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

Craniosynostosis Clinical Trial

Official title:

Craniosynostosis Network

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03025763
• Other study ID #: GCO 13-0147
• Secondary ID: P01HD078233
• Status: Active, not recruiting
• Start date: January 13, 2015
• Est. completion date: January 31, 2028

Study information

• Verified date: September 2023
• Source: Icahn School of Medicine at Mount Sinai
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical 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. 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 2145
• Est. completion date: January 31, 2028
• Est. primary completion date: January 31, 2028
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: N/A to 80 Years

Eligibility

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.

Related Conditions & MeSH terms

• Craniosynostoses
• Craniosynostosis

Intervention

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

Locations

Country	Name	City	State
France	INSERM/ Hospital Necker-Enfants Malades	Paris	Cedex 14
France	University of Bordeaux	Talence	Aquitaine
Germany	University Hospital Heidelberg	Heidelberg
Spain	Hospital Sant Joan de Deu	Barcelona	Esplugues De Llobregat
United Kingdom	Oxford University	Oxford	Oxfordshire
United States	Birth Defect Registries of New York State	Albany	New York
United States	Seton Family of Hospitals	Austin	Texas
United States	Johns Hopkins University	Baltimore	Maryland
United States	Boston Children's Hospital	Boston	Massachusetts
United States	Ann & Robert H. Lurie Children's Hospital of Chicago	Chicago	Illinois
United States	Medical City Children's Hospital	Dallas	Texas
United States	University of Texas at Southwestern	Dallas	Texas
United States	The International Craniosynostosis Consortium at University of California at Davis	Davis	California
United States	Yale University	Hartford	Connecticut
United States	Pennsylvania State Milton S. Hershey Medical Center	Hershey	Pennsylvania
United States	National Birth Defects Prevention Study at University of Iowa	Iowa City	Iowa
United States	Icahn School of Medicine at Mount Sinai	New York	New York
United States	New York University	New York	New York
United States	University of Utah	Salt Lake City	Utah
United States	Pennsylvania State University	University Park	Pennsylvania

Sponsors (2)

Lead Sponsor	Collaborator
Icahn School of Medicine at Mount Sinai	Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Countries where clinical trial is conducted

United States,  France,  Germany,  Spain,  United Kingdom, 

References & Publications (44)

Di 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. — View Citation

Flaherty K, Richtsmeier JT. It's about Time: Ossification Center Formation in C57BL/6 Mice from E12(-)E16. J Dev Biol. 2018 Dec 15;6(4):31. doi: 10.3390/jdb6040031. — View Citation

Flaherty K, Singh N, Richtsmeier JT. Understanding craniosynostosis as a growth disorder. Wiley Interdiscip Rev Dev Biol. 2016 Jul;5(4):429-59. doi: 10.1002/wdev.227. Epub 2016 Mar 22. — View Citation

Heuze 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. — View Citation

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. — View Citation

Heuze Y, Kawasaki K, Schwarz T, Schoenebeck JJ, Richtsmeier JT. Developmental and Evolutionary Significance of the Zygomatic Bone. Anat Rec (Hoboken). 2016 Dec;299(12):1616-1630. doi: 10.1002/ar.23449. — View Citation

Heuze 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. — View Citation

Heuze 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. — View Citation

Heuze 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. — View Citation

Holmes G, Gonzalez-Reiche AS, Lu N, Zhou X, Rivera J, Kriti D, Sebra R, Williams AA, Donovan MJ, Potter SS, Pinto D, Zhang B, van Bakel H, Jabs EW. Integrated Transcriptome and Network Analysis Reveals Spatiotemporal Dynamics of Calvarial Suturogenesis. C — View Citation

Holmes G, Gonzalez-Reiche AS, Saturne M, Motch Perrine SM, Zhou X, Borges AC, Shewale B, Richtsmeier JT, Zhang B, van Bakel H, Jabs EW. Single-cell analysis identifies a key role for Hhip in murine coronal suture development. Nat Commun. 2021 Dec 8;12(1): — View Citation

Holmes G, O'Rourke C, Motch Perrine SM, Lu N, van Bakel H, Richtsmeier JT, Jabs EW. Midface and upper airway dysgenesis in FGFR2-related craniosynostosis involves multiple tissue-specific and cell cycle effects. Development. 2018 Oct 5;145(19):dev166488. — View Citation

