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Cytochrome P450 Oxidoreductase Deficiency

Synonym: POR Deficiency. Includes: Antley-Bixler Syndrome, Congenital Adrenal Hyperplasia due to Apparent Combined P450c17 and P450c21 Deficiency

, MS, CGC and , MD.

Author Information
, MS, CGC
University of Tampa
Tampa, Florida
, MD
Clinical Geneticist, Children's Hospital Medical Center and
University of Cincinnati College of Medicine
Cincinnati, Ohio

Initial Posting: ; Last Update: August 18, 2009.

Summary

Disease characteristics. Cytochrome P450 oxidoreductase (POR) deficiency is a disorder of steroidogenesis with a phenotypic spectrum ranging from cortisol deficiency at the milder end to classic Antley-Bixler syndrome (ABS) at the severe end. Cortisol deficiency can range from clinically insignificant to life threatening; manifestations can include ambiguous genitalia in both males and females; primary amenorrhea and enlarged cystic ovaries in females; poor masculinization during puberty in males; and maternal virilization during pregnancy with an affected fetus. Manifestations of ABS include craniosynostosis; hydrocephalus; distinctive facies; choanal stenosis or atresia; low-set dysplastic ears with stenotic external auditory canals; skeletal anomalies (radiohumeral synostosis, neonatal fractures, congenital bowing of the long bones, joint contractures, arachnodactyly, clubfeet); renal anomalies (ectopic kidneys, duplication of the kidneys, renal hypoplasia, horseshoe kidney, hydronephrosis); and reduction of cognitive function and developmental delay. In moderate POR deficiency, craniofacial and skeletal anomalies are less severe than in ABS.

Diagnosis/testing. Diagnosis of POR deficiency depends on detection of sterol or steroid abnormalities using gas chromatography-mass spectrometry. Urinary steroid anomalies include increased concentration of metabolites of pregnenolone and progesterone and an elevated ratio of metabolites associated with deficiencies of 17-hydroxylase and 21-hydroxylase. POR deficiency is caused by mutations in POR. .

Management. Treatment of manifestations: Endotracheal intubation, nasal stints or tracheotomy, and tracheostomy as needed; hydrocortisone replacement therapy for cortisol deficiency with stress-dose steroids; testosterone injections for micropenis; surgery as needed for craniosynostosis, hypospadias, and cryptorchidism in males, and clitoromegaly in females; physical therapy for joint contractures.

Surveillance: Periodic developmental assessments.

Genetic counseling. POR deficiency is inherited in an autosomal recessive manner. 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. Carrier testing for at-risk family members and prenatal testing for pregnancies at increased risk are possible through laboratories offering either testing for the gene of interest or custom testing.

Diagnosis

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 1

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 2

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 3

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].

Molecular Genetic Testing

Gene. POR is the only gene known to be associated with cytochrome P450 oxidoreductase deficiency.

Clinical testing

Sequence analysis of POR. Sequence analysis of all exons and all intron-exon boundaries is possible. Mutation detection frequency using sequence analysis is unknown.

In a few individuals whose phenotype and steroid profiles are consistent with POR deficiency, a disease-causing mutation has been identified in only one POR allele. Although it is possible that an individual with only one identifiable allele may be a manifesting carrier, evidence suggests that these individuals may have one of the following:

  • An unidentified second POR mutation that affects POR gene expression. For example, affected individuals with only one mutation have been found to have nearly complete absence of mRNA made from the allele in which no mutation had been found [Fukami et al 2009].
  • Mutation(s) in a different gene involved in steroidogenesis, e.g., a female who was found to have a single POR mutation in addition to mutations in both copies of CYP21 [Scott et al 2007].
  • A POR mutation that was missed on initial testing. For example, an individual with classic ABS with craniosynostosis, radio-ulnar synostosis, and genital anomalies who was initially reported to be heterozygous for a POR mutation was later found to have a novel splice-site mutation in the second allele [Rieckmann et al 2009]. This individual also had a mutation in FGFRL1 (the first human mutation reported in this receptor), leading the authors of this paper to suggest that it may be the frameshift mutation in FGFRL1 that is primarily responsible for the severe skeletal findings [Rieckmann et al 2009].

Table 1. Summary of Molecular Genetic Testing Used in Cytochrome P450 Oxidoreductase Deficiency

Gene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1
PORSequence analysisSequence variants 2Unknown

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

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.

Clinical Description

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.

Antley-Bixler Syndrome — Severe End of the POR Deficiency Spectrum

Craniofacial anomalies. Craniosynostosis is usually severe and most commonly involves the coronal and lambdoid sutures, resulting in a characteristic trapezobrachycephalic skull shape; however, synostosis of other cranial sutures has been reported.

