Cytochrome P450 oxidoreductase deficiency

Cytochrome P450 oxidoreductase deficiency is a disorder of hormone production. This condition specifically affects steroid hormones, which are needed for normal development and reproduction. The hormonal changes associated with cytochrome P450 oxidoreductase deficiency can affect the development of the reproductive system, skeleton, and other parts of the body.

The signs and symptoms of cytochrome P450 oxidoreductase deficiency vary from mild to severe. In mild cases, the condition causes subtle hormonal abnormalities and few or no physical changes. These abnormalities can be so mild that an affected person is never diagnosed with the condition. People with moderate cases of P450 oxidoreductase deficiency may have external genitalia that do not look clearly male or female (ambiguous genitalia), and they may be unable to have biological children (infertile). These changes are caused by hormonal abnormalities before birth and at puberty. People with moderate P450 oxidoreductase deficiency usually do not have skeletal abnormalities.

Severe cases of cytochrome P450 oxidoreductase deficiency are often given the name Antley-Bixler syndrome. The signs and symptoms of this condition are present at birth or become apparent in early childhood. Both males and females with Antley-Bixler syndrome may have ambiguous genitalia or other genital abnormalities caused by hormonal changes before birth. Hormonal changes may also disrupt sexual development at puberty, leading to infertility. Antley-Bixler syndrome is also characterized by skeletal abnormalities, particularly involving bones of the head and face. These include premature fusion of the skull bones (craniosynostosis), a flattened mid-face, a prominent forehead, and low-set ears. Other skeletal abnormalities can include joint deformities (contractures) that limit movement, and radiohumeral synostosis, which is a bone abnormality that locks the elbows in a bent position. A blockage of the nasal passages (choanal atresia), intellectual disability, and delayed development are also associated with Antley-Bixler syndrome.

The prevalence of cytochrome P450 oxidoreductase deficiency is unknown. About 60 affected individuals have been reported worldwide.

Researchers suspect that mild cases of this disorder may be relatively common. Because the signs and symptoms can be difficult to detect, people with mild cytochrome P450 oxidoreductase deficiency may never come to medical attention.

Cytochrome P450 oxidoreductase deficiency is caused by mutations in the POR gene. This gene provides instructions for making the enzyme cytochrome P450 oxidoreductase, which plays a critical role in the formation of steroid hormones. This group of hormones includes testosterone and estrogen, which are essential for normal sexual development and reproduction; corticosteroids, which are involved in the body's response to stress; and aldosterone, which helps regulate the body's salt and water balance.

Mutations in the POR gene reduce the activity of cytochrome P450 oxidoreductase, which disrupts the production of steroid hormones. Changes in sex hormones such as testosterone and estrogen lead to problems with sexual development before birth and at puberty. It is less clear how impairment of cytochrome P450 oxidoreductase leads to skeletal abnormalities in people with Antley-Bixler syndrome. Studies suggest that these abnormalities may be related, at least in part, to the abnormal production of cholesterol. Cholesterol is a substance that is altered to produce steroid hormones. It is necessary for normal embryonic development and is involved in bone formation.

Although Antley-Bixler syndrome is often caused by mutations in the POR gene, the characteristic features of this disorder can also result from mutations in another gene, FGFR2. Some researchers use the name Antley-Bixler syndrome to describe this pattern of features regardless of the cause. However, others argue that the name should be reserved for severe cases of cytochrome P450 oxidoreductase deficiency caused by POR gene mutations.

Read more about the POR gene.

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.