NORD gratefully acknowledges Gareth Baynam, MBBS, PhD, Clinical Geneticist, King Edward Memorial Hospital, Australia and A/ Head, Western Australian Register of Developmental Anomalies, for assistance in the preparation of this report.
Saethre Chotzen syndrome (SCS) belongs to a group of rare genetic disorders known as “acrocephalosyndactyly” disorders. All of these are characterized by premature closure of the fibrous joints (cranial sutures) between certain bones of the skull (craniosynostosis), and/or webbing or fusion (syndactyly) of certain fingers or toes (digits).
In many infants with SCS, cranial sutures may fuse unevenly and this may contribute to the head and face appearing to be dissimilar from one side to the other (craniofacial asymmetry). Additional variations of the skull and facial (craniofacial) region may also be present, such as widely spaced eyes (ocular hypertelorism) with unusually shallow eye cavities (orbits); drooping of the upper eyelids (ptosis); and a state where the eyes do not point in the same direction (strabismus). Some affected individuals may also have a “beaked” nose; deviation of the partition that separates the nostrils (deviated nasal septum); small, low-set ears; and an underdeveloped upper jaw (hypoplastic maxilla). The disorder is also associated with variations of the hands and feet, such as partial fusion of soft tissues (cutaneous syndactyly) of certain fingers and toes (digits); unusually short digits (brachydactyly); and broad great toes. Intelligence is usually normal. SCS is inherited in an autosomal dominant manner.
SCS is primarily characterized by premature closure of the fibrous joints (cranial sutures) between certain bones in the skull (craniosynostosis), distinctive facial variations, and/or variations of the fingers and toes (digits). However, associated symptoms and findings may be extremely variable, including among affected members of the same family. For example, there have been reports in which some family members have had characteristic digital abnormalities alone, whereas others have been primarily affected by craniosynostosis.
When craniosynostosis is present, the degree of skull (cranial) malformation may be variable, depending on the specific cranial sutures involved and the order and rate of progression. In many affected infants and children, early closure of the coronal suture which is found between bones forming the forehead (frontal bone) and the upper sides of the skull causes the top of the head to appear pointed (acrocephaly) or the head to seem unusually short or broad (brachycephaly). In addition, the cranial sutures often fuse unevenly, causing the head and face to appear somewhat dissimilar from one side to the other (plagiocephaly and facial asymmetry). Cases have also been reported in which the head appears triangular in shape (trigonocephaly) or the forehead is unusually prominent due to premature closure of the suture of the frontal bone (i.e. frontal or metopic suture). In some instances, early closure of certain cranial sutures may lead to abnormally increased pressure within the skull (intracranial pressure).
Many individuals with SCS have additional craniofacial variations, resulting in a subtle, but distinctive, facial appearance. Such abnormalities may include a broad forehead with a low hairline; drooping of the upper eyelids (ptosis); a “beaked” nose, depressed nasal bridge, and deviated nasal septum; unusually broad, flat mid-facial regions (midface hypoplasia); and a small upper jaw (hypoplastic maxilla), with protrusion of the lower jaw (relative mandibular prognathism). Additional eye (ocular) abnormalities are also often present, such as widely spaced eyes (ocular hypertelorism); shallow eye cavities (orbits); strabismus; and/or abnormal narrowing of the tear ducts (lacrimal duct stenosis), potentially causing decreased tearing and an increased susceptibility to eye infections.
Other craniofacial variations may also be associated with the disorder. Many affected individuals have small, low-set, or differences in parts of the ear (e.g. prominent ear crura). In addition, mild hearing impairment is frequent. Abnormalities of the mouth (oral) region often include a highly arched roof of the mouth (palate) and dental defects, such as absence or malformation of certain teeth, the presence of extra (supernumerary) teeth, and/or improper contact of the teeth of the upper jaw with those of the lower jaw (malocclusion) may occur. In rare cases, there may be incomplete closure of the roof of the mouth (cleft palate).