Other craniofacial anomalies include frontal bossing, enlarged anterior fontanel, severe midface hypoplasia, choanal stenosis or atresia, short bulbous or pear-shaped nose, depressed nasal bridge, small mouth, high arched narrow palate, dysplastic ears that may be low set, and stenotic external auditory canals.

Hydrocephalus has also been reported in a number of cases [Crisponi et al 1997, Lee et al 2001, Cragun et al 2004].

Skeletal anomalies. Elbow ankylosis, resulting most commonly from radiohumeral synostosis, causes fixation of the elbow in a flexed position. Neonatal fractures and congenital bowing of the long bones (especially the femurs) are common. Other common skeletal features include long palms, camptodactyly, contractures, arachnodactyly, clubfeet, irregularly positioned toes, and rocker bottom feet. Vertebral and rib anomalies, hypoplasia of the scapula, scoliosis, and narrow chest and/or pelvis have been reported.

Urogenital anomalies. Urogenital anomalies in addition to ambiguous genitalia may include hypoplastic uterus, ectopic kidneys, renal duplication, renal hypoplasia, horseshoe kidney, hydronephrosis, and ureteral obstruction.

Cognitive function. Developmental delays have been reported in a number of children with ABS. Cognitive functioning ranges from moderate intellectual disability to normal intelligence. Early and effective management of upper airway obstruction, craniosynostosis, and hydrocephalus appear to be a prerequisite for good cognitive development. However, effective management of these problems does not ensure normal intelligence.

Other anomalies. Congenital heart defects, identified in some persons with ABS, include transposition of the great vessels, ventricular septal defect, patent foramen ovale, atrial septal defect, and hypoplastic right atrium [Crisponi et al 1997].

Gastrointestinal malformations are rare; however, malrotation of the gut with partial agenesis of the ascending and transverse colon and mesocolon has been reported in one individual [Crisponi et al 1997]; imperforate anus has been reported in a few individuals [Antich et al 1993, LeHeup et al 1995].

Prognosis. Prognosis is guarded in infancy and improves with age. Early death caused by respiratory complications is a concern. However, with careful airway management, many children with ABS survive and the prognosis may be reasonably good.

Moderate Cytochrome P450 Oxidoreductase Deficiency

Craniofacial and skeletal anomalies. The craniofacial and skeletal features, if present, may not be as easily identified at birth and/or tend to be less severe than those in individuals with classic ABS. Elbow extension may be restricted in the absence of radiohumeral synostosis. Although craniosynostosis and/or brachycephaly may be observed, surgical treatment may not require as many procedures.

Other skeletal anomalies, uncommon in individuals with ABS but reported in individuals with POR deficiency include diastases of the radioulnar joint, ulnar deviation of the wrists, marfanoid habitus, flattened metacarpal epiphyses, cubitus valgus brachymetacarpia, and brachytelephalangia [Arlt et al 2004, Fluck et al 2004].

Cognitive function. Cognitive functioning is usually within the normal range; this observation is based on a limited number of individuals identified to date who are at the mild-to-moderate end of the phenotypic 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.

Differential Diagnosis

Congenital adrenal hyperplasia (CAH) is a heterogeneous group of conditions that result in impaired synthesis of cortisol, mineralocorticoids, and/or C-19 steroids. Based on this definition, the term CAH can be used to describe cytochrome P450 oxidoreductase (POR) deficiency. POR deficiency and the following etiologies of CAH may be distinguished by differences in urinary steroid profiles, molecular genetic testing, and/or the presence of skeletal anomalies, as skeletal anomalies are never found in other forms of CAH, but may occur in POR deficiency.

  • 21-hydroxylase deficiency (21-OHD), the most common form of CAH, is associated with masculinization of the external genitalia in females and normal genitalia in males. Unlike cytochrome P450 oxidoreductase deficiency, 21-OHD is characterized by elevated serum concentrations of adrenal androgens.
  • 3ß-hydroxysteroid dehydrogenase deficiency is a rare condition that can lead to ambiguous genitalia in both females and males.
  • 17-hydroxylase deficiency and/or 17,20 lyase deficiency (CYP17). 46,XY individuals with CYP17 deficiency usually have external genitalia resembling those of typical females.

Note: Males and females with ambiguous genitalia as a result of cytochrome P450 oxidoreductase deficiency may have been given a diagnosis of congenital adrenal hyperplasia with apparent combined P450c21 and P450c17 deficiency, atypical 21-OHD, or aromatase deficiency [Fukami et al 2006]. Some males with POR mutations have previously been diagnosed with isolated17,20 lyase deficiency [Hershkovitz et al 2008].

