What Is Saethre Chotzen Syndrome?

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Saethre Chotzen syndrome (SCS) is a genetic condition that affects the fusion of certain skull bones, changing the shape of the head and face. It is usually evident immediately upon birth due to physical changes that affect an infant’s appearance and may have other associated signs and consequences. SCS is also known as acrocephalosyndactyly type 3. It is caused by a mutation or deletion affecting the TWIST1 gene and is often inherited in an autosomal dominant fashion. SCS affects 1 in 25,000 to 50,000 people.

Saethre Chotzen Syndrome Symptoms

Often noted at birth due to the characteristic physical changes, Saethre Chotzen syndrome (SCS) is a genetic condition characterized by premature fusion of certain skull bones (called craniosynostosis), webbing of fingers or toes (called syndactyly), small or unusually shaped ears, and abnormalities of the vertebral bones in the spine.

The skull is usually fused along the coronal suture (a growth line that goes over the top of the head from ear to ear), and this prevents normal growth that affects the shape of the head and face.

The physical findings that characterize Saethre Chotzen syndrome are often the earliest signs of the condition, noted before specific symptoms develop. These signs may include:

  • Skull shape abnormality 
  • High forehead
  • Low frontal hairline
  • Facial asymmetry
  • Widely spaced eyes
  • Droopy eyelids (ptosis)
  • Crossed eyes (strabismus)
  • Tear (lacrimal) duct stenosis affecting tearing
  • Broad nasal bridge
  • Small, unusually shaped ears (prominent crus)
  • Hand or feet abnormalities

One of the classic signs of SCS affecting the hands is fusion of the skin between the second and third fingers. Other abnormalities may include a broad or duplicated big toe or permanent curving of the pinkie finger.

Most people diagnosed with SCS are of normal intelligence, but some children may experience developmental delay or other learning difficulties, especially if a larger section of the relevant chromosome is affected. This may contribute to an intellectual disability.

If the skull deformity is left untreated, it is possible than an elevation of the intracranial pressure may lead to headaches, loss of vision, seizures, and even death. Therefore, treatment can be very important to prevent long-term consequences.

Beyond what is noted above, there are other findings or associated conditions that may occur less often in SCS, such as:

  • Short stature
  • Vertebrae abnormalities
  • Hearing loss (conductive and/or sensorineural)
  • Heart defects
  • Cleft palate
  • Hypertelorism (wide-set eyes)
  • Bifid (divided) uvula
  • Maxillary hypoplasia (small or underdeveloped maxilla)
  • Obstructive sleep apnea

In general, the constellation of physical findings in a newborn may lead to a more careful evaluation, including a possible genetic test to identify the underlying potential cause of the noted abnormalities.

Causes

Most cases of Saethre Chotzen syndrome are caused by a mutation or deletion affecting the TWIST1 gene on chromosome 7p21. This change leads to a loss of function that impacts cell lineage determination and differentiation, inducing premature cranial suture fusion. How does this occur?

Normally, this gene provides instructions for making a protein called a transcription factor. This protein binds to specific regions of DNA and helps control particular genes that have an important role in early development. It is believed that the TWIST1 gene has an active role in cells that give rise to bones, muscles, and other tissues in the head and face. It also impacts limb development.

The genetic change is inherited in an autosomal dominant pattern. Therefore, if one copy of the gene is altered even though the other copy is normal, this is sufficient to cause the disorder. It may be inherited from an affected parent, or it may result from a new mutation (de novo). It is possible for someone to not have obvious features of the syndrome, and yet still possess an abnormal gene that may be passed on to their children.

There are small numbers of cases that suggest other deletions or rearrangements affecting chromosome 7 may also play a role. Overlapping pathways may be affected, including those that are critical for differentiation of osteoblasts (cells important for bone creation). Some of the other genes that may be affected and contribute to similar presentations include:

  • FGFR2
  • FGFR3
  • TCF12
  • RECQL4
  • EFNB1

It is believed that larger deletions affecting neighboring genes may also cause more severe presentations (called phenotypes), including more significant neurocognitive delays and intellectual disability. The loss of other nearby genes may play a role in this variation.

