Information on the following diseases can be found in the Related Disorders section of this report:

• Pfeiffer Syndrome, Types I, II, and III
• Apert Syndrome
• Crouzon syndrome
• Apert-Crouzon Disease (Vogt Cephalodactyly)
• Jackson-Weiss Syndrome
• Antley-Bixler Syndrome
• Acrocephalopolysyndactyly (General)
• Associated Congenital Disorders (General)
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Saethre-Chotzen syndrome is primarily characterized by premature closure of the fibrous joints (cranial sutures) between certain bones in the skull (craniosynostosis), distinctive facial abnormalities, and/or malformations of the fingers and toes (digits). However, associated symptoms and findings may be extremely variable from case to case, including among affected members of the same family (kindred). 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 suture (i.e., coronal suture) 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 Saethre-Chotzen syndrome have additional craniofacial abnormalities, resulting in a 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 midfacial 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); deviation of one eye in relation to the other (strabismus); and/or abnormal narrowing of the tear ducts (lacrimal duct stenosis), potentially causing decreased tearing and an increased susceptibility to eye infections. In addition, in some rare cases, early closure of certain cranial sutures may lead to degeneration of the nerves that transmit impulses from the innermost, nerve-rich membranes of the eyes (retinas) to the brain (optic atrophy).

Other craniofacial malformations may also be associated with the disorder. Many affected individuals have small, low-set, or unusually shaped ears (i.e., 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). In rare cases, there may be incomplete closure of the roof of the mouth (cleft palate).

Saethre-Chotzen syndrome may also be characterized by distinctive malformations of the fingers and toes (digits). Many affected individuals have partial webbing or fusion of soft tissues (cutaneous syndactyly) of certain digits, particularly between the second and third fingers and second and third toes. However, in some instances, 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. Affected individuals may also have abnormal skin ridge patterns on the fingers and palms.

Additional physical abnormalities may also be associated with Saethre-Chotzen syndrome. Some affected individuals have short stature. 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). In some instances, 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 Saethre-Chotzen syndrome have normal intelligence. However, mild to moderate mental retardation is sometimes present.

According to reports in the medical literature, some individuals with the disorder may have significant learning difficulties in addition to the physical features classically associated with Saethre-Chotzen syndrome. (For further information, please see the "Causes" section of this report below regarding the "TWIST gene.")
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Saethre-Chotzen syndrome is usually inherited as an autosomal dominant trait. Human traits, including the classic genetic diseases, are the product of the interaction of two genes, one received from the father and one from the mother.

In dominant disorders, a single copy of the disease gene (received from either the mother or father) will be expressed "dominating" the other normal gene and resulting in the appearance of the disease. The risk of transmitting the disorder from affected parent to offspring is 50 percent for each pregnancy regardless of the sex of the resulting child.

In some cases, affected individuals may have no family history of the disease. In such instances, Saethre-Chotzen syndrome may result from new genetic changes (mutations) that occur randomly for unknown reasons (sporadically).

In most individuals, Saethre-Chotzen syndrome appears to be caused by deletions, insertions, or other changes (mutations) within a gene known as the "TWIST transcription factor gene." The TWIST 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.

As mentioned above, some individuals with Saethre-Chotzen syndrome may have learning difficulties in addition to the physical findings classically associated with the disorder. Evidence suggests that such individuals may have relatively large deletions in chromosome 7p21.1 that include the TWIST gene as well as additional adjacent genes, contributing to developmental delays.

Some cases of Saethre-Chotzen syndrome have also been reported in which affected individuals have mutations of a gene known as fibroblast growth factor receptor-3 (FGFR3). The FGFR3 gene has been mapped to the short arm (p) of chromosome 4 (4p16.3). In addition, in at least one individual, the disorder appeared to result from mutation of another gene, called fibroblast growth factor receptor-2 (FGFR2). The FGFR2 gene is located on the long arm (q) of chromosome 10 (10q26). The FGFR genes regulate production of proteins known as fibroblast growth factor receptors. Genetic mutations that disrupt the functioning of such proteins may result in abnormalities of bone growth and development, ultimately leading to certain malformations of the craniofacial area and the hands and feet. Evidence also suggests that the TWIST gene plays some role in affecting craniofacial and limb development.

