Clinical Diagnosis

Cytochrome P450 oxidoreductase (POR) deficiency describes a group of allelic conditions characterized by disordered steroidogenesis. These conditions form a broad phenotypic spectrum ranging from apparently healthy infants identified with 21-hydroxylase deficiency on newborn screening or whose mothers were virilized during pregnancy to classic Antley-Bixler syndrome (ABS), which is characterized by the following severe congenital craniofacial and skeletal anomalies:

• Craniosynostosis
• Brachycephaly
• Severe midface hypoplasia
• Radiohumeral synostosis
• Multiple joint contractures

Individuals with ambiguous genitalia and/or milder skeletal anomalies appear to fall somewhere in between the mild and severe end of the POR deficiency spectrum.

Note: (1) Although craniosynostosis and elbow synostosis have often been considered minimal diagnostic criteria for ABS, some individuals diagnosed with ABS lack one of these two features [LeBard & Thiemann 1998, Lee et al 2001, Yamamoto et al 2001, Fukami et al 2005]. At least two of these individuals are now known to possess disease-causing mutations in POR [Adachi et al 2004b, Fukami et al 2005]. (2) The diagnosis of classic ABS is usually made in the newborn period; however, in some individuals (presumably those with milder skeletal and craniofacial features), the diagnosis is not made until childhood or adolescence.

Testing

Because POR is required for maximal enzymatic function at various steps within the cholesterol and steroid synthesis pathways, individuals with POR deficiency exhibit characteristic abnormalities in both sterol and steroid metabolism (see Figures 1, 2, and 3).

Figure

Figure 1. Steroid synthesis
Principal intermediates of steroidogenesis illustrating the location of multiple partial biochemical blocks at steps that rely on cytochrome p450 oxidoreductase. These partial blocks lead to increased serum pregnenolone, (more...)

Figure

Figure 2. Steroid anomalies and pregnancy
Partial blockages, which occur at each step catalyzed by cytochrome p450 (CYP) dependent enzymes, presumably explain the finding of low maternal serum uE3 during pregnancies with an affected fetus. Impaired (more...)

Figure

Figure 3. Cholesterol synthesis pathway (distal portion)
Evidence for a partial biochemical block in sterol synthesis at the level of 14- α-demethylase comes from the finding of significantly increased levels of lanosterol and dihydrolanosterol (more...)

Steroid abnormalities

• ACTH plasma concentration is normal or elevated at baseline; hyper-responsive to CRH stimulation.
• Cortisol serum concentration is often normal at baseline, but may not increase as expected following ACTH stimulation.
• Pregnenolone, progesterone, 17-OH pregnenolone, and 17-OH progesterone serum concentrations are often elevated at baseline and/or after ACTH stimulation.
• Dehyroepiandrosterone (DHEA) and androstenedione serum concentrations are normal or decreased before and/or after ACTH stimulation.
• Androgen serum concentration may be low and unresponsive to ACTH or hCG stimulation.

Urinary steroid anomalies detected by gas chromatography-mass spectrometry (GC-MS). Steroid abnormalities in individuals with POR deficiency are consistent with attenuated activity of 21-hydroxylase (encoded by CYP21A2), 17,20 lyase (encoded by CYP17), and 17-hydroxlyase (also encoded by CYP17) [Shackleton & Malunowicz 2003, Adachi et al 2004a, Cragun et al 2004, Shackleton et al 2004b], and are characterized by:

• Increased concentration of metabolites of pregnenolone (pregnenediol) and progesterone (pregnanediol)
• Significantly elevated ratio of metabolites associated with:
  • Deficiency of 17-hydroxylase (5 α-tetrahydrocorticosterone, tetrahydrocorticosterone, and 11 dehydrometabolites)
  • Deficiency of 21-hydroxylase (17 α-hydroxypregnanolone, pregnanetriol, and pregnanetriolone)

Note: The term "apparent pregnene hydroxylation deficiency (APHD)" refers to individuals with this unique urinary steroid profile [Shackleton & Malunowicz 2003]. Despite sharing common characteristics, steroid profiles vary somewhat among affected individuals, presumably because of differences in how the various POR mutations affect different enzymatic reactions [Pandey et al 2007, Huang et al 2008, Miller et al 2009].

Evidence of steroid anomalies during pregnancy. Low or undetectable maternal serum unconjugated estriol (uE3) and/or failure of urinary E3 excretion to increase have been noted during pregnancies in which fetuses have POR deficiency [Cragun et al 2004, Shackleton et al 2004a].

