Saethre-Chotzen syndrome

Definition

Saethre-Chotzen syndrome is an inherited disorder that affects one in every 50,000 individuals. The syndrome is characterized by early and uneven fusion of the bones that make the skull (cranium). This affects the shape of the head and face, which may cause the two sides to appear unequal. The eyelids are droopy; the eyes widely spaced. The disorder is also associated with minor birth defects of the hands and feet. In addition, some individuals have mild mental retardation. Some individuals with Saethre-Chotzen syndrome may require some medical or surgical intervention.

Description

Saethre-Chotzen (say-thre chote-zen) syndrome belongs to a group of rare genetic disorders with craniosynostosis . Craniosynostosis means there is premature closure of the sutures (seams) between certain bones of the cranium. This causes the shape of the head to be tall, asymmetric, or otherwise altered in shape (acrocephaly). There is also webbing (syndactyly) of certain fingers and toes. Another name for Saethre-Chotzen syndrome is acrocephalosyndactyly type III. It is one of the more mild craniosynostosis syndromes.

The story of Saethre-Chotzen syndrome goes back to the early 1930s. It was then that a Norwegian psychiatrist, Haakon Saethre wrote about a mother and two daughters in the medical literature. Each had a low frontal hairline; long and uneven facial features; short fingers; and webbing of the second and third fingers, and second, third, and fourth toes. A year later in 1931, F. Chotzen, a German psychiatrist, reported a family with similar features. However, these individuals were also quite short and had additional features of mild mental retardation and hearing loss.

Genetic profile

Saethre-Chotzen is usually found in several generations of a family. It is an autosomal dominant disorder and can be inherited, and passed on, by men as well as women. Almost all genes come in pairs. One copy of each pair of genes is inherited from the father and the other copy of each pair of genes is inherited from the mother. Therefore, if a parent carries a gene mutation for Saethre-Chotzen, each of his or her children has a 50% chance of inheriting the gene mutation. Each child also has a 50% chance of inheriting the working copy of the gene, in which case they would not have Saethre-Chotzen syndrome.

The search for the gene for Saethre-Chotzen syndrome is an interesting story. The first clue as to the cause of the disorder came in 1986, with the identification of patients who had a chromosome deletion of the short arm of chromosome 7. Linkage studies in the early 1990s narrowed the region for this gene to a specific site, at 7p21. Then, in 1996, scientists at Johns Hopkins Children's Center began to study a gene called TWIST as the candidate gene for Saethre-Chotzen syndrome. The TWIST gene was suspected because of earlier studies that showed how this gene works in the mouse.

The mouse TWIST gene normally works in forming the skeleton and muscle of the head, face, hands, and feet. Mice lacking both copies of the gene die before birth. Many have severe birth defects, including failure of the neural tube to close. They have an abnormal head and limb defects. However, mice with just one non-working copy of the TWIST gene did not die. Closer examination of these mice showed that they had only minor hand, foot and skull defects. The features were similar to those seen in Saethre-Chotzen syndrome.

It was also known that the mouse TWIST gene was located on chromosome 12 in mice, a location that corresponds to the short arm of chromosome 7 in humans. With this evidence, the researchers went on to map and isolate the human TWIST gene on human chromosome 7. They showed that this gene was in the same location that was missing in some individuals with Saethre-Chotzen. The TWIST gene is a small gene, containing only two exons (coding regions). Upon searching for alterations (mutations) in the TWIST gene, they found five different types of mutations in affected individuals. Since none of these mutations were found in unaffected individuals, this was proof positive that the TWIST gene was the cause of Saethre-Chotzen syndrome.

Scientists have also used animal models and the fruit fly Drosophila, to study the function of the TWIST gene. They have found that it takes two TWIST protein molecules to combine together, in order to function as a transcription factor for DNA . The normal function of the TWIST protein is to bind to the DNA helix at specific places. By doing so, it works to regulate which genes are activated or "turned on". Most of the mutations identified in the TWIST gene so far seem to interfere with how the protein product binds to DNA. In effect, other genes that would normally be activated during development of the embryo may in fact not be turned on.

More recent studies suggest that the TWIST protein may induce the activation of genes in the fibroblast growth factor receptor (FGFR) pathway. Mutations in the FGFR family of genes cause other conditions with craniosynostosis such as Crouzon syndrome . Crouzon syndrome, like Saethre-Chotzen syndrome, is a mild craniosynostosis disorder. There is much overlap in the features of the face and hands in each condition. In fact, some patients initially thought to have Saethre-Chotzen were given a new diagnosis of Crouzon syndrome after studying both the TWIST and the FGFR genes for mutations.

In all, it is thought that the TWIST protein most likely acts to turn on the FGFR genes. These genes, in turn, instruct various cells of the head, face, and limb structures to grow and differentiate. If the TWIST gene or other genes of the FGFR pathway are altered, an individual will have one of the craniosynostosis syndromes.

