Antley-Bixler Syndrome is a rare genetic disorder that is primarily characterized by distinctive malformations of the head and facial (craniofacial) area and additional skeletal abnormalities. For example, the disorder is typically associated with premature closure of the fibrous joints (cranial sutures) between particular bones of the skull (craniosynostosis). Many affected infants and children also may have a prominent forehead, underdeveloped midfacial regions (midfacial hypoplasia), protruding eyes (proptosis), and other craniofacial abnormalities. Additional skeletal malformations are usually present, such as 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, certain joints may become permanently flexed or extended in fixed postures (joint contractures), resulting in restricted movements.
Antley-Bixler Syndrome often appears to be inherited as an autosomal recessive trait. However, according to researchers, other cases may result from spontaneous (sporadic) genetic changes (mutations) that may be transmitted as an autosomal dominant trait.
Antley-Bixler Syndrome is typically characterized by distinctive malformations of the head and facial (craniofacial) area. In most affected infants, there is premature closure of the fibrous joints (sutures) between bones of the front, upper sides, and back portion of the skull (i.e., craniosynostosis involving the coronal and lambdoidal sutures). As a result, the head may appear abnormally short and broad (brachycephalic) and when viewed from above appears like a trapezoid. Additional craniofacial abnormalities may include a large, prominent forehead (frontal bossing, underdeveloped middle regions of the face (midfacial hypoplasia); a large nose with a low nasal bridge; protruding eyes (proptosis); and low-set, malformed (dysplastic) ears.
Antley-Bixler Syndrome is also characterized by additional, distinctive skeletal abnormalities. These may include fusion of adjacent bones of the arms, particularly the forearm bone on the thumb side of the arm (radius) and the long bone of the upper arm (radiohumeral synostosis). In some cases, the forearm bone on the “pinky” side of the arm (ulna) may also be affected. 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. Affected individuals may also have unusually long, thin fingers and toes (digits) with permanent flexion of one or more digits (camptodactyly), malformations of the feet (“rocker-bottom” feet); or bowing and/or fractures of the thigh bones.
In some affected infants, a bony or thin layer of tissue may block the passageway between the nose and throat (choanal stenosis or atresia), leading to difficulties breathing. In such cases, without prompt, appropriate treatment, potentially life-threatening complications may result. There are many affected individuals, however, who live relatively long longs.
Some individuals with Antley-Bixler Syndrome may have additional physical abnormalities. These may include certain malformations of the heart and/or the urinary and genital organs (urogenital defects).
The specific underlying cause of Antley-Bixler Syndrome remains unclear. In many cases, the disorder appears to be inherited as an autosomal recessive trait. However, in other affected individuals, Antley-Bixler Syndrome is thought to be caused by spontaneous (sporadic) mutations of a gene (known as FGFR2) that may be transmitted as an autosomal dominant trait in subsequent generations. 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 recessive disorders, the condition does not appear unless a person inherits the same defective gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk of transmitting the disease to the children of a couple, both of whom are carriers for a recessive disorder, is 25 percent. Fifty percent of their children risk being carriers of the disease but generally will not show symptoms of the disorder. Twenty-five percent of their children may receive both normal genes, one from each parent, and will be genetically normal (for that particular trait). The risk is the same for each pregnancy.
Parents of several individuals with Antley-Bixler Syndrome have been closely related by blood (consanguineous). In recessive disorders, if both parents carry the same gene for the same disease trait, there is an increased risk that their children may inherit the two genes necessary for development of the disease.
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.
As mentioned above, sporadic dominant mutations of the FGFR2 gene have been identified in some individuals with Antley-Bixler Syndrome. This gene regulates (encodes) the production of a protein known as a fibroblast growth factor receptor (FGFR). According to researchers, genetic mutations that disrupt the functioning of such proteins may result in certain abnormalities during embryonic development, such as malformations of the craniofacial area and the limbs. A number of syndromes have been identified that are associated with mutations of the FGFR2 gene including Apert, Crouzon, and Pfeiffer Syndromes. (For further information on these disorders, please see the “Related Disorders” section of this report below.)
The gene that encodes the fibroblast growth factor receptor-2 protein has been mapped to the long arm (q) of chromosome 10 (10q26). Chromosomes are found in the nucleus of all body (somatic) 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.
In a few individuals with symptoms characteristic of Antley-Bixler Syndrome, associated abnormalities have appeared to result from maternal use of the antifungal medication fluconazole during early pregnancy. The implications of these findings are unknown.
According to cases reported in the medical literature, Antley-Bixler Syndrome has appeared to affect females more often than males. Since the disorder was originally described in 1975, more than 20 cases have been discussed in the literature.
In some cases, a diagnosis of Antley-Bixler Syndrome may be suggested before birth (prenatally) based upon specialized tests such as ultrasound. During fetal ultrasonography, reflected sound waves are used to generate an image of the developing fetus. Ultrasound studies may reveal characteristic findings that may be associated with the disorder.
The diagnosis of Antley-Bixler Syndrome is usually made after birth (postnatally) based upon a thorough clinical evaluation and characteristic physical findings. Specialized testing, such as certain advanced imaging techniques, may also be conducted to detect certain findings that may be associated with the disorder.
The treatment of Antley-Bixler 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 who may need to systematically and comprehensively plan an affected child's treatment. These professionals may include pediatricians, physicians who specialize in disorders of the skeleton, joints, muscles, and related tissues (orthopedists), physicians who diagnose and treat heart abnormalities (cardiologists), physical therapists, and/or other health care professionals.
In individuals with Antley-Bixler Syndrome, treatment may include surgical repair of malformations. For example, in those with choanal atresia or stenosis, surgery or other appropriate methods may be required to decrease the airway obstruction or correct the malformation. Surgery may also be recommended to correct certain craniofacial, skeletal, cardiac, urogenital, or other abnormalities potentially associated with the disorder. The surgical procedures performed will depend upon the severity of the anatomical abnormalities, their associated symptoms, and other factors.
Early intervention may be important in ensuring that affected children reach their potential. For example, physical therapy is typically recommended to help improve the range of movement at certain joint contractures. Additional special services that may be beneficial include other medical, social, and/or vocational services.
Genetic counseling will also be of benefit for individuals with Antley-Bixler Syndrome and their families. Other treatment is symptomatic and supportive.
Research on birth defects and their causes is ongoing. The National Institutes of Health (NIH) is sponsoring the Human Genome Project which is aimed at mapping every gene in the human body and learning why they sometimes malfunction. It is hoped that this new knowledge will lead to prevention and treatment of birth defects in the future.
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Online Mendelian Inheritance in Man, OMIM (TM). John Hopkins University, Baltimore, MD. MIM Number 207410; 4/20/99. Available at: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?207410.
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Antley Bixler syndrome
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