Newborn screening for congenital adrenal hyperplasia. In some cases newborn screening may be positive with moderately elevated serum 17-OH progesterone [Fukami et al 2005]. However, newborn screening does not appear to be sensitive enough to detect all cases of POR deficiency.

Cholesterol abnormalities. Subtle sterol abnormalities consistent with a partial block in cholesterol synthesis at the level of CYP51 may be present (Figure 3) [Kelley et al 2002, Cragun et al 2004, Fukami et al 2005]. CYP51 catalyzes the conversion of lanosterol into principal intermediates of the distal portion of the cholesterol biosynthesis pathway. Although serum concentrations of cholesterol are grossly normal in individuals with ABS [Fukami et al 2005], lanosterol and dihydrolanosterol accumulate when cells from affected individuals are grown in cholesterol-depleted medium. Sterol profiling of amniotic fluid in an affected pregnancy may reveal di- and trimethylated sterols, but this finding is not unique to ABS [Chevy et al, 2005].

Testing Strategy

Confirmation of the diagnosis in a proband requires a urinary steroid profile, followed by confirmation with molecular genetic testing.

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.

Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family. However, a diagnosis can also be made using steroid profiling on amniotic fluid. Although recognizable skeletal features of ABS may be seen on ultrasound examination, milder cases of POR deficiency are unlikely to be identified on ultrasound examination.

Genetically Related (Allelic) Disorders

No other phenotypes are known to be associated with POR deficiency.

Natural History

The natural history of cytochrome P450 oxidoreductase (POR) deficiency varies because it encompasses a wide phenotypic spectrum. However, steroid abnormalities, which occur in all individuals with POR deficiency, can be associated with a number of characteristics:

• Cortisol deficiency found in POR deficiency varies, ranging from clinically insignificant (detected only with a urinary steroid profile, which typically shows low cortisol metabolites only in relation to other urinary metabolites) to severe deficiency that could be life threatening without treatment.
• Ambiguous genitalia, a fairly common feature of POR deficiency, may consist of a small penis and undescended testes in males, and vaginal atresia, fused labia minora, hypoplastic labia majora, and/or large clitoris in females.
• Primary amenorrhea was the presenting feature in at least one woman with POR deficiency (milder phenotype) [Fluck et al 2004].
• Enlarged cystic ovaries are present in a number of females with POR deficiency [Fukami et al 2009].
• Poor masculinization during puberty has been reported in some males in the moderate-to-severe end of the spectrum [Fukami et al 2005].
• Signs of maternal virilization during pregnancy with an affected fetus, including hirsutism, enlargement of the nose and lips, deepening of the voice, and acne, have been reported in women during pregnancies in which fetuses were later found to have POR deficiency [Yamamoto et al 2001, Cragun et al 2004, Shackleton et al 2004a].

Individuals with POR deficiency may also have craniofacial and skeletal abnormalities, overlapping with and including those of classic ABS. Individuals with milder skeletal features similar to those in classic ABS probably have moderate POR deficiency. On the other hand, those with mild POR deficiency tend to have few if any notable physical characteristics.

Fertility may be a concern. Ovarian cysts have been present in at least five females with POR deficiency, two of whom required oophorectomy [Arlt et al 2004, Fluck et al 2004, Fukami et al 2005]. In addition, hypospermatogenesis was documented on testicular biopsy in a male with POR deficiency [Fukami et al 2005].

The natural history and characteristics of classic ABS are discussed first, followed by discussion of the moderate end of the POR deficiency spectrum.

Genotype-Phenotype Correlations

Although individuals with the same mutations (even siblings) can show phenotypic variations, some commonalities are observed among individuals with the same genotype.

The broad phenotypic spectrum of POR deficiency may be caused by the effect of various POR mutations on different enzymatic reactions [Pandey et al 2007, Huang et al 2008, Miller et al 2009]. For example, the ability to synthesize adequate amounts of cortisol seems to be negatively correlated with the percentage of residual 17-hydroxylase and 17,20 lyase enzyme activities and hence, genotype [Huang et al 2005]. This conclusion is supported by the finding of Fukami et al [2009] that individuals homozygous for the p.Arg457His mutation were less likely to experience adrenal crisis.

Other observations include:

• Homozygotes for p.Arg457His tend to have fewer severe skeletal abnormalities [Fukami et al 2009].
• Homozygotes for p.Ala284Pro tend to have overt skeletal anomalies.
• Alleles predicted or shown to severely decrease 17-hydroxylase and 17,20 lyase enzyme activities (including p.Ala284Pro) also tend to be associated with the presence of craniofacial and skeletal features [Fluck et al 2004, Huang et al 2005].

