craniosynostoses

Definition: Craniosynostosis is the premature fusion of one or more cranial sutures.

Types

 simple craniosynostosis

• sagittal craniosynostosis
• coronal craniosynostosis
• metopic craniosynostosis
• lambdoid craniosynostosis
• oxycephaly

 cloverleaf skull

Etiology

 monogenic conditions

• Apert syndrome
• Crouzon syndrome
• Jackson-Weiss syndrome
• Pfeiffer syndrome
• Muenke syndrome
• Boston type craniosynostosis
• Greig cephalopolysyndactyly (7p13)
• Saethre-Chotzen syndrome (7p21-p22)

 chromosomal diseases

• trisomy 5q (5q-trisomy) (MSX2) (17955513)

 rickets
 fetal hyperthydoidism
 inherited metabolic diseases

• mucopolysaccharidoses
  • Hurler syndrome
  • Morquio syndrome
  • beta-glucuronidase deficiency

• mucolipidoses
  • mucolipidose III

 hematological diseases

• thalassemias
• sickle cell anemia
• congenital hemolytic icterus
• polycythemia vera

 teratogens

• aminopterin
• diphenylhydantoin
• retinoic acid
• valproic acid

Associations

 malformations

• microcephaly
• encephalocele
• shunted hydrocephalus
• holoprosencephaly

Molecular biology

 identical proline—>arginine gain-of-function mutations in fibroblast growth factor receptor (FGFR1) (Pro252Arg), FGFR2 (Pro253Arg) and FGFR3 (Pro250Arg) in

• type I Pfeiffer
• Apert syndrome
• Muenke syndrome

Retinoic acid

Excess exogenous retinoic acid (RA) has been well documented to have teratogenic effects in the limb and craniofacial skeleton.

Malformations that have been observed in this context include craniosynostosis, a common developmental defect of the skull that occurs in 1 in 2500 individuals and results from premature fusion of the cranial sutures.

Genetically based alterations in RA signaling interfere with human development.

Human null and hypomorphic mutations have been identified in the gene encoding the RA-degrading enzyme CYP26B1 that lead to skeletal and craniofacial anomalies, including fusions of long bones, calvarial bone hypoplasia, and craniosynostosis. (22019272)

Analyses of murine embryos exposed to a chemical inhibitor of Cyp26 enzymes and zebrafish lines with mutations in cyp26b1 suggest that the endochondral bone fusions are due to unrestricted chondrogenesis at the presumptive sites of joint formation within cartilaginous templates, whereas craniosynostosis is induced by a defect in osteoblastic differentiation. (22019272)

Ultrastructural analysis, in situ expression studies, and in vitro quantitative RT-PCR experiments of cellular markers of osseous differentiation indicate that the most likely cause for these phenomena is aberrant osteoblast-osteocyte transitioning. (22019272)

Studies reveals a physiological role for RA in partitioning skeletal elements and in the maintenance of cranial suture patency. (22019272)

References

 Craniosynostosis and Multiple Skeletal Anomalies in Humans and Zebrafish Result from a Defect in the Localized Degradation of Retinoic Acid. Laue K, Pogoda HM, Daniel PB, van Haeringen A, Alanay Y, von Ameln S, Rachwalski M, Morgan T, Gray MJ, Breuning MH, Sawyer GM, Sutherland-Smith AJ, Nikkels PG, Kubisch C, Bloch W, Wollnik B, Hammerschmidt M, Robertson SP. Am J Hum Genet. 2011 Oct 18. PMID: 22019272

 Wilkie AO. Craniosynostosis : genes and mechanisms. Hum Mol Genet. 1997 ;6(10):1647-56. PMID : 9300656

 Park WJ, Meyers GA, Li X, Theda C, Day D, Orlow SJ, Jones MC, Jabs EW. Novel FGFR2 mutations in Crouzon and Jackson-Weiss syndromes show allelic heterogeneity and phenotypic variability. Hum Mol Genet. 1995 Jul;4(7):1229-33. PMID: 8528214