAL VAULT USING A COUPLED REACTION-DIFFUSION-STRAIN MODEL. J Mech Med Biol. 2017 Jun;17(4). pii: 1750073. doi: 10.1142/S0219519417500737. Epub 2017 May 29.

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