Finally, Robinow-Sorauf syndrome results from mutations in the same TWIST1 gene and may represent a mild variant of the condition.

Diagnosis

Unfortunately, the recognition and diagnosis of rare genetic diseases like Saethre Chotzen syndrome can be challenging. The pediatrician may be the first to recognize the presence of some of the classic clinical findings noted in the condition. Later, it may be necessary to meet with an expert in genetic disorders.

After taking a careful medical history to understand any predisposing factors and associated symptoms, and completing a physical examination, some laboratory testing may be performed. This may help to rule out other potential conditions.

The differential diagnosis for SCS includes other syndromes that may cause craniosynostosis, including:

To better understand the anatomy of the skull, spine, or limbs, diagnostic imaging including a CT scan or X-ray radiographs may be ordered.

To identify a TWIST1 mutation or deletion, molecular genetic testing may be ordered and this often involves a consultation with a geneticist. When a family history is present, prenatal testing is also possible.

As a rare disorder, the required level of medical care may necessitate seeing specialists at a university-based or tertiary medical center. Fortunately, these specialized providers may also be more experienced with complex cases and have access to cutting-edge research, new technology, and the latest treatment options.

Treatment

Ultimately, the treatment required for Saethre Chotzen syndrome may depend on the presence and severity of the abnormalities identified. Interventions may target specific symptoms or physical issues, and may range from a one-time surgery to ongoing therapy or monitoring.

Early in life, surgery is often needed to prevent or correct early closure of the cranial sutures. Cranioplasty in the first year helps to increase the intracranial volume, restoring a more normal head shape, and preventing increased intracranial pressures. Further surgical expansion procedures may be required if these pressures later increase.

Further procedures may correct craniofacial (skull-and-face) abnormalities, syndactyly affecting the hands, or other skeletal defects. This may involve help from a multidisciplinary team who will follow the affected person into young adulthood.

Sometimes midfacial surgery is required, especially in the context of airway obstruction (such as may exacerbate sleep apnea). If a cleft palate is present, this may require closure, and a speech therapy plan may be helpful.

Care from an orthodontist may address malocclusion, in which the teeth do not come together properly, affecting the bite.

Routine evaluations are needed to monitor facial growth. It is important to assess for hearing loss and provide support for any difficulties, including deafness. Evaluation by an ophthalmologist will identify eye problems related to strabismus, amblyopia, or chronic papilledema (due to increased intracranial pressure).

If there is a delay in psychomotor development, a specialized education plan and early intervention programs for children with a persistent intellectual disability may be warranted.

Fortunately, many children do well with these interventions.

Coping

It can be difficult to cope with a rare diagnosis that affects the appearance and potential development of a child. It may be helpful to network with other families who have had a child with similar issues. Fortunately, there are national groups that may provide additional educational materials, support, and resources. Within the United States, consider the following groups:

There are also additional resources available internationally, including About Face International in Toronto, Canada, and Headlines Craniofacial Support in the United Kingdom.

Prognosis

There is a silver lining to the diagnosis of Saethre Chotzen syndrome—for most people affected, the long-term prognosis is excellent. From an early age, specific treatments may be required and ongoing monitoring may be important to ensure normal development. 

Keep in mind that if a gene deletion is present rather than a point mutation—potentially affecting a larger part of the chromosome—the impacts may be more significant and contribute to the risk of intellectual disability.

SCS is a condition that has a normal life expectancy.

Each child of an individual affected by SCS has a 50% chance of inheriting the mutation and this may influence the decision to have children.

A Word From Verywell

Saethre Chotzen syndrome is a rare disorder that affects the appearance of the skull and face and may have other associated findings. If left untreated, it may have more significant impacts on health and well-being. It is important to work with a team of specialists, ensuring that timely interventions optimize the child’s growth and development. Consider participating in a national association to network with other parents and find the support needed to work through any challenges that may occur. 

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  2. Genetic and Rare Disease Information Center. Saethre-Chotzen syndrome. Updated May 1, 2020.

  3. Orphanet. Saethre-Chotzen. Updated 2020.