Saethre–Chotzen syndrome

Saethre–Chotzen syndrome (SCS), also known as acrocephalosyndactyly type III, is a rare congenital disorder associated with craniosynostosis (premature closure of one or more of the sutures between the bones of the skull). This affects the shape of the head and face, resulting in a cone-shaped head and an asymmetrical face. Individuals with SCS also have droopy eyelids (ptosis), widely spaced eyes (hypertelorism), and minor abnormalities of the hands and feet (syndactyly). Individuals with more severe cases of SCS may have mild to moderate mental retardation or learning disabilities. Depending on the level of severity, some individuals with SCS may require some form of medical or surgical intervention. Most individuals with SCS live fairly normal lives, regardless of whether medical treatment is needed or not. Saethre–Chotzen syndrome (SCS), also known as acrocephalosyndactyly type III, is a rare congenital disorder associated with craniosynostosis (premature closure of one or more of the sutures between the bones of the skull). This affects the shape of the head and face, resulting in a cone-shaped head and an asymmetrical face. Individuals with SCS also have droopy eyelids (ptosis), widely spaced eyes (hypertelorism), and minor abnormalities of the hands and feet (syndactyly). Individuals with more severe cases of SCS may have mild to moderate mental retardation or learning disabilities. Depending on the level of severity, some individuals with SCS may require some form of medical or surgical intervention. Most individuals with SCS live fairly normal lives, regardless of whether medical treatment is needed or not. SCS presents in a variable fashion. The majority of individuals with SCS are moderately affected, with uneven facial features and a relatively flat face due to underdeveloped eye sockets, cheekbones, and lower jaw. In addition to the physical abnormalities, people with SCS also experience growth delays, which results in a relatively short stature. Although, most individuals with SCS are of normal intelligence, some individuals may have mild to moderate mental delays. More severe cases of SCS, with more serious facial deformities, occurs when multiple cranial sutures close prematurely. The cranium consists of three main sections including the base of the cranium (occipital bone), the face (frontal bone), and the top (parietal bones) and sides (temporal bone) of the head. Most of the bones of the cranium are permanently set into place prior to birth. However, the temporal and parietal bones are separated by sutures, which remain open, allowing the head to slightly change in shape during childbirth. The cranial sutures eventually close within the first couple of years following birth, after the brain has finished growing. In individuals with SCS, the coronal suture separating the frontal bones from the parietal bones, closes prematurely (craniosynostosis), occasionally even before birth. If the coronal suture closes asymmetrically or unilaterally, then the face and forehead will form unevenly, from side-to-side. People with SCS have pointy, tower-like heads because their brain is growing faster than their skull, resulting in increased intracranial pressure (ICP) and causing the top of the head and/or forehead to bulge out to allow for brain growth. The face appears uneven, particularly in the areas of the eyes and cheeks, and the forehead appears wide and tall. Because of the abnormal forehead, there is less space for the normal facial features to develop. This results in shallow eye sockets and flat cheekbones. The shallow eye sockets make the eyes more prominent or bulging and cause the eyes to be more separated than normal (hypertelorism). The underdeveloped eye sockets, cheekbones, and lower jaw cause the face to appear flat. Furthermore, the minor downward slant of the eyes along with the drooping eyelids (ptosis) adds to the overall unevenness of the face. SCS is typically inherited as an autosomal dominant trait. However, on occasion, children with a microdeletion of 7p21 (chromosome containing the locus responsible for SCS) develop new abnormalities and typically show significant neurological abnormalities. An increased parental age may play a role in the development of new mutations and abnormalities. Linkage analysis and chromosomal rearrangement revealed the cause of SCS to be mutations in the TWIST gene (twist transcription factor gene) located on chromosome 7p21. The TWIST gene encodes a basic helix-loop-helix (b-HLH) transcription factor that controls head mesenchyme development as the cranial tube forms. More than 35 varying TWIST mutations involving the b-HLH domain of the protein have been identified in people with SCS. The mutations include missense, nonsense, and frameshift deletion/insertion mutations that either shorten or disrupt the b-HLH domain. Most individuals with SCS have a single large deletion in the region 7p21, which contains the region that codes for the TWIST gene. In searching for the gene responsible for SCS, scientists at Johns Hopkins Children’s Center began studying the TWIST gene because its effects on mice. The TWIST gene in mice, functions in the development of the muscle and skeleton of the face, head, hands, and feet. Mice that were lacking both copies of the TWIST gene were spontaneously aborted prior to birth, and had serious deformities including abnormal limb and head defects and failure of the neural tube to properly close. However, mice with a single copy of the non-working TWIST gene survived. Further examination revealed that these mice had only minor skull, hand, and foot defects similar to those seen in SCS. The mouse TWIST gene is located on chromosome 12 in mice, which corresponds to the short arm of chromosome 7 in humans. With this information, scientists began to isolate and map the human TWIST gene on the short arm of human chromosome 7. They revealed that the human TWIST gene was in the same region that was absent in people with SCS. While looking for different mutations in the human TWIST gene, five different types of mutations were discovered in individuals with SCS. Since none of these mutations were seen in normal individuals who didn't have SCS, this provided enough evidence to conclude that the TWIST gene was the causative agent of SCS1. Researchers also studied the TWIST gene in Drosophila (fruit fly) in order to determine its function. They discovered that in the presence of two TWIST protein molecules combined together, the TWIST gene functions as a DNA transcription factor, meaning it binds to the DNA double-helix at specific locations in order to control which genes are 'turned on' or activated. The majority of the identified mutations in the TWIST gene interfere with how the protein attaches to DNA, preventing the activation of other genes that would normally be turned on during fetal development. Prenatal diagnosis of Saethre-Chotzen Syndrome in high risk pregnancies is doable, but very uncommon and rarely performed. Furthermore, this is only possible if the mutation causing the disease has already been identified within the family genome. There are a few different techniques in which prenatal testing can be carried out. Prenatal testing is usually performed around 15–18 weeks, using amniocentesis to extract DNA from the fetus's cells. Prenatal testing can also be performed during weeks 10–12 using chorionic villus sampling (CVS) to extract DNA from the fetus. Recently, there has been an increased interest in utilizing ultrasound equipment in order to detect fetal skull abnormalities due to immature fusion of the cranial sutures.