In most cases, individuals with a mutated gene for Saethre-Chotzen syndrome will manifest symptoms and findings associated with the disorder (high penetrance). However, such characteristics may vary greatly in range and severity from case to case (variable expressivity).
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Saethre-Chotzen syndrome affects males and females in relatively equal numbers. Since the disorder was originally described in the medical literature in the early 1930s (Saethre H and Chotzen F), it has been observed in many members of several multigenerational families (kindreds).

Due to the variability of associated symptoms, Saethre-Chotzen syndrome may often go unrecognized. Therefore, it is difficult to determine the true frequency of the disorder in the general population.
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Symptoms of the following disorders may be similar to those of Saethre-Chotzen syndrome. Comparisons may be useful for a differential diagnosis:

Pfeiffer syndrome is a rare genetic disorder that is characterized by craniofacial abnormalities and distinctive malformations of the fingers and toes (digits). Also known as acrocephalosyndactyly type V, Pfeiffer syndrome is generally accepted to be the same disease entity as Noack syndrome (acrocephalopolysyndactyly type I). Researchers have categorized three major subtypes of Pfeiffer syndrome: i.e., Pfeiffer syndrome types I, II, and III. Findings that may be associated with all subtypes include premature closure of the fibrous joints (cranial sutures) between particular bones of the skull (craniosynostosis); unusually broad, deviating thumbs and great toes; and webbing or fusion (syndactyly) of certain fingers and toes. Pfeiffer syndrome may result from new (sporadic) genetic changes (mutations) or be inherited as an autosomal dominant trait. Evidence suggests that the disorder may be caused by specific mutations in the fibroblast growth factor receptor-2 (FGFR2) gene or another gene known as fibroblast growth factor receptor-1 (FGFR1). It remains unclear whether there is a specific relationship between mutation of a particular disease gene responsible for Pfeiffer syndrome and the subtype of the disorder that results.

In the classic form of Pfeiffer syndrome (type I), craniosynostosis causes the head to appear short and unusually pointed at the top (turribrachycephaly). Additional craniofacial malformations often include a high, full forehead; unusually flat, underdeveloped midfacial regions (midface hypoplasia); widely spaced eyes (ocular hypertelorism); a small upper jaw (hypoplastic maxilla); a prominent lower jaw; and dental abnormalities. Intelligence is typically normal. Pfeiffer syndrome type I may result from spontaneous genetic mutations or be inherited as an autosomal dominant trait.

In Pfeiffer syndrome type II, early closure of multiple cranial sutures (Kleeblattschadel type craniosynostosis) causes the skull to be abnormally divided into three lobes (cloverleaf skull deformity). Additional physical malformations may include severe bulging or protrusion of the eyes (proptosis); abnormal fixation and restricted movement of the elbow joints; malformations of internal organs in the abdominal area (visceral anomalies); and progressive hydrocephalus. The latter is a condition characterized by impaired flow or absorption of the fluid that circulates through cavities (ventricles) of the brain and the spinal canal (cerebrospinal fluid [CSF]), potentially leading to increasing fluid pressure in the brain and other associated findings. Infants with Pfeiffer syndrome type II often experience impaired mental development and neurological problems due to severe involvement of the brain. Pfeiffer syndrome type II appears to be due to new genetic mutations that occur spontaneously. Certain mutations in the fibroblast growth factor receptor-2 (FGFR2) gene have been implicated in some cases of Pfeiffer syndrome type II. In some families, mutations in the fibroblast growth factor receptor-3 (FGFR3) gene have been implicated.