Holmes G, Zhang L, Rivera J, Murphy R, Assouline C, Sullivan L, Oppeneer T, Jabs EW. C-type natriuretic peptide analog treatment of craniosynostosis in a Crouzon syndrome mouse model. PLoS One. 2018 Jul 26;13(7):e0201492. doi: 10.1371/journal.pone.0201492 — View Citation

Justice 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. — View Citation

Kawasaki K, Mikami M, Goto M, Shindo J, Amano M, Ishiyama M. The Evolution of Unusually Small Amelogenin Genes in Cetaceans; Pseudogenization, X-Y Gene Conversion, and Feeding Strategy. J Mol Evol. 2020 Mar;88(2):122-135. doi: 10.1007/s00239-019-09917-0. — View Citation

Kawasaki K, Richtsmeier J. Building Bones. Percival CJ, Richtsmeier JT, editors. Cambridge. Cambridge University Press; 2017. Chapter Appendix, Appendix to Chapter 3 ; 303-315p.

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.

Lam AS, Liu CC, Deutsch GH, Rivera J, Perkins JA, Holmes G, Jabs EW, Cunningham ML, Dahl JP. Genotype-Phenotype Correlation of Tracheal Cartilaginous Sleeves and Fgfr2 Mutations in Mice. Laryngoscope. 2021 Apr;131(4):E1349-E1356. doi: 10.1002/lary.29060. — View Citation

Lee C, Richtsmeier JT, Kraft RH. A computational analysis of bone formation in the cranial vault in the mouse. Front Bioeng Biotechnol. 2015 Mar 19;3:24. doi: 10.3389/fbioe.2015.00024. eCollection 2015. — View Citation

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):1750073. doi: 10.1142/S0219519417500737. Epub 2017 May 29. — View Citation

Lee C, Richtsmeier JT, Kraft RH. A coupled reaction-diffusion-strain model predicts cranial vault formation in development and disease. Biomech Model Mechanobiol. 2019 Aug;18(4):1197-1211. doi: 10.1007/s10237-019-01139-z. Epub 2019 Apr 20. — View Citation

Lesciotto KM, Heuze Y, Jabs EW, Bernstein JM, Richtsmeier JT. Choanal Atresia and Craniosynostosis: Development and Disease. Plast Reconstr Surg. 2018 Jan;141(1):156-168. doi: 10.1097/PRS.0000000000003928. — View Citation

Lesciotto KM, Richtsmeier JT. Craniofacial skeletal response to encephalization: How do we know what we think we know? Am J Phys Anthropol. 2019 Jan;168 Suppl 67(Suppl 67):27-46. doi: 10.1002/ajpa.23766. — View Citation

Lesciotto KM, Tomlinson L, Leonard S, Richtsmeier JT. Embryonic and early postnatal cranial bone volume and tissue mineral density values for C57BL/6J laboratory mice. Dev Dyn. 2022 Jul;251(7):1196-1208. doi: 10.1002/dvdy.458. Epub 2022 Feb 7. — View Citation

Martinez-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. — View Citation

Martinez-Abadias N, Mateu Estivill R, Sastre Tomas J, Motch Perrine S, Yoon M, Robert-Moreno A, Swoger J, Russo L, Kawasaki K, Richtsmeier J, Sharpe J. Quantification of gene expression patterns to reveal the origins of abnormal morphogenesis. Elife. 2018 — View Citation

Motch Perrine SM, Stecko T, Neuberger T, Jabs EW, Ryan TM, Richtsmeier JT. Integration of Brain and Skull in Prenatal Mouse Models of Apert and Crouzon Syndromes. Front Hum Neurosci. 2017 Jul 25;11:369. doi: 10.3389/fnhum.2017.00369. eCollection 2017. — View Citation

Motch Perrine SM, Wu M, Stephens NB, Kriti D, van Bakel H, Jabs EW, Richtsmeier JT. Mandibular dysmorphology due to abnormal embryonic osteogenesis in FGFR2-related craniosynostosis mice. Dis Model Mech. 2019 May 30;12(5):dmm038513. doi: 10.1242/dmm.03851 — View Citation

Musy M, Flaherty K, Raspopovic J, Robert-Moreno A, Richtsmeier JT, Sharpe J. A quantitative method for staging mouse embryos based on limb morphometry. Development. 2018 Apr 5;145(7):dev154856. doi: 10.1242/dev.154856. — View Citation

Norwood JN, Zhang Q, Card D, Craine A, Ryan TM, Drew PJ. Anatomical basis and physiological role of cerebrospinal fluid transport through the murine cribriform plate. Elife. 2019 May 7;8:e44278. doi: 10.7554/eLife.44278. — View Citation

Percival 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.

