What are the other Names for this Condition? (Also known as/Symptoms)

• Antley-Bixler Syndrome with Disordered Steroidogenesis
• Combined Partial Deficiency of 17-Hydroxylase and 21-Hydroxylase
• POR Deficiency Disorder

What is Cytochrome P450 Oxidoreductase Deficiency Disorder? (Definition/Background Information)

• Cytochrome P450 Oxidoreductase Deficiency Disorder is a rare genetic disorder. It involves a deficiency in several steroid hormones of the body. The disorder is inherited in an autosomal recessive manner
• Mutations in the POR gene cause Cytochrome P450 Oxidoreductase Deficiency Disorder. The POR gene codes for cytochrome P450 oxidoreductase enzyme, which is involved in the synthesis of steroid hormones and cholesterol, as well as in the breakdown of retinoic acid. A mutation in the POR gene can cause an aberrant or inactive enzyme, leading to the spectrum of symptoms observed in affected individuals
• Another gene known as FGFR2 gene may also be involved in the disorder. Mutations in this gene can cause severe skeletal abnormalities. Individuals with both POR and FGFR2 gene mutations may be considered to have “Antley-Bixler Syndrome with Genital Anomalies and Disordered Steroidogenesis”
• The symptoms of Cytochrome P450 Oxidoreductase Deficiency Disorder can include abnormalities in the bones of the skull, fingers, toes, chest, arms and legs, a flattening of face, low-set ears, breathing difficulties, genital abnormalities, infertility, emotional sensitivity, reduced mental acuity, and developmental delays
• A diagnosis of Cytochrome P450 Oxidoreductase Deficiency Disorder can be accomplished either before or after birth. Prenatal diagnosis may involve checking the mother’s serum for certain hormones and genetic testing of fetal cells. After birth, a diagnosis of the condition can be made through physical examination, evaluation of family history of the condition, and through assessment of symptoms including various tests and imaging studies
• Some complications associated with Cytochrome P450 Oxidoreductase Deficiency Disorder can include respiratory distress, developmental delays, cognitive impairment, anxiety, decreased range of movement, and infection following some surgical procedures
• There is currently no treatment available to cure Cytochrome P450 Oxidoreductase Deficiency Disorder. The treatment options are only tailored to address the individual symptoms. Hormone injections and replacement, surgery, physiotherapy, special education, and occupational therapy, are some of the symptomatic treatment options for those with this deficiency disorder
• The prognosis of the disease is guarded for infants, since they can develop respiratory complications. However, the outcome is reported to improve once the infants are able to combat complications of the condition successfully. Many individuals with Cytochrome P450 Oxidoreductase Deficiency Disorder may experience developmental delays

Who gets Cytochrome P450 Oxidoreductase Deficiency Disorder? (Age and Sex Distribution)

• The exact prevalence of Cytochrome P450 Oxidoreductase Deficiency Disorder is not known. So far, only 65 cases have been recorded worldwide in the medical field
• However, researchers state that many cases may not be diagnosed, since individuals with mild symptoms generally do not seek medical attention
• It is known to occur in both male and female genders
• No racial or ethnic preference is observed

What are the Risk Factors for Cytochrome P450 Oxidoreductase Deficiency Disorder? (Predisposing Factors)

• Cytochrome P450 Oxidoreductase Deficiency Disorder is a genetic disorder, and hence, a family history of the condition is a major risk factor

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases ones chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Cytochrome P450 Oxidoreductase Deficiency Disorder? (Etiology)

Cytochrome P450 Oxidoreductase Deficiency Disorder is caused by mutation(s) in the POR gene. The disorder is inherited in an autosomal recessive manner.

• Under normal circumstances, the gene codes for the enzyme cytochrome P450 oxidoreductase. This enzyme is important in the secretion of steroid hormones such as the following:
  • Sex hormones, including estrogen and testosterone, which are crucial to normal sexual development and reproduction
  • Aldosterone, which is involved in balancing of salt and water in the body
  • Corticosteroids, which are key to a body’s response to stress
• The enzyme is also needed for the synthesis of cholesterol, which is required for the production of steroid hormones, as well as proper growth of bones
• Cytochrome P450 oxidoreductase enzyme is required for the breakdown of retinoic acid, which aids in the function of vitamin A for proper growth and development

When the POR gene is mutated, there occurs a deficiency or reduced activity of cytochrome P450 oxidoreductase, and consequently, several processes in the body are affected.

• When steroid hormone synthesis is aberrant, it can lead to abnormalities in sexual development during the fetal stages, as well as in puberty
• Corticosteroid insufficiency can lead to an inability to cope with stress
• Abnormally low cholesterol can lead to skeletal malformations
• Aldosterone deficiency may lead to sodium wasting, resulting in decreased sodium levels in the body
• Retinoic acid buildup can have abnormal impact on bone growth and development

Skeletal abnormalities, such as those observed in Cytochrome P450 Oxidoreductase Deficiency Disorder, can also be the result of mutation(s) in the FGFR2 gene.

