Craniosynostosis 3
A number sign (#) is used with this entry because of evidence that craniosynostosis-3 (CRS3) is caused by heterozygous mutation in the TCF12 gene (600480) on chromosome 15q21.
DescriptionCraniosynostosis is a primary abnormality of skull growth involving premature fusion of the cranial sutures such that the growth velocity of the skull often cannot match that of the developing brain. This produces skull deformity and, in some cases, raises intracranial pressure, which must be treated promptly to avoid permanent neurodevelopmental disability (summary by Fitzpatrick, 2013). Craniosynostosis-3 includes coronal, sagittal, and multisuture forms (Sharma et al., 2013).
For discussion of genetic heterogeneity of craniosynostosis, see CRS1 (123100).
Clinical FeaturesSharma et al. (2013) studied 72 individuals with craniosynostosis who had a mutation in the TCF12 gene (see MOLECULAR GENETICS). The most common presentation was bilateral coronal synostosis, which was seen in 25 patients; another 18 patients had right coronal synostosis, and 5 had left coronal synostosis. In 2 cases, coronal synostosis was combined with sagittal synostosis, and 2 individuals had only sagittal synostosis. In addition, 20 mutation-positive adults did not exhibit craniosynostosis; Sharma et al. (2013) stated that this represents substantial nonpenetrance (53%), and noted that it was likely to be underestimated because all index cases were ascertained through craniofacial clinics. Additional features included strabismus in 11 patients, which always occurred in association with unilateral coronal synostosis; class I/II dental malocclusion in 7 patients; craniofacial features suggestive of Saethre-Chotzen syndrome (101400) in 19 patients, most commonly minor ear anomalies, low anterior hairline, and/or blepharoptosis; limb anomalies, such as transverse palmar creases, hallux valgus, syndactyly of 2 adjacent toes, and brachydactyly; and abnormal brain anatomy on CT scan, including prominent ventricles and/or CSF spaces in 7 patients and partial or complete agenesis of the corpus callosum in 2, as well as miscellaneous findings such as paraventricular cyst, pineal mass, and thinning of the optic chiasm. In 30 individuals, the brain scan was reported as normal. Significant developmental delay or learning disability was present in 10 patients, including 1 adult and 1 child with autism and 1 child with Asperger syndrome.
Population GeneticsFitzpatrick (2013) stated that craniosynostosis affects 1 in 2,200 individuals.
Molecular GeneticsBy exome sequencing of 347 DNA samples from unrelated individuals with craniosynostosis, Sharma et al. (2013) identified heterozygosity for 36 different mutations in the TCF12 gene (see, e.g., 600480.0001-600480.0007) in 38 families. The mutations occurred predominantly in patients with coronal synostosis, accounting for 32% and 10% of individuals with bilateral and unilateral pathology, respectively; 2 patients had bicoronal and sagittal synostosis, and 2 patients had only sagittal synostosis. No genotype-phenotype correlation was detected.