Nomenclature

Names used for ABS in the past:

• Multisynostotic osteodysgenesis (MO) with long-bone fractures, trapezoidocephaly-multiple synostosis syndrome
• Acrocephalosynankie

Peterson et al [1985] was the first to report a male with ambiguous genitalia and apparent combined partial 21-hydroxylase (P450c21) deficiency and partial 17-hydroxylase (P450c17) deficiency, and referred to this condition as “mixed oxidase disease”. This condition, also known as congenital adrenal hyperplasia due to apparent combined P450c17 and P450c21 deficiency, has been shown to be caused by POR deficiency.

Prevalence

The prevalence of ABS is unknown. More than 60 individuals have been reported since it was described by Antley & Bixler [1975]; however, both under-reporting and reporting of FGFR2-related craniosynostosis as ABS (see Differential Diagnosis) limit the usefulness of this number.

The prevalence of POR deficiency has yet to be determined. POR mutations are likely to be more common than is inferred by the low incidence of ABS. Since POR mutations were first reported in 2004 approximately 50 individuals with POR deficiency have been reported. However, because of the extreme phenotypic variability of this condition and its relatively recent discovery, it is likely that the condition is not commonly recognized among individuals with mild symptoms.

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with cytochrome P450 oxidoreductase (POR) deficiency, the following evaluations are recommended:

• Evaluations by appropriate specialists in otolaryngology, medical genetics, neurosurgery, endocrinology, and cardiology
• Assessment for airway problems in individuals with Antley-Bixler Syndrome (ABS)-like features
• Functional adrenal studies, regardless of the presence or absence of genital abnormalities
• Additional studies that may be indicated:
  • Cranial CT scan and/or MRI to determine the degree of craniosynostosis, choanal stenosis, and orbital depth
  • Radiographs to identify long-bone fractures and/or bowing, bony synostoses, and/or joint contractures
  • Echocardiogram if a heart defect is suspected
  • Abdominal ultrasound examination to identify internal sex organs and detect any renal anomalies

Treatment of Manifestations

Airway management is often a primary concern in individuals with ABS as a result of choanal atresia/stenosis, small chest, narrow trachea, and/or shortening of the larynx.

• Endotracheal intubation is often required in the first minutes after delivery.
• Nasal stints or tracheotomy may be required.
• Tracheostomy may be necessary until age three to five years when the pharyngeal encroachment can be corrected.

Cortisol deficiency

• Hydrocortisone replacement therapy is indicated if baseline serum cortisol concentrations are low.
• Stress-dose steroids should be provided post-operatively and during times of physiologic stress in individuals in whom cortisol response to ACTH stimulation is below normal [Fukami et al 2005].

Genital abnormalities

• Testosterone injections have been successful in some males with micropenis [Cragun et al 2004, Fukami et al 2005]. Testosterone replacement has been initiated in males in whom testosterone levels remained relatively low after onset of puberty [Hershkovitz et al 2008].
• Hypospadias and cryptorchidism may be corrected with surgery.
• When clitoromegaly is severe, surgical reduction and plastic reconstruction of the clitoris may be considered.
• Vaginal reconstruction may be performed in females with vaginal hypoplasia.

Craniosynostosis. Treatment for craniosynostosis is similar to that for other syndromes associated with premature fusion of cranial sutures. Although surgical correction can be performed at any age, it is generally believed that the earlier it is done, the better the cognitive outcome.

Hydrocephalus. If present, hydrocephalus may be treated by surgical placement of a ventriculoperitoneal shunt.

Joint contractures usually improve with age and with physical therapy.

Because recurrence of bony fusion developed within three months following resection of radiohumeral synostosis in one individual with ABS [DeLozier et al 1980], resection of elbow synostosis is usually avoided [Rumball et al 1999]. However, the authors are aware of at least one individual in whom surgery was successful in restoring a limited amount of elbow movement [personal observation].

Prevention of Primary Manifestations

Currently, no proven strategies to prevent the primary manifestations of POR deficiency have been described.

Prevention of Secondary Complications

Physical and occupational therapy can help individuals with joint contractures or elbow synostosis develop fine and gross motor skills.

Early intervention services may improve the outcome for individuals at risk for developmental delays and learning difficulties.

Supplementation with appropriate steroid hormones in individuals who are deficient has helped alleviate:

• Lack of or poor pubertal development in males and females
• Mild hypertension
• Sleepiness and fatigue

Treatment with estradiol appeared to successfully reduce the size of ovarian cysts in females with POR deficiency [Fukami et al 2009].