Pitirri MK, Durham EL, Romano NA, Santos JI, Coupe AP, Zheng H, Chen DZ, Kawasaki K, Jabs EW, Richtsmeier JT, Wu M, Motch Perrine SM. Meckel's Cartilage in Mandibular Development and Dysmorphogenesis. Front Genet. 2022 May 16;13:871927. doi: 10.3389/fgene — View Citation

Pitirri MK, Kawasaki K, Richtsmeier JT. It takes two: Building the vertebrate skull from chondrocranium and dermatocranium. Vertebr Zool. 2020 Apr;70(4):587-600. Epub 2020 Oct 28. — View Citation

Pitirri MK, Richtsmeier JT, Kawasaki M, Coupe AP, Perrine SM, Kawasaki K. Come together over me: Cells that form the dermatocranium and chondrocranium in mice. Anat Rec (Hoboken). 2023 Jul 27. doi: 10.1002/ar.25295. Online ahead of print. — View Citation

Richtsmeier JT. A century of development. Am J Phys Anthropol. 2018 Apr;165(4):726-740. doi: 10.1002/ajpa.23379. No abstract available. — View Citation

Sewda A, White SR, Erazo M, Hao K, Garcia-Fructuoso G, Fernandez-Rodriguez I, Heuze Y, Richtsmeier JT, Romitti PA, Reva B, Jabs EW, Peter I. Nonsyndromic craniosynostosis: novel coding variants. Pediatr Res. 2019 Mar;85(4):463-468. doi: 10.1038/s41390-019 — View Citation

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. — View Citation

Singh R, Cohen ASA, Poulton C, Hjortshoj TD, Akahira-Azuma M, Mendiratta G, Khan WA, Azmanov DN, Woodward KJ, Kirchhoff M, Shi L, Edelmann L, Baynam G, Scott SA, Jabs EW. Deletion of ERF and CIC causes abnormal skull morphology and global developmental de — View Citation

Starbuck JM, Cole TM 3rd, Reeves RH, Richtsmeier JT. The Influence of trisomy 21 on facial form and variability. Am J Med Genet A. 2017 Nov;173(11):2861-2872. doi: 10.1002/ajmg.a.38464. Epub 2017 Sep 21. — View Citation

Trainor 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. — View Citation

Wang 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. — View Citation

Weiss K, Buchanan A, Richtsmeier J. How are we made?: Even well-controlled experiments show the complexity of our traits. Evol Anthropol. 2015 Jul-Aug;24(4):130-6. doi: 10.1002/evan.21454. No abstract available. — View Citation

Wu M, Kriti D, van Bakel H, Jabs EW, Holmes G. Laser Capture Microdissection of Mouse Embryonic Cartilage and Bone for Gene Expression Analysis. J Vis Exp. 2019 Dec 18;(154). doi: 10.3791/60503. — View Citation

Ye X, Guilmatre A, Reva B, Peter I, Heuze Y, Richtsmeier JT, Fox DJ, Goedken RJ, Jabs EW, Romitti PA. Mutation Screening of Candidate Genes in Patients with Nonsyndromic Sagittal Craniosynostosis. Plast Reconstr Surg. 2016 Mar;137(3):952-961. doi: 10.1097 — View Citation

* Note: There are 44 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	up to 5 years
Secondary	Incidence of gene mutations	gene mutations and variants may be found that are significantly associated with coronal nonsyndromic craniosynostosis	up to 5 years

External Links

•   Information about craniosynostosis and the Craniosynostosis Network Project
•   The eMOSS staging system-free, public webtool for any PI requiring increased temporal resolution for research using embryonic mice. Developed thru a collaboration-Dr. Joan Richtsmeier lab, Penn State Univ & Dr. James Sharpe lab, Center for G