Crouzon syndrome is a rare genetic disorder that may be evident at birth (congenital) or during infancy. The disorder is characterized by distinctive malformations of the skull and facial (craniofacial) region. Such abnormalities may vary greatly in range and severity from case to case, including among affected family members. However, in most infants with Crouzon syndrome, the fibrous joints between certain bones of the skull (cranial sutures) close prematurely (craniosynostosis). In addition, facial abnormalities typically include unusual bulging or 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).
In some instances, Crouzon syndrome is inherited as an autosomal dominant trait. In other cases, affected individuals have no family history of the disease. In such instances, Crouzon syndrome is thought to result from new genetic changes (mutations) that occur randomly for unknown reasons (sporadically).
Crouzon syndrome, also known as craniofacial dysostosis, is primarily characterized by premature closure of the fibrous joints (cranial sutures) between certain bones in the skull (craniosynostosis) and distinctive facial abnormalities. Cranial and facial malformations may vary, ranging from mild to potentially severe, including among members of the same family (kindred).
For example, the degree of cranial malformation may be variable, depending on the specific cranial sutures involved as well as the order and rate of progression. In most affected individuals, there is premature fusion of the sutures (i.e., coronal and sagittal sutures) between bones forming the forehead (frontal bone) and the upper sides of the skull (parietal bones). In addition, the suture between the back and the sides of the skull (i.e., lambdoidal suture) or other sutures may be involved in some cases. In most individuals with Crouzon syndrome, early sutural fusion causes the head to appear unusually short and broad (brachycephaly). In other cases, the head may appear long and narrow (scaphocephaly) or triangular in shape (trigonocephaly). Rarely, premature closure of multiple sutures (known as Kleeblattschadel type craniosynostosis) causes the skull to be abnormally divided into three lobes (cloverleaf skull deformity). In those with Crouzon syndrome, craniosynostosis typically begins during the first year of life and progresses until approximately age two to three. However, craniosynostosis may sometimes be apparent at birth or, more rarely, may not be noted during childhood.
In most individuals with Crouzon syndrome, there is unusual shallowness of the orbits or the bony cavities of the skull that accommodate the eyeballs. As a result, the eyeballs appear to protrude or bulge forward (proptosis). Due to such abnormalities, affected individuals are unusually susceptible to developing inflammation of the front, transparent regions of the eyes (i.e., exposure keratitis) as well as the membranes that line the inner surfaces of the eyelids and cover the whites of the eyes (exposure conjunctivitis). Additional eye (ocular) abnormalities are often present, including widely spaced eyes (ocular hypertelorism) and deviation of one eye away from the other (divergent strabismus or exotropia). Less commonly, Crouzon syndrome may be associated with other ocular defects, such as degeneration of the nerves that transmit impulses from the retinas to the brain (optic atrophy); rapid, rhythmic, involuntary eye movements (nystagmus); clouding of the lenses of the eyes (cataracts); and/or partial absence of tissue from the colored regions of the eyes (iris coloboma). Approximately half of affected individuals have poor vision and about seven percent may be affected by blindness. The degree of visual impairment depends upon the severity and combination of eye abnormalities present.
Crouzon syndrome is also often associated with additional craniofacial abnormalities. Affected individuals often have a prominent forehead; a curved, “parrot-beaked” nose; unusually flat or underdeveloped midfacial regions (midface hypoplasia); and a short upper lip. In addition, many with the disorder have a small, underdeveloped upper jaw (hypoplastic maxilla), with protrusion of the lower jaw (relative mandibular prognathism). Clefting of the lip and/or palate (incomplete closure of the palate or an abnormal groove in the upper lip) occur rarely, but typical dental problems include a highly arched narrow palate with crowded teeth, and front teeth that don’t touch (anterior open bite).
Many individuals with Crouzon syndrome also have various dental abnormalities due to underdevelopment of the upper jaw (maxillary hypoplasia). These may include improper contact of the teeth of the upper jaw with those of the lower jaw (malocclusion) and crowding of the front teeth of the upper jaw.
Crouzon syndrome may also be associated with certain neurological abnormalities. For example, one study reported that approximately 30 percent of affected individuals frequently had headaches and about 12 percent experienced episodes of uncontrolled electrical activity in the brain (seizures). Mental retardation was present in approximately three percent. In addition, although rare, craniosynostosis may be associated with progressive hydrocephalus in some individuals with Crouzon syndrome. Hydrocephalus is characterized by impaired flow or absorption of the fluid (i.e., cerebrospinal fluid [CSF]) that circulates through cavities (ventricles) of the brain and the spinal canal, potentially leading to increasing fluid pressure within the skull (intracranial pressure) and the brain and other associated findings.