Demographics

Saetre-Chotzen syndrome affects both males and females equally. It most likely occurs in every racial and ethnic group. Approximately one or two in every 50,000 individuals has Saetre-Chotzen syndrome, making it the most common of the craniosynostosis syndromes.

Signs and symptoms

The cranium is made up of three main sections. The three sections are the face, the base of the cranium, and the top and sides of the head. Most of the cranium assumes its permanent shape before birth. However, the bones that make up the top and side of the head are not fixed in place, and the seams between the bones (cranial sutures) remain open. This allows the top of the head to adjust in shape, as the unborn baby passes through the narrow birth canal during labor. After birth, the cranial sutures will close, most often within the first few years of life. The shape of the cranium is then complete.

In Saethre-Chotzen, the shape of the cranium is abnormally formed. The reason is that the coronal suture closes too early, sometimes even before birth. The coronal suture separates the two frontal bones (forehead) from the parietal bones (top of the head). If the early closure is unilateral or asymmetric, then the forehead and face will form unevenly, from one side to the other. This also forces the top of the head to become more pointed, almost tower-like. The forehead looks high and wide. The face will appear uneven on each side, especially in the area of the eyes and cheeks.

There is also less space for the normal features of the face to develop. For instance, the eye sockets are more shallow and the cheekbones are flat. This makes the eyes more prominent, and spaced further apart than normal. Adding to the unevenness of the face is drooping of the upper eyelids, and a slight down slant to the eyes. The nose may look beaked or bent slightly downward at the tip. In some individuals, the ears look small and low-set on the face.

The other main feature of the syndrome is minor abnormalities of the hands and feet. Webbing (syndactyly) commonly occurs between the second and third fingers and toes. The thumbs are short and flat. The fifth finger may be permanently curved or bent at the tip.

Each individual with Saetre-Chotzen is affected somewhat differently. The features are usually quite variable even within the same family. Most individuals are mildly affected. Their facial features may be somewhat flat and uneven, but not strikingly so. However, if more than one cranial suture closes too early (and this can happen in some individuals), there is more severe disfigurement to their face.

In addition to the physical characteristics, individuals with Saetre-Chotzen may have growth delays, leading to less than average adult height. Most individuals are of normal intelligence, although some may have mild to moderate mental retardation (IQ from 50-70). For the growth and mental delays, it becomes necessary to provide special assistance and anticipatory guidance.

Diagnosis

For many years, there was widespread discussion among physicians (geneticists) over whether a given patient would have either Saethre-Chotzen or Crouzon syndrome. There may even be confusion with other craniosynostosis syndromes or with isolated craniosynostosis. However, the availability of direct gene testing now allows for a more definitive diagnosis for these patients. Simply using a blood sample, a direct gene test for mutations in the TWIST gene can be done. If an individual also has mental retardation or other significant birth defects, it is suggested that they be screened more fully for deletions of the TWIST gene.

Treatment and management

Very often, the physical characteristics of Saethre-Chotzen are so mild that no surgical treatment is necessary. The facial appearance tends to improve as the child grows. However, sometimes surgery is needed to correct the early fusion of the cranial bones. A specialized craniofacial medical team, experienced with these types of patients, should do this surgery. Surgery may also be done to release the webbing of the fingers and toes.

Some of the more severely affected individuals with Saethre-Chotzen may experience problems with their vision. There may be less space in the eye socket due to the bone abnormalities of the face. This can lead to damage of the nerves of the eye and may require corrective surgery. The tear ducts of the eye can also be missing or abnormal. Re-constructive surgery is sometimes performed to correct the drooping of the eyelids or narrowing of the nasal passage.

Prognosis

Most individuals with Saethre-Chotzen syndrome appear to have a normal life span.

Resources

ORGANIZATIONS

Children's Craniofacial Association. PO Box 280297, Dallas, TX 75243-4522. (972) 994-9902 or (800) 535-3643. [email protected]. <http://www.ccakids.com>.

FACES: The National Craniofacial Association. PO Box 11082, Chattanooga, TN 37401. (423) 266-1632 or (800) 332-2373. [email protected]. <http://www.faces-cranio.org>.

Forward Face, Inc. 317 East 34th Street, Room 901, New York, NY 10016. (212) 684-5860, (800) 393-3223.

MUMS. National Parent to Parent Organization. 150 Custer Court, Green Bay, WI 54301-1243. (920)336-5333. <http://www.netnet.net/mums>.

WEBSITES

"Entry 101400: Seathre-Chotzen Syndrome." OMIM—OnlineMendelian Inheritance in Man.<http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=101400>.

Kevin M. Sweet, MS, CGC