Antley-Bixler syndrome

Causes

What gene change causes Antley-Bixler syndrome?

There are two genetically distinct forms of Antley-Bixler syndrome (ABS). ABS with genital anomalies and disordered steroidogenesis is caused by changes (mutations) to the POR gene, which encodes instructions to make the enzyme cytochrome P450 oxidoreductase. This enzyme is important in the formation of steroid hormones, such as testosterone and estrogen. Changes to the POR gene decreases activity of the cytochrome P450 oxidoreductase leading to the disruption of steroid hormone production. Consequently, sexual development problems occur before birth and at puberty.

The enzyme cytochrome P450 oxidoreductase also plays a role in cholesterol production; which is also needed in the production of steroid hormones and in bone formation and growth. Disruptions in the POR gene can cause abnormal bone growth and fusion of bones.

The alternative form; ABS without genital anomalies and disordered steroidogenesis, is caused by changes to the FGFR2 gene, which provides instructions to make a protein called fibroblast growth factor receptor 2. This protein is involved in many biological processes, especially during embryonic development. For example, it plays a role in cell division, regulation of cell growth and maturation, and formation of blood vessels. It also contributes to bone growth by signalling cells in the developing embryo to become bones cells. Changes to the FGFR2 gene can cause increased signalling by FGFR2 protein, which causes premature closure of the bones in the skull.

Learn more about how the POR and FGFR2 gene works by visiting the Genetics Home Reference

References
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Why does Antley-Bixler syndrome cause craniosynostosis?

Why does Antley-Bixler syndrome cause ambiguous genitalia?

Does everyone with Antley-Bixler syndrome have a gene mutation?

Why does Antley-Bixler syndrome cause craniosynostosis?

One main symptom of Antley-Bixler syndrome (ABS) is craniosynostosis. Craniosynostosis is premature closure of skull bones causing problems with normal brain and skull growth. Depending on the form of ABS, the individual will have either reduced activity of the enzyme cytochrome P450 oxidoreductase or increased activity of FGFR2 protein signaling. The cytochrome P450 oxidoreductase enzyme is needed for the production of cholesterol. A shortage of cholesterol leads to abnormal fusion of bones, including skull bones. The FGFR2 protein signals immature cells in the developing embryo to become bone cells. Changes to the FGFR2 gene causes the FGFR2 protein to overactivate leading to premature fusion of bones in the skull.

References
Why does Antley-Bixler syndrome cause ambiguous genitalia?

Ambiguous genitalia is often associated with one form of Antley-Bixler syndrome. In females, ambiguous genitalia can present as enlarged clitoris and/or fused and underdevelopment labia. Males can present with a small penis and/or undescended testes. These symptoms in individuals with this condition are due to deficiencies in steroid hormone production, including testosterone and estrogen. These hormones are essential for normal sexual development and reproduction.

Get more detailed information about how changes in the POR gene cause symptoms by visiting the Genetics Home Reference or GeneReviews.

References
Does everyone with Antley-Bixler syndrome have a gene mutation?

Everyone with Antley-Bixler syndrome has a gene mutation in either the FGFR2 gene or the POR gene.

There have been 5 reported cases of ABS-like features due to early prenatal exposure to oral, high-dose fluconazole. However, only a few select symptoms were seen in these babies.

A genetic counselor can help you learn more. Genetic counselors can be found on the National Society of Genetic Counselors website.

References

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