Individuals with Pfeiffer syndrome type III have symptoms and findings similar to those seen in type II, with the exception of the cloverleaf skull deformity. Additional abnormalities may include a shortened base of the skull; severe protrusion of the eyes (proptosis) due to abnormal shallowness of the eye cavities; and/or various malformations of internal organs in the abdominal area (visceral anomalies). As seen with type II, infants with type III often experience impaired mental development and neurological problems due to severe involvement of the brain. Pfeiffer syndrome type III is thought to be caused by new (sporadic) genetic mutations. (For further information on Pfeiffer syndrome types I, II, or III, choose "Pfeiffer" as your search term in the Rare Disease Database.)

Apert syndrome (acrocephalosyndactyly type I) is a rare genetic disorder that is apparent at birth (congenital). The disorder is characterized by distinctive craniofacial malformations and abnormalities of the hands and feet. In some cases, mental retardation may also be present. In infants with Apert syndrome, early closure of certain cranial sutures (craniosynostosis) causes the head to appear pointed at the top (acrocephaly). Affected infants also have characteristic facial abnormalities, such as widely spaced eyes (ocular hypertelorism), protrusion of the eyes (proptosis), underdevelopment of midfacial regions (midface hypoplasia), and a narrow roof of the mouth (palate). Malformations of the hands and feet may include abnormally broad thumbs and great toes, short fingers (brachydactyly), and/or partial to complete fusion (syndactyly) of certain fingers and toes (digits). Most commonly, there is complete fusion of bones within the second to the fourth fingers and the presence of a single common nail ("mitten-like" syndactyly). Apert syndrome usually results from sporadic genetic mutations. In other cases, the disorder is inherited as an autosomal dominant trait. Sporadic and familial cases may result from certain mutations of the fibroblast growth factor receptor-2 (FGFR2) gene. (For further information, choose "Apert" as your search term in the Rare Disease Database.)

Crouzon syndrome, also known as craniofacial dysostosis, is a rare genetic disorder that may be evident at birth or during infancy. Although associated symptoms may be extremely variable, the disorder is typically characterized by early closure of the fibrous joints between certain bones of the skull (craniosynostosis) and distinctive facial abnormalities. These may include protrusion of the eyeballs (proptosis) due to shallow eye cavities (orbits); outward deviation of one of the eyes (divergent strabismus or exotropia); widely spaced eyes (ocular hypertelorism); and a small, underdeveloped upper jaw (hypoplastic maxilla), with protrusion of the lower jaw (relative mandibular prognathism). Crouzon syndrome may be inherited as an autosomal dominant trait or result from new genetic mutations that appear to occur randomly for unknown reasons. In some familial and sporadic cases, Crouzon syndrome has been shown to result from specific mutations in the FGFR2 gene. Reports indicate that certain FGFR2 mutations may result in Crouzon syndrome in some families (kindreds), whereas the same mutations cause Pfeiffer syndrome in other kindreds. The implications of such findings are not completely understood. (For further information, choose "Crouzon" as your search term in the Rare Disease Database.)

Apert-Crouzon disease (acrocephalosyndactyly type II) is also known as Vogt cephalodactyly. This rare genetic disorder is characterized by a combination of the hand and foot malformations seen in Apert syndrome and the facial abnormalities present in Crouzon syndrome. Such facial characteristics are thought to result from severe underdevelopment of the upper jaw bone (hypoplastic maxilla). In individuals with Apert-Crouzon disease, webbing or fusion (syndactyly) of the digits may not be as severe as that seen in Apert syndrome. Apert-Crouzon disease may also be characterized by mental retardation. The disorder appears to result from new genetic mutations.