Surveillance

Because of the presence of developmental delays in many individuals with ABS, periodic formal developmental assessments may be indicated. However, interpretation of these studies may be complicated by the physical limitations of the disorder. Screening evaluations are likely to underestimate cognitive abilities. Therefore, evaluations should be done in centers with expertise and experience in developmental testing.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

While no studies demonstrate increased sensitivity to certain medications or agents in vivo, it is possible that certain substances taken during pregnancy contribute to phenotypic variations in POR deficiency. Deletion of Por in mice results in elevated retinoic acid and is lethal during embryonic development. Decreasing retinoic acid levels in these knockout mice during pregnancy increased the duration of embryonic survival. In a different mouse model in which Por was knocked out only at the time of limb formation, a diet high in cholesterol did appear to reduce the severity of limb defects slightly [Schmidt et al 2009]. Currently data are insufficient to support dietary alterations during high-risk pregnancies in humans.

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Other

POR plays an important role in the metabolism of medications by hepatic P450 enzymes. Initial studies using bacterially expressed POR mutations and two hepatic P450 enzymes suggest that mutations in POR may alter drug metabolism [Miller et al 2009]. In these studies different mutations resulted in different effects, ranging from no apparent activity to elevated activity of the hepatic P450 enzymes; these activities were not correlated with their activity in CYP17A1 assays. For example, the same mutation resulted in loss of POR function with CYP17A1 but a gain of function with the hepatic enzyme CYP1A2 [Miller et al 2009].

Mode of Inheritance

Cytochrome P450 oxidoreductase (POR) deficiency is inherited in an autosomal recessive manner.

Evidence for autosomal recessive inheritance of Antley-Bixler Syndrome (ABS) is based on a number of reports of children with ABS born to consanguineous parents [DeLozier et al 1980, Bradley et al 2003] and reports of recurrences [Cragun et al 2004]. Autosomal recessive inheritance has been confirmed with the discovery of deleterious mutations in POR [Adachi et al 2004a, Fluck et al 2004, Fukami et al 2005, Huang et al 2005].

Risk to Family Members

Parents of a proband

• The parents of an affected child are obligate heterozygotes and therefore carry one mutant allele.
• Heterozygotes (carriers) are typically asymptomatic.

Sibs of a proband

• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
• Heterozygotes (carriers) are asymptomatic.

Offspring of a proband. No reports describe reproduction in individuals with POR deficiency; thus, the prevalence of infertility among individuals with POR deficiency remains uncertain.

Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier.

Carrier Detection

Carrier testing for at-risk family members is possible once the disease-causing mutations have been identified in the family.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or at risk of being carriers.

DNA banking. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA (typically extracted from white blood cells) of affected individuals for possible future use. DNA banking is particularly relevant when the sensitivity of currently available testing is less than 100%.

Prenatal Testing

High-risk pregnancies

• Fetal ultrasound examination. Prenatal diagnosis of ABS by mid-trimester ultrasound examination is possible, particularly in pregnancies at 25% risk [LeHeup et al 1995, Cragun et al 2004]. Fixed flexion of the elbows is an important finding. Other supportive findings include bowing of the long bones, hypoplastic midface, depressed nasal bridge, brachycephaly, and rocker bottom feet.
• Maternal serum screening. Low or undetectable levels of maternal serum uE3 have been noted in some women carrying a fetus with POR deficiency with and without classic ABS. Although low maternal serum concentration of uE3 in the presence of other suggestive findings may provide additional evidence for the diagnosis of POR deficiency in an affected fetus, there are other causes of low or undetectable uE3 and it is unknown whether normal maternal serum concentration of uE3 can reliably rule out POR deficiency.
• Molecular genetic testing. If the disease-causing mutations have been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).
  
  Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Low-risk pregnancies. Maternal serum marker screening may be useful in detecting some fetuses with POR deficiency. Low or undetectable levels of maternal serum uE3 have been reported during pregnancy in two siblings with ABS [Cragun et al 2004] and during the second affected pregnancy of a woman who had previously given birth to a female infant with ambiguous genitalia and molecularly confirmed POR deficiency [Arlt et al 2004, Shackleton et al 2004a]. Although low estriol synthesis during pregnancy occurs in other disorders, it has been proposed that low maternal serum estriol concentration together with excessive maternal urinary excretion of epiallopregnanediol is diagnostic of POR deficiency in the prenatal period [Shackleton et al 2004a].

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutations have been identified.

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Acknowledgments

The authors would like to thank Dr. Cedric Shackleton, Dr. Richard Kelley, and Dr. Wiebke Arlt for providing information and inspiration for this project.

Revision History

• 18 August 2009 (me) Comprehensive update posted live
• 8 September 2005 (me) Review posted to live Web site
• 9 September 2004 (dlc) Original submission