Antley-Bixler syndrome is a rare genetic disorder that can cause structural changes to the skull, bones of the face, and other skeletal abnormalities. It is a rare, distinct craniosynostosis syndrome, accompanied by ambiguous genitalia and impaired steroidogenesis. It is reported that this disorder is caused by mutations in the P450 oxidoreductase (POR; OMIM #124015) gene via autosomal recessive inheritance. The disorder is typically associated with premature closure of 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 low-set ears.
Additional skeletal abnormalities are usually present, such as fusion of certain 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 in the arms and legs may become permanently flexed or extended in fixed postures (joint contractures), resulting in restricted movements.
Antley-Bixler syndrome can be caused by changes (mutations) in the POR gene and the FGFR2 gene.
Symptoms
Antley-Bixler syndrome is typically characterized by structural changes in the skull, bones of the face, and other skeletal abnormalities. In most affected infants, there is premature closure of the joints (sutures) between different portions of the skull (craniosynostosis) 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 other distinctive skeletal changes. These may include the fusion of bones of the arms that are next to each other (adjacent), particularly the forearm bone on the thumb side of the arm (radius) and the long bone of the upper arm (radiohumeral synostosis). In addition, there can be permanent flexion or extension of certain joints in a fixed position (joint contractures), leading to limited movements of the fingers, wrists, ankles, knees, and/or hips. Affected individuals may also have unusually long, thin fingers and toes (camptodactyly), structural changes on the bottom 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 difficulty breathing. If this symptom is not treated promptly early in life, it may cause life-threatening respiratory problems.
Some individuals with Antley-Bixler syndrome may have additional symptoms. These may include certain structural defects of the urinary and genital organs (urogenital defects), inability to produce cholesterol from steroids (impaired steroidogenesis), developmental delay, and intellectual disability. ABS1 is the name given to the subtype that includes genital anomalies and disordered steroidogenesis. ABS1 is also a severe form of cytochrome P450 oxidoreductase deficiency. ABS2 is the name given to the subtype that does not include genital anomalies and disordered steroidogenesis.
Causes
Antley-Bixler syndrome can be caused by mutations in two different genes. ABS1 is associated with mutations in the POR gene and is inherited in an autosomal recessive pattern. This means that a person will have ABS1 when he or she inherits two non-working copies of the POR gene, one from each parent. If an individual receives one working copy of the gene and one not working copy of the gene, the person will be a carrier of the syndrome but will not show symptoms. When both parents are carriers of the syndrome, there is a 25 percent chance the child will have ABS1. Additionally, there is a fifty percent chance their child will be carriers of the condition (just like their parents) and a twenty-five percent chance that their child will receive both working copies of the gene. The risk is the same for each pregnancy.
ABS2 is associated with mutations in the FGFR2 gene. In this subtype, the condition is thought to be caused by spontaneous (new) changes in the gene. The condition then may be transmitted in an autosomal dominant pattern in subsequent generations. Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. The non-working gene can be inherited from either parent or can be the result of a mutated gene in the affected individual. The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.
It is important to note that several syndromes have been identified which 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.)
There have been a few reported cases that show that symptoms similar to Antley-Bixler syndrome may have resulted from maternal use of the antifungal medication (fluconazole) during early pregnancy. There is not a lot of research showing why this medication causes symptoms similar to Antley-Bixler syndrome.
Initially, medical exome sequencing was applied using the parents’ peripheral blood genome DNA. Next, bidirectional Sanger sequencing and quantitative real-time PCR (qRT-PCR) were conducted to confirm the sequencing results. The infant was diagnosed as ABS at birth, with typical midface hypoplasia, craniosynostosis, femoral bowing, radio-ulnar synostosis, and genital anomalies. Clinical features of ABS patients include midface hypoplasia, craniosynostosis, radio-ulnar synostosis, choanal atresia or stenosis, femoral bowing and fractures, joint contractures, and arachnodactyly (rx)
Diagnosis
The diagnosis of Antley-Bixler syndrome is usually made after birth (postnatally) based upon a thorough clinical evaluation and characteristic physical findings. Other imaging procedures and genetic testing may also be conducted to diagnose the disorder.
In some children, a diagnosis of Antley-Bixler syndrome may be suggested before birth (prenatally) based uonttestssuch as ultrasound. Ultrasound allows us to generate an image of the developing fetus, which may then reveal characteristic findings that are associated with the disorder. If there is a known family history of the condition, targeted genetic testing is available for patient families.
Treatment
The treatment of Antley-Bixler syndrome is directed toward the specific symptoms that are seen in each individual. Such treatment requires the coordinated efforts of a team of medical professionals who may need to systematically and comprehensively plan the treatment for a child with this condition. These professionals may include pediatricians, surgeons, and physicians who specialize in disorders of specific body areas and organs. In individuals with Antley-Bixler syndrome, treatment typically includes surgery. The surgical procedures performed will depend upon the severity of the skeletal problems and their associated symptoms. multiple surgeries may be needed to treat the malformations present.
There is no cure for the condition. All treatment is supportive and aimed at managing symptoms. However, 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. Other therapies that may aid in managing symptoms include occupational therapy and speech therapy.
Because this is a genetic condition, individuals with Antley-Bixler syndrome and their families would benefit from meeting with a genetic counselor. Genetic counselors are professionals who have specialized education in genetics and counseling to provide personalized help patients may need as they make decisions about their genetic health.
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