Autosomal recessive: Autosomal recessive conditions are traits or disorders that occur when two copies of an abnormal gene have been inherited on a non-sex chromosome. If both parents have an autosomal recessive condition, there is a 100% likelihood of passing on the mutated genes to their children. If, however, only one mutant copy of the gene is inherited, the individual will be a carrier of the condition, but will not be present with any symptoms. Children, born to two carriers, have a 25% chance of being homozygous dominant (unaffected), a 50% chance of being heterozygous (carrier), and a 25% chance of being homozygous recessive (affected).

Note:

• The term Antley-Bixler syndrome may be used to collectively describe the conditions caused by mutations in FGFR2 as well as POR genes
• Alternatively, some scientists use the term “Antley-Bixler Syndrome with Genital Anomalies and Disordered Steroidogenesis” for disease caused by POR mutations, and Antley-Bixler syndrome for disease caused by FGFR2 gene mutations

What are the Signs and Symptoms of Cytochrome P450 Oxidoreductase Deficiency Disorder?

The signs and symptoms of Cytochrome P450 Oxidoreductase Deficiency Disorder may be mild, moderate, or severe, and it may vary from one individual to another. Some of the signs and symptoms reported for this deficiency disorder include:

• Sexual development: Individuals with moderate POR deficiency may have genitalia that are not clearly identifiable as either male or female

In females, the following may be seen:

• Improper development and ambiguity of genitals
• Amenorrhea or absence of menstruation; girls might fail to begin menstruation by 16 years of age
• Vaginal hypoplasia or incomplete development of vagina
• Clitoromegaly or abnormal enlargement of clitoris
• Polycystic ovary syndrome (PCOS) can lead to irregular menstrual cycle, weight gain, skin problems, and abnormal growth of body hair

In males, the following may be seen:

• Micropenis or small penis
• Cryptorchidism, when testes fail to descend into the scrotum
• Hypospadias or having the opening of the urethra on the underside of penis
• Infertility

Skeletal development: Skeletal abnormalities are observed in severe cases of POR deficiency and may include:

• Craniosynostosis or abnormal shape of skull due to fusion of skull bones
• Hydrocephalus or fluid accumulation in the brain (particularly in children) that can cause brain damage
• Choanal stenosis or narrowing of the passage on the back of nose
• Choanal atresia or blocked nasal passage due to a bony or skin growth
• Face that appears flat in the middle, prominent forehead, low set ears
• Joint deformities known as contractures, which can hinder movement
• Radiohumeral synostosis, or elbows staying in a bent position due to a bone deformity
• Arachnodactyly, or the presence of abnormally thin and long fingers that resemble a spider’s legs
• Bowed thigh bones
• Vertical talus or rocker bottom feet, where the feet resemble the base of a rocking chair

Growth and development related signs and symptoms:

• Reduced mental acuity and cognitive abilities
• Delay in reaching developmental milestones

Stress related:

• Anxiety, depression
• Weight loss
• Extreme emotional sensitivity
• Heart palpitations
• Dizziness and nausea

Respiratory abnormalities: Apart from choanal atresia and choanal stenosis, the following may be observed, causing respiratory distress.

• Narrow chest
• Narrow trachea, which may be with a shortening of vocal cords (larynx)

Additionally, the following signs and symptoms may be seen:

• Congenital heart defects
• Problems with the structure and/or function of the kidneys

During pregnancy: If a woman is carrying a fetus with a POR gene deficiency, she may experience mild symptoms of the condition. These generally disappear after childbirth. The symptoms may include:

• Abnormal growth of body hair
• Deep voice
• Skin conditions such as acne

Individuals with Cytochrome P450 Oxidoreductase Deficiency Disorder may not be able to metabolize certain medications resulting in significant side effects from the medications. A healthcare provider will determine the recommended medications that can be safely taken by the affected individuals.

How is Cytochrome P450 Oxidoreductase Deficiency Disorder Diagnosed?

