Last updated:
2/26/2025
Years published: 1997, 1998, 2002, 2003, 2025
NORD gratefully acknowledges Gioconda Alyea, MD (FMG), MS, National Organization for Rare Disorders, for assistance in the preparation of this report.
Summary
Setleis syndrome is a very rare genetic disorder characterized by a distinctive face that may be apparent at birth (congenital).1
Signs and symptoms include scar-like depressions on each side of the forehead, puffy, wrinkled skin around the eyes (periorbital area), eyebrows that go vertically upward, missing eyelashes on either eyelids or multiple rows of eyelashes in the upper eyelid and none in the lower eyelid. Additional facial features may include wrinkled facial skin, a bulbous nose, thick protruding lips and chin defects. Due to such facial abnormalities, infants with Setleis syndrome may have an aged and/or lion-like (leonine) appearance. Some children have mild psychomotor delays, even though their growth and development are normal. Other features in other organs of the body have been reported.2,3,4
Setleis syndrome is caused by changes (variants) in the TWIST2 gene, which regulates expression of genes for facial development. Inheritance is autosomal recessive. Researchers have identified other causes for Setleis syndrome1,4,5
A diagnosis may be suspected in someone who has the typical facial features and diagnosis is confirmed by genetic testing identifying variants in the TWIST2 gene or other possible causes.4
Treatment is directed to the specific symptoms that the person has and may include plastic surgery to correct some of the facial features.4
Introduction
Setleis syndrome is also known as focal facial dermal dysplasia type III. Focal facio-dermal dysplasias (FFDD) are a group of four conditions that mainly affect the skin on the face. Each type is identified by small, scar-like indentations that appear in specific areas. Types I–III cause depressions on both temples, resembling forceps marks at birth. Type IV leads to skin defects around the ears, similar to cutis aplasia (missing skin). These marks are present from birth and are key features used to help diagnose the condition.1,3
Setleis syndrome was first described in 1963 in Puerto Rico, and it has been found in people from other parts of the world.2 Very few cases have been reported in the medical literature.1
The signs and symptoms vary among affected people. Some individuals have only a few of these symptoms, while others may have more pronounced features. The severity of the condition can differ even among family members.
Setleis syndrome primarily affects facial development but can also involve the skin, eyes, and other parts of the body.
Distinctive facial features include bitemporal skin lesions that appear as scar-like depressions on both sides of the forehead and resemble forceps marks (forceps are medical tool that are used during the delivery of a baby) and loose, wrinkled, or puckered facial skin where the skin around the eyes and face may be soft and redundant, leading to an aged or lion-like (leonine) appearance. Other distinctive facial features may include:1,3,4,5,6,7
Although Setleis syndrome mainly affects the face, eyes and skin, some affected people may also have:5,6,7
People affected with Setleis syndrome usually have normal growth and intelligence, but some may have:4,6,7
People who carry only one copy of the genetic mutation (heterozygotes) may have milder symptoms, such as:
Very few people with Setleis syndrome have reported heart defects and genital anomalies.
Setleis syndrome is caused by changes (variants) in the TWIST2 gene or by copy number variants (duplications or triplications) in a specific region of the short arm (p) of chromosome 1, in a segment that goes from 1p36.22 to 36.21 (1p36.22p36.21). This results in extra copies of genetic material in this region which can cause additional symptoms.8 Copy number variation (CNV) refers to situations in which the number of copies of a specific segment of DNA varies among different people’s genomes.
Many people with Setleis syndrome do not have variants in the TWIST2 gene or any changes in the chromosome 1p36.8,9 It is thought that other, yet undefined genetic changes may also contribute to the syndrome, making it a genetically diverse condition.
People with duplication or triplication of the chromosomal region 1p36.22p36.21 have also been reported to have the characteristic symptoms of Setleis syndrome with additional neurological and developmental challenges (rarely seen in individuals with TWIST2 gene variants) that vary in severity. Triplication of this region is also associated with more severe problems compared to duplication.10
The TWIST2 gene codes for the TWIST2 protein that acts as a “switch” that turns certain genes on or off, depending on what the body needs. It is especially important for the development of skin, muscle (myoblasts) and bone-forming cells (osteoblasts) as it helps maintain stem cells (cells that can develop into different types of specialized cells) until they are ready to change into skin, muscle, or bone cells. The TWIST2 protein also interacts with other proteins to regulate different processes in cell growth and development.8,9,10
Because of these functions, the TWIST2 gene is critical in shaping facial structures, eyelids and limbs during early development.