SCS may also be characterized by variations of the fingers and toes (digits). Some affected individuals have partial webbing or fusion of the soft tissues (cutaneous syndactyly) of certain digits, particularly between the second and third fingers and second and third toes. However, less commonly, syndactyly extends from the second to the fourth fingers or involves other toes. Additional digital malformations may include unusually short fingers and toes (brachydactyly); abnormal bending or deviation (clinodactyly) of the fifth fingers (“pinkies”); “finger-like” thumbs; and/or broad, deviating great toes.
Additional physical abnormalities may also be associated with SCS. Some affected individuals have short stature. Less commonly, musculoskeletal abnormalities may also be present, such as union or fusion of certain bones of the spinal column within the neck (cervical vertebrae), abnormal fusion of the forearm bones (radioulnar synostosis), limited extension of the elbows or knees, short collarbones (clavicles), and/or hip deformities (coxa valga). Occasional additional findings may include failure of the testes to descend into the scrotum (cryptorchidism) in affected males; kidney (renal) abnormalities; and/or heart (cardiac) defects.
Most individuals with SCS have normal intelligence. However, mild to moderate intellectual disability is sometimes present.
For further information, please see the “Causes” section of this report below regarding the “TWIST1” gene.
In most individuals, SCS is caused by mutations in the TWIST1 gene. The TWIST1 gene has been mapped to the short arm (p) of chromosome 7 (7p21). Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females. Each chromosome has a short arm designated as “p” and a long arm identified by the letter “q.” Chromosomes are further subdivided into bands that are numbered. For example, “7p21” refers to band 21 on the short arm of chromosome 7.
Although learning differences may be noted in individuals with mutations in TWIST1, severe delay or intellectual disability is not typical. In contrast, individuals with a deletion (missing piece) of chromosome 7p21, that includes TWIST1 and other adjacent genes, usually show significant intellectual disability. In most cases, individuals with a SCS associated mutation will manifest some features of this condition (high penetrance). However, they type and severity of manifestations may vary greatly between individuals (variable expressivity).
The majority of individuals with an identified mutation have a fault in the TWIST gene, however at least one individual has been identified with a mutation in the FGFR2 gene.
SCS is an autosomal dominant condition. Dominant genetic disorders occur when only a single copy of an abnormal gene is sufficient to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% (1 in2) for each pregnancy. The risk is the same for males and females.
In some individuals, the disorder is due to a spontaneous (de novo) genetic mutation that occurs in the egg or sperm cell. In such situations, the disorder is not inherited from the parents.
SCS affects males and females in equal numbers. Due to its variability including that manifestations can be mild, SCS may often go unrecognized. Therefore, it is difficult to determine the true frequency of the disorder in the general population.
The diagnosis of SCS is primarily based on physical signs and symptoms. Molecular genetic testing for mutations in the TWIST1 gene can be identified in some, but not all, individuals.
The management of SCS is directed toward identifying potentially medically important manifestations in an individual and treating those manifestations. Such treatment may require the coordinated efforts of a team of medical professionals, such as pediatricians; surgeons; physicians who diagnose and treat disorders of the skeleton, joints, muscles, and related tissues (orthopedists); physicians who specialize in disorders of the ears, nose, and throat (otolaryngologists); physicians who diagnose and treat neurological disorders (neurologists); and/or other health care professionals.
Surgery may be advised in the first year of life to help prevent or correct early closure of cranial sutures, to prevent increased intracranial pressure, and to prevent progressive facial asymmetry. Corrective and reconstructive surgery may also be performed to help correct certain craniofacial malformations and associated findings, syndactyly, other skeletal defects, or other physical abnormalities potentially associated with the disorder. The surgical procedures performed will depend upon the severity and location of the anatomical abnormalities, their associated symptoms, and other factors.
Evaluation by an ophthalmologist for eye and vision abnormalities and audiologic evaluation for hearing loss is recommended. X-ray of the neck bones should be considered at around age 2 years. Other tests may be considered depending on an individual’s findings.
If intellectual disability is identified, early intervention may be important to ensure that children with SCS reach their potential. Special services that may be beneficial include special education and/or other medical, social, or vocational services.
Genetic counseling will be of benefit for affected individuals and their families. If mutation is not identified, an evaluation to assess for features of SCS should be considered for the relevant family members.
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