A diagnosis of Cytochrome P450 Oxidoreductase Deficiency Disorder may be made either prenatally or after childbirth. The following diagnostic tools may be used: 

Prenatal diagnosis:

• Ultrasound examination of fetus to check for characteristic physical features of the disease, such as long, thin fingers, abnormal skull, and flat face, among other features
• Checking mother’s blood for levels of unbound estriol (uE3), low levels of which can indicate potential abnormalities with the fetus
• Genetic testing of fetal cells for mutation(s) in the POR or FGFR2 genes

After birth of the child:

• A physical examination
• An assessment of symptoms
• An evaluation of family medical history
• Urine test to check for steroid concentrations using gas chromatography-mass spectrometry (GC-MS) method
• Blood tests to check for levels of steroid hormones
• Imaging studies, such as MRI and CT scans, to check for skeletal abnormalities of the skull
• X-ray imaging for bone deformities and fractures
• Ultrasound imaging studies of the abdomen to check for extent of development of sexual organs, and for abnormalities in the kidneys
• Echocardiogram for heart defects
• Imaging and functional tests to identify extent of damage to the respiratory apparatus
• Tests for checking the function of adrenal glands, in response to stress
• Genetic testing in the following cases:
  • Expecting parents, who may be suspected carriers of the disorder
  • An individual who may have signs and symptoms suggesting a POR deficiency

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of Cytochrome P450 Oxidoreductase Deficiency Disorder?

Some potential complications of Cytochrome P450 Oxidoreductase Deficiency Disorder may include:

• Presence of ambiguous genitals
• Ovarian cysts in females
• Infertility
• Bone deformities in the head and other parts of the body
• Infection may occur in individuals who have a ventriculoperitoneal shunt for structural abnormality of the brain
• Breathing difficulties, owing to blocked nasal pathways
• Limited movement, owing to skeletal abnormalities
• Delayed development and intellectual insufficiency

How is Cytochrome P450 Oxidoreductase Deficiency Disorder Treated?

Treatment options for Cytochrome P450 Oxidoreductase Deficiency Disorder are tailored towards addressing individual symptoms. A team of healthcare specialists may be involved in caring for an affected individual. Some treatment options may include:

• For blocked nasal passage and respiratory distress, often at the time of birth:
  • Endotracheal intubation, which is the placement of a tube in the nose or mouth to ease breathing
  • Tracheotomy, or a surgical cut (incision) in the windpipe to ease breathing
  • The use of a nasal stent to open a narrow nasal pathway
• For hormone deficiency:
  • Oral hydrocortisone to replace cortisol deficiency
  • Stress-dose steroid when an individual is experiencing psychological stress
  • Testosterone injections for micropenis
  • Testosterone replacement therapy for those who have low hormone levels after puberty
  • Estradiol treatment for ovarian cysts
• For genital abnormalities:
  • Surgery to correct male genital abnormalities such as hypospadias and cryptorchidism
  • Reconstructive surgery for abnormalities in the vagina and clitoris
• For skeletal abnormalities:
  • For abnormalities in bones of the head, surgical correction at the earliest possible opportunity following birth of the child, to avoid cognitive impairment
  • Ventriculoperitoneal shunt, which is the surgical placement of a catheter to drain the fluid from the brain into the abdominal cavity
  • Physiotherapy to improve range of motion
• For congenital heart defects, appropriate treatment, as deemed necessary by the attending healthcare professional, based on diagnosis may be provided
• For renal insufficiency, a healthcare professional will decide on the kind and duration of treatment, depending on the type and severity of symptoms
• For learning difficulties and cognitive impairment:
  • Special education
  • Occupational therapy

Secondary complications can be managed through physical, occupational and steroid hormone therapies.

How can Cytochrome P450 Oxidoreductase Deficiency Disorder be Prevented?

• Currently, there are no specific methods or guidelines to prevent Cytochrome P450 Oxidoreductase Deficiency Disorder, since it is a genetic condition
• Genetic testing of the expecting parents (and related family members) and prenatal diagnosis (molecular testing of the fetus during pregnancy) may help in understanding the risks better during pregnancy
• If there is a family history of the condition, then genetic counseling will help assess risks, before planning for a child
• Active research is currently being performed to explore the possibilities for treatment and prevention of inherited and acquired genetic disorders such as Cytochrome P450 Oxidoreductase Deficiency Disorder
• Regular medical screening at periodic intervals with tests, and physical examinations are strongly recommended

What is the Prognosis of Cytochrome P450 Oxidoreductase Deficiency Disorder (Outcomes/Resolutions)

The prognosis of Cytochrome P450 Oxidoreductase Deficiency Disorder depends on the age of the affected individual and the severity of sign and symptoms.

• Generally, infants have a high risk of complications from respiratory distress, which can be fatal. The prognosis is guarded at this stage
• Successful management of respiratory complications can improve the prognosis
• Many individuals with the condition may experience developmental delays
• In general, individuals with mild signs and symptoms have better prognosis than those with severe signs and symptoms

Additional and Relevant Useful Information for Cytochrome P450 Oxidoreductase Deficiency Disorder:

Antley-Bixler syndrome is a very rare disorder resulting from the presence of abnormal genes in the human genome.

The following link will help you understand Antley-Bixler syndrome:

https://www.dovemed.com/diseases-conditions/antley-bixler-syndrome/