Jackson-Weiss syndrome is a rare genetic disorder characterized by craniosynostosis; unusually flat, underdeveloped midfacial regions (midface hypoplasia); broad, deviating great toes; and webbing or fusion of the second and third toes. Additional craniofacial abnormalities may include widely spaced eyes (ocular hypertelorism); drooping of the upper eyelids (ptosis); deviation of one eye in relation to the other (strabismus); a flat nasal bridge; an underdeveloped upper jawbone (maxillary hypoplasia); and/or malformed ears. Although most affected individuals have average or above average intelligence, varying levels of mental retardation have been reported in a few cases. The range and severity of symptoms and findings may vary greatly from case to case, including in members of the same family. Jackson-Weiss syndrome may result from sporadic genetic mutations or be inherited as an autosomal dominant trait. According to reports in the literature, certain mutations of the FGFR2 gene may cause Jackson-Weiss syndrome in some sporadic and familial cases. (For more information on this disorder, choose "Jackson Weiss" as your search term in the Rare Disease Database.)

Antley-Bixler syndrome is a rare genetic disorder that is characterized by distinctive craniofacial malformations and additional skeletal abnormalities. Affected individuals may have craniosynostosis; a prominent forehead; underdeveloped midfacial regions; protruding eyes (proptosis); low-set, malformed ears; and other craniofacial abnormalities. Skeletal malformations may include fusion of certain adjacent bones of the arms (e.g., radiohumeral or radioulnar synostosis); long, thin fingers and toes (arachnodactyly); and bowing of the thigh bones. In addition, due to permanent flexion or extension of certain joints in fixed postures (joint contractures), there may be limited movements of the fingers, wrists, ankles, knees, and/or hips. Antley-Bixler syndrome often appears to be inherited as an autosomal recessive trait. However, in other cases, the disorder is thought to result from spontaneous mutations of the FGFR2 gene. (For further information, choose " Antley Bixler" as your search term in the Rare Disease Database.)

The acrocephalopolysyndactyly (ACPS) disorders are a group of rare genetic disorders including Noack syndrome (type I), which is generally accepted to be the same condition as Pfeiffer syndrome; Carpenter syndrome (type II); Sakati syndrome (type III); and Goodman syndrome (type IV). All are characterized by craniosynostosis causing the top of the head to appear pointed (acrocephaly); extra fingers or toes (polydactyly); and/or webbing or fusion (syndactyly) of certain digits. (For further information on these disorders, choose "Pfeiffer," "Carpenter," "Sakati," "Goodman," or "acrocephalopolysyndactyly" as your search term in the Rare Disease Database.)

Other congenital disorders may be characterized by various forms of craniosynostosis, additional craniofacial malformations, syndactyly, broad great toes, and/or other symptoms and findings similar to those potentially associated with Saethre-Chotzen syndrome. (For more information on these disorders, choose the exact disease name in question as your search term in the Rare Disease Database.)
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Diagnosis
Saethre-Chotzen syndrome is usually diagnosed at birth or during infancy based upon a thorough clinical evaluation, identification of characteristic physical findings, and a variety of specialized tests. Such testing may include advanced imaging techniques, such as computerized tomography (CT) scanning or magnetic resonance imaging (MRI), or other studies to help detect or characterize certain malformations that may be associated with the disorder (e.g., craniosynostosis, syndactyly, other skeletal abnormalities, etc.). During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of internal structures. MRI uses a magnetic field and radio waves to create detailed cross-sectional images of certain organs and tissues.

Treatment
The treatment of Saethre-Chotzen syndrome is directed toward the specific symptoms that are apparent in each individual. 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.

Specific therapies for individuals with Saethre-Chotzen syndrome are symptomatic and supportive. Because craniosynostosis may sometimes result in abnormally increased pressure within the skull (intracranial pressure) and on the brain, early surgery may be advised to help prevent or correct early closure of cranial sutures. 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.

Early intervention may be important to ensure that children with Saethre-Chotzen syndrome 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. Diagnostic evaluations are also important for family members of individuals with the disorder to detect any findings that may be associated with Saethre-Chotzen syndrome. Other treatment for the disorder is symptomatic and supportive.
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