Craniosynostosis, the premature fusion of one or more cranial sutures, is a common malformation occurring in 1 out of every 2500 live births and shows marked variation of phenotypes. The skull shape in craniosynostosis can not be explained simply by the premature fusion of sutures, but involves widespread abnormal development of the head. A number of mutations have now been identified that are associated with certain clinically defined craniosynostosis conditions. Eight of the craniosynostosis disorders including Crouzon, Apert and Pfeiffer syndromes are caused by mutations in fibroblast growth factor receptors (FGFR)-1, -2 or -3. FGFR tyrosine kinases and their ligands play fundamental and widespread roles in development and are known to play a crucial role in the control of cell migration, proliferation, differentiation and survival by activation of multiple pathways and interaction among signaling pathways. Importantly, FGFRs are involved in development of the skull, meninges, and the brain. We propose a unifying study of molecular and morphological research aimed at identifying the intermediate developmental steps in the genotype-phenotype continuum of craniosynostosis. Ours is a """"""""phenogenetic"""""""" approach that attempts to connect biological phenotypes with their underlying genetic processes such as regional differentiation by activation of signaling. Through a study of archived MR and CT images of humans with isolated craniosynostosis we defined phenotypic correlations of traits on skull and brain in isolated and syndromic craniosynostosis. These correlations are indicative of strong developmental associations between brain and skull. These associations will be further tested using additional 3D data from CT and MR images of cases of coronal craniosynostosis and Apert, Crouzon and Pfeiffer syndromes and micro-CT and micro-MR of two Fgfr2 mouse models for these syndromes. Using anatomical sites identified by our investigations of human skull and brain covariation as a temporal and spatial guide, we will document patterns of abnormal proliferation, differentiation, apoptosis, and Fgf/Fgfr signaling in developing cranial tissues of Fgfr2+/S252W and FgfrcC342Y/+ mutant mice at three developmental stages. Our hypothesis is that the spatiotemporal map of abnormal Fgf/Fgfr signaling in formative skull and brain is the basis for a series of developmental events that result in anomalous cellular processes local to those sites and ultimately result in the abnormal head and brain shape in craniosynostosis. Our morphological analyses will inform our molecular investigations of how two particular mutations affect phenogenetic processes to produce developmental relationships that lead to craniosynostosis phenotypes.

Public Health Relevance

Craniosynostosis is a common malformation which is defined by the premature fusion of skull bones, most commonly those of the calvaria.
Our aims are to study the integrated nature of skull and brain development in craniosynostosis using data from human populations with nonsyndromic coronal craniosynostosis and Apert, Crouzon and Pfeiffer syndrome, as well as data from mouse models for Apert and Crouzon syndrome to understand the production of the entire head in these disorders and not just the closed suture.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Research Project (R01)
Project #
Application #
Study Section
Skeletal Biology Development and Disease Study Section (SBDD)
Program Officer
Scholnick, Steven
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Pennsylvania State University
Social Sciences
Schools of Arts and Sciences
University Park
United States
Zip Code
Richtsmeier, Joan T (2018) A century of development. Am J Phys Anthropol 165:726-740
Lesciotto, Kate M; Heuzé, Yann; Jabs, Ethylin Wang et al. (2018) Choanal Atresia and Craniosynostosis: Development and Disease. Plast Reconstr Surg 141:156-168
Motch Perrine, Susan M; Stecko, Tim; Neuberger, Thomas et al. (2017) Integration of Brain and Skull in Prenatal Mouse Models of Apert and Crouzon Syndromes. Front Hum Neurosci 11:369
Starbuck, John M; Cole 3rd, Theodore M; Reeves, Roger H et al. (2017) The Influence of trisomy 21 on facial form and variability. Am J Med Genet A 173:2861-2872
Heuzé, Yann; Kawasaki, Kazuhiko; Schwarz, Tobias et al. (2016) Developmental and Evolutionary Significance of the Zygomatic Bone. Anat Rec (Hoboken) 299:1616-1630
Singh, Nandini; Dutka, Tara; Reeves, Roger H et al. (2016) Chronic up-regulation of sonic hedgehog has little effect on postnatal craniofacial morphology of euploid and trisomic mice. Dev Dyn 245:114-22
Flaherty, Kevin; Singh, Nandini; Richtsmeier, Joan T (2016) Understanding craniosynostosis as a growth disorder. Wiley Interdiscip Rev Dev Biol 5:429-59
Layden, Michael J; Rentzsch, Fabian; Röttinger, Eric (2016) The rise of the starlet sea anemone Nematostella vectensis as a model system to investigate development and regeneration. Wiley Interdiscip Rev Dev Biol 5:408-28
Weiss, Ken; Buchanan, Anne; Richtsmeier, Joan (2015) How are we made?: Even well-controlled experiments show the complexity of our traits. Evol Anthropol 24:130-6
Singh, Nandini; Dutka, Tara; Devenney, Benjamin M et al. (2015) Acute upregulation of hedgehog signaling in mice causes differential effects on cranial morphology. Dis Model Mech 8:271-9

Showing the most recent 10 out of 52 publications