Saethre-Chotzen syndrome

Saethre-Chotzen syndrome is a genetic condition characterized by the premature fusion of certain skull bones (craniosynostosis). This early fusion prevents the skull from growing normally and affects the shape and symmetry of the head and face. Other features may include webbing of certain fingers or toes (syndactyly), small or unusually shaped ears, short stature, and abnormalities of the bones in the spine (the vertebrae). The signs and symptoms of Saethre-Chotzen syndrome vary widely, even among affected individuals in the same family. Mutations (variants) in the TWIST1 gene cause most cases of Saethre-Chotzen syndrome. The condition is inherited in an autosomal dominant pattern. In some cases, an affected person inherits the mutation from one affected parent. Other cases may result from new mutations in the gene.^[1][2] Treatment is aimed at addressing the symptoms found in each individual and may require the coordinated efforts of a team of specialists. Surgery is often needed to prevent or correct early closure of the cranial sutures and correct certain craniofacial abnormalities, syndactyly and/or skeletal defects.^[2] 

Most cases of Saethre-Chotzen syndrome are caused by mutations (pathogenic variants) in the TWIST1 gene.^[1][2] The TWIST1 gene provides instructions for making a protein that plays an important role in early development. This protein is a transcription factor, which means that it attaches (binds) to specific regions of DNA and helps control the activity of particular genes. The TWIST1 protein is active in cells that give rise to bones, muscles, and other tissues in the head and face. It is also involved in the development of the limbs.^[1]

Mutations (variants) in the TWIST1 gene prevent one copy of the gene in each cell from making any functional protein. A shortage of the TWIST1 protein affects the development and maturation of cells in the skull, face, and limbs. These abnormalities underlie the signs and symptoms of Saethre-Chotzen syndrome, including the premature fusion of certain skull bones.^[1]

A small number of cases of Saethre-Chotzen syndrome have resulted from a structural chromosomal abnormality, such as a deletion or rearrangement of genetic material, in the region of chromosome 7 that contains the TWIST1 gene (7p21). When Saethre-Chotzen syndrome is caused by a chromosomal deletion instead of a mutation within the TWIST1 gene, affected children are much more likely to have intellectual disability, developmental delay, and learning difficulties.^[1][2][3]

At least one individual with Saethre-Chotzen syndrome has been described with a mutation (variant) in the FGFR2 gene.^[2][4]

Saethre-Chotzen syndrome is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder.^[1][3] In some cases, an affected person inherits the mutation from one affected parent. Other cases may result from new mutations in the gene. These cases occur in people with no history of the disorder in their family.^[1] 

Each child of an individual with Saethre-Chotzen syndrome has a 50% chance of inheriting the mutation.^[3]

Some people with a TWIST1 mutation (variant) do not have any of the obvious features of Saethre-Chotzen syndrome. These people are still at risk of passing on the gene mutation, and may have a child with craniosynostosis and the other typical signs and symptoms of the condition.^[1]

Individuals who are known to have mutations in the TWIST1 gene may benefit from discussing their risks of passing on the mutation to their offspring with a genetics professional.

To find a medical professional who specializes in genetics, you can ask your doctor for a referral or you can search for one yourself. Online directories are provided by the American College of Medical Genetics and the National Society of Genetic Counselors. If you need additional help, contact a GARD Information Specialist. You can also learn more about genetic consultations from Genetics Home Reference.