Autosomal dominant craniosynostosis syndromes. Craniosynostosis occurs in the autosomal dominant FGFR-related craniosynostosis syndromes that include Pfeiffer syndrome, Crouzon syndrome, Jackson-Weiss syndrome, Apert syndrome, and Beare-Stevenson syndrome (see FGFR-Related Craniosynostosis). The presence of ambiguous genitalia in ABS can help distinguish ABS resulting from POR deficiency from autosomal dominant FGFR-related craniosynostosis syndromes:

  • Pfeiffer and Crouzon syndromes. Although some individuals with FGFR mutations have been given the clinical diagnosis of ABS, these individuals probably have a severe FGFR-related craniosynostosis syndrome. FGFR mutations have not been associated with genital anomalies or steroid abnormalities. Individuals with FGFR mutations may have more severe proptosis compared to those with POR deficiency. Although common in POR deficiency, a pear-shaped or bulbous nose, low-set and dysplastic ears, arachnodactyly, and rockerbottom feet are not usually described in FGFR-related craniosynostosis syndromes.
  • Apert syndrome can usually be distinguished from ABS by the presence of the typical syndactyly.

Note: The significance of an FGFR1 mutation (1300T) in a male with ambiguous genitalia and features of ABS is unknown [Hurley et al 2004]. However, Huang et al [2005] determined that this individual also has POR deficiency with compound heterozygosity for mutations in POR. Additionally, the significance of a frameshift mutation in FGFRL1 (the first human mutation reported in this receptor) in an individual with classic ABS and a molecular diagnosis of POR deficiency is also uncertain [Rieckmann et al 2009].

Thanatophoric dysplasia. The combination of femoral bowing and craniosynostosis may be seen in thanatophoric dysplasia, but genital anomalies do not occur in this condition. Unlike ABS, thanatophoric dysplasia is characterized by severe rhizomelic shortening of the long bones. Thanatophoric dysplasia is caused by mutations in FGFR3.

Shprintzen-Goldberg syndrome (SGS) overlaps with ABS in that both can have camptodactyly, arachnodactyly, femoral bowing, and craniosynostosis; however, individuals with SGS do not have ambiguous genitalia or the distinctive facial features of ABS.

SGS overlaps phenotypically with POR deficiency in that both can have a marfanoid habitus. At least two individuals with POR deficiency without ABS were originally classified as having SGS [Shackleton & Malunowicz 2003, Adachi et al 2004b]. The cause of SGS is unknown.

Bent-bone dysplasias, which include campomelic dysplasia, kyphomelic dysplasia, and Stüve-Wiedemann dysplasia, are commonly associated with long-bone bowing, primarily of the femora. These conditions are distinguished from ABS by the lack of craniosynostosis or radiohumeral synostosis.

Long-bone fractures occur in campomelic dysplasia, but usually after the neonatal period, whereas fractures in ABS usually occur during the neonatal period. Campomelic dysplasia is often associated with sex reversal (i.e., phenotypic female with a 46,XY karyotype) and is caused by mutations in SOX9. Inheritance of campomelic dysplasia is autosomal dominant.

Osteogenesis imperfecta (OI) is associated with neonatal fractures, but lacks the characteristic craniofacial, limb, and urogenital anomalies of ABS. Unlike OI, ABS is not associated with osteoporosis or wormian bones.

Teratogen exposure. Early prenatal exposure to oral, high-dose fluconazole has resulted in an ABS-like phenotype in five reported cases [Aleck & Bartley 1997, Lopez-Rangel & Van Allen 2005]. However, frontal bossing, choanal stenosis/atresia, genital abnormalities, and camptodactyly were not observed. Pregnancy history is important in identifying this exposure.

Management

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].

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

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.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • AboutFace International
    123 Edward Street
    Suite 1003
    Toronto Ontario M5G 1E2
    Canada
    Phone: 800-665-3223 (toll-free); 416-597-2229
    Fax: 416-597-8494
    Email: info@aboutfaceinternational.org
  • Children's Craniofacial Association (CCA)
    13140 Coit Road
    Suite 517
    Dallas TX 75240
    Phone: 800-535-3643 (toll-free); 214-570-9099
    Fax: 214-570-8811
    Email: contactCCA@ccakids.com
  • FACES: The National Craniofacial Association
    PO Box 11082
    Chattanooga TN 37401
    Phone: 800-332-2373 (toll-free)
    Email: faces@faces-cranio.org
  • National Institute of Neurological Disorders and Stroke (NINDS)
    PO Box 5801
    Bethesda MD 20824
    Phone: 800-352-9424 (toll-free); 301-496-5751; 301-468-5981 (TTY)

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Cytochrome P450 Oxidoreductase Deficiency: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Cytochrome P450 Oxidoreductase Deficiency (View All in OMIM)