In conditions like Setleis syndrome, a specific variant in the TWIST2 gene leads to abnormal skin and facial development, causing features like wrinkled skin, missing eyelashes and facial dimples.
In most people, Setleis syndrome is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits a disease-causing gene variant from each parent. If an individual receives one normal gene and one disease-causing gene variant, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the gene variant and have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.4,5
Many cases are sporadic, without other affected people in the family.1,4,8 Carriers (heterozygotes) with TWIST2 gene variants can sometimes have symptoms of the condition, even though the inheritance pattern is considered recessive. This is because certain types of TWIST2 variants can act as “dominant-negative” alleles, meaning that the altered TWIST2 protein can interfere with the normal protein’s function when present in just one copy, leading to noticeable symptoms in heterozygotes. This is particularly possible if the variant affects a critical area necessary for protein function, like the DNA-binding region in the TWIST2 gene.5,9
People who are related (consanguineous) have a higher chance of having a child with a recessive disorder, and some of the people reported to have Setleis syndrome had parents who were related by blood.
Setleis syndrome is very rare. As in 2023, less than 30 cases have been reported in medical literature. The syndrome was first described in 1963 in Puerto Rico, and it has been found in patients from other parts of the world.5,10
Doctors may suspect of Setleis syndrome in a child that has the distinctive facial appearance, like the scar-like depressions on both sides of the forehead, the aged “leonine” face or the other characteristic features such as the problems of the eyes.1,4
The diagnosis can be confirmed by genetic testing of TWIST2. However, as commented in the causes section, there are many affected people with typical FFDD3 features who do not have TWIST2 gene variants. A change in the chromosome 1p36 region can also confirm the diagnosis.
A small sample of the skin (skin biopsy) can be analyzed to identify the characteristic skin lesions that demonstrate loss of subcutaneous fat and almost complete continuity between the epidermis (the outer layer of the skin) and underlying skeletal muscle, in addition of areas of skin puckering.1,4
Treatment
There is no cure or specific treatment yet. Current treatment is directed toward the specific symptoms that the affected person has. Pursed lips and eye abnormalities may be surgically corrected, but there is limited experience with plastic surgery.4
Surgical options for extra eyelashes (distichiasis) include partial tarsal plate excision, wedge resection and palpebral conjunctival resection. Nonsurgical options include electrolysis, epilation and cryotherapy.13
Careful padding of the affected regions against pressure and trauma during anesthesia is recommended.12
People without cognitive issues are expected to have a normal life span. People with developmental delays may have other organ system involvement which may affect health and life span. It may be recommended to screen affected people to identify any health problems with regular clinical evaluations.4
Genetic counseling is recommended for affected people and their families.
Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
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Email: [email protected]
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https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact:
https://www.centerwatch.com/
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
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Learn more https://rarediseases.org/patient-assistance-programs/caregiver-respite/The information provided on this page is for informational purposes only. The National Organization for Rare Disorders (NORD) does not endorse the information presented. The content has been gathered in partnership with the MONDO Disease Ontology. Please consult with a healthcare professional for medical advice and treatment.
The Genetic and Rare Diseases Information Center (GARD) has information and resources for patients, caregivers, and families that may be helpful before and after diagnosis of this condition. GARD is a program of the National Center for Advancing Translational Sciences (NCATS), part of the National Institutes of Health (NIH).
View reportOrphanet has a summary about this condition that may include information on the diagnosis, care, and treatment as well as other resources. Some of the information and resources are available in languages other than English. The summary may include medical terms, so we encourage you to share and discuss this information with your doctor. Orphanet is the French National Institute for Health and Medical Research and the Health Programme of the European Union.
View reportOnline Mendelian Inheritance In Man (OMIM) has a summary of published research about this condition and includes references from the medical literature. The summary contains medical and scientific terms, so we encourage you to share and discuss this information with your doctor. OMIM is authored and edited at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine.
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