In some cases, Crouzon syndrome may be associated with additional physical abnormalities. For example, many affected individuals have hearing impairment due to improper conduction of sound from the outer or middle ear to the inner ear (conductive hearing loss), abnormalities of the nerves (i.e., acoustic nerves) that transmit sound impulses to the brain (sensorineural hearing loss), or both (mixed hearing loss). Some individuals with Crouzon syndrome also have abnormal deviation of the partition that separates the nostrils (deviated nasal septum) and/or unusual smallness of the air-filled cavities that open into the nose (paranasal sinuses). In some cases, obstruction of the nasal cavities and the upper region of the throat (nasopharyngeal obstruction) may cause respiratory difficulties during infancy. In addition, for some individuals, upper airway obstruction may result in the need to breathe through the mouth (“obligatory mouth breathing”).
According to several reports, Crouzon syndrome may also be associated with certain musculoskeletal abnormalities. These may include abnormal union or fusion of certain bones of the spinal column within the neck (cervical vertebrae [e.g., C2 and C3]); partial dislocation (subluxation) of the upper end (head) of the bone on the thumb side of the forearm (radius); and/or stiffness of the elbows.
In some affected individuals, Crouzon syndrome is inherited as an autosomal dominant trait with variable expression. 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. The risk is the same for each pregnancy.
Other individuals with Crouzon syndrome may have no family history of the disease. Such cases are thought to result from new genetic changes (mutations) that appear to occur randomly for unknown reasons (sporadically). According to reports in the medical literature, sporadic cases may be associated with increased age of the father (advanced paternal age of greater than 34 years).
In most cases, individuals with a mutated gene for Crouzon 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).
In some familial and sporadic cases, Crouzon syndrome has been shown to result from certain mutations in a gene known as fibroblast growth factor receptor-2 (FGFR2). The gene has been mapped to the long arm (q) of chromosome 10 (10q26). 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, “10q26″ refers to band 26 on the long arm of chromosome 10.
The FGFR2 gene regulates the production of a protein known as a fibroblast growth factor receptor (FGFR). 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. Evidence indicates that different mutations in the FGFR2 gene may cause a number of other related disorders, including some cases of Apert syndrome and Jackson-Weiss syndrome. In addition, according to some reports, 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 on these disorders, please see the “Related Disorders” section of this report below.)
Crouzon syndrome appears to affect males and females in relatively equal numbers. The disorder was originally described in 1912 (Crouzon O) in a mother and daughter.
Crouzon syndrome has been estimated to occur in approximately one in 25,000 live births. However, due to the variability of associated symptoms (variable expressivity), Crouzon syndrome may be underdiagnosed; therefore, it is difficult to determine the true frequency of the disorder in the general population.
Crouzon 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 abnormalities that may be associated with the disorder (e.g., craniosynostosis, 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. During MRI, a magnetic field and radio waves create detailed cross-sectional images of certain organs and tissues.
The treatment of Crouzon 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. These may include 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); hearing specialists; physicians who diagnose and treat neurological disorders (neurologists); eye specialists (ophthalmologists); and/or other health care professionals.
Specific therapies for Crouzon syndrome are symptomatic and supportive. Craniosynostosis and, in some cases, associated hydrocephalus may result in abnormally increased pressure within the skull (intracranial pressure) and on the brain. Therefore, early surgery may be advised to correct craniosynostosis and, for those with hydrocephalus, to insert a tube (shunt) to drain excess cerebrospinal fluid (CSF) away from the brain and into another part of the body where the CSF may be absorbed. Corrective and reconstructive surgery may also be performed to help correct certain craniofacial abnormalities and associated findings. In fact, many affected individuals undergo combined braces (orthodontic) and surgery (orthognatic) to reposition the upper jaw (maxilla) more forward and permit the teeth to fit together properly. In addition, in some cases in which obstruction of the upper airways causes respiratory difficulties, medical treatment or surgical intervention may be required. The specific surgical procedures performed will depend upon the severity and location of anatomical abnormalities, their associated symptoms, and other factors.
Early intervention may be important to ensure that children with Crouzon syndrome reach their potential. Special services that may be beneficial to affected children include special social support, speech therapy, and/or other medical, social, or vocational services.
Genetic counseling will be of benefit for affected individuals and their families. Diagnostic evaluations (including clinical examination and x-ray studies) are also important for family members of individuals with the disorder to detect any symptoms and physical characteristics that may be associated with Crouzon syndrome. Other treatment for this disorder is symptomatic and supportive.
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eMedicine – Crouzon Syndrome-Author: Harold Chen, MD, MS, FAAP, FACMG,
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