124015CYTOCHROME P450 OXIDOREDUCTASE; POR
201750ANTLEY-BIXLER SYNDROME WITH GENITAL ANOMALIES AND DISORDERED STEROIDOGENESIS; ABS1
207410ANTLEY-BIXLER SYNDROME WITHOUT GENITAL ANOMALIES OR DISORDERED STEROIDOGENESIS; ABS2
613571DISORDERED STEROIDOGENESIS DUE TO CYTOCHROME P450 OXIDOREDUCTASE DEFICIENCY

Normal allelic variants. The normal POR consists of 15 protein-coding exons and a non-coding exon upstream of the translation initiation site. A number of SNPs are reported in the NCBI database, most of which are synonymous or occur in non-coding regions [SNP Database]. Sequence analysis identified no POR disease-causing mutations among 100 healthy, white controls from the United Kingdom [Arlt et al 2004] or 50 Japanese controls [Adachi et al 2004a]. Huang et al [2008] sequenced the POR promoter region, exons, and exon/intron boundaries in 842 healthy Americans from different ethnic backgrounds (northern European, African, Chinese, and Mexican). They found 108 noncoding SNPs, eight indels (the only indel present in the coding region was a previously described variant), and 32 SNPS in protein-coding regions (15 of these altered the encoded amino acid). A number of the missense mutations were associated with decreased catalytic activity during in vitro studies and may represent previously unidentified disease-causing alleles present in normal carriers [Miller et al 2009]. A previously described common polymorphism (p.Ala503Val), found in 20%-35% of the ethnic groups studied, showed decreased catalytic activity (50%-60%) for CYP17A1, but no decreased activity for CYP1A2 or 2C19 [Miller et al 2009].

A 15A3G variant may confer a modestly increased risk for breast cancer in African-American women [Haiman et al 2007].

Pathologic allelic variants. POR mutations have been reported in approximately 50 individuals with cytochrome P450 oxidoreductase (POR) deficiency with or without a diagnosis of ABS [Huang et al 2008, Scott & Miller 2008]. Two mutations, p.Ala287Pro and p.Arg457His, appear to be quite common: p.Ala287Pro accounts for about 40% of mutations among individuals of European ancestry and p.Arg457His accounts for about 60% of mutations among individuals of Japanese ancestry, although it is important to note that p.Arg457His has also been reported in individuals of European and African ancestry [Scott & Miller 2008]. The 35 known POR missense mutations and their enzymatic activities in various in vitro assays are reported by Miller et al [2009]. Additional mutations that have been identified include frameshift mutations, splice site mutations, insertions, and deletions [Adachi et al 2004a, Fluck et al 2004, Fukami et al 2005, Miller et al 2009].

Note: Nomenclature for POR mutations can be confusing. Some researchers previously used the nomenclature from the rat model, although it is more accurate to use the GenBank reference sequence accession number NM_000941.2, which increases the amino acid residue numbers by three when compared to the rat model.

Normal gene product. POR is required for the activity of all 50 of the known human microsomal (type II) P450 enzymes, which play an important role in steroid and sterol synthesis as well as hepatic drug metabolism. POR binds NADPH and accepts a pair of electrons through its FAD moiety. Electrons are then transferred to the FMN moiety and then directly to P450 enzymes.

Human and rat POR share 92.2% sequence identity. Knockout of Por results in embryonic lethality in mice [Shen et al 2002, Otto et al 2003], while a liver-specific knockout of Por in mice results in a normal morphologic and reproductive phenotype [Gu et al 2003].

Abnormal gene product. Expression of recombinant mutant proteins with amino acid substitutions in yeast or bacteria reveals a deficient or reduced capacity for various POR mutants to oxidize cytochrome c, NADPH, CYP17A1, CYP21A2, CYP19A1, CYP4A4, CYP1A2, and/or CYP2C19 [Arlt et al 2004, Fluck et al 2004, Huang et al 2005, Marohnic et al 2006, Dhir et al 2007, Pandey et al 2007, Kranendonk et al 2008, Miller et al 2009].The diminished enzyme activity is believed to be caused by the effects of the amino acid substitution on steric conformation, charge, and/or FAD-binding affinity. POR mutations impair the activity of each P450 enzyme to different degrees. (For details see Dhir et al [2007], Pandey et al [2007], Miller et al [2009]).

Mutations causing a premature stop codon are predicted to result in a nonfunctional protein [Adachi et al 2004a, Fluck et al 2004, Fukami et al 2005, Huang et al 2005]. The silent mutation in exon 1 (p.Gly5Gly) is predicted to disturb an exonic splicing enhancer motif [Fukami et al 2005]. Using the EsyPred3D analysis, the p.Leu612_Trp620delinsArg appears to disrupt an alpha helix in the corresponding region, affecting proper protein conformation [Fukami et al 2005].

References

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Chapter Notes

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
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