Cytochrome P450-oxidoreductase (POR) deficiency (ORD)

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mehrian Jafarizade, M.D [2]

Synonyms and keywords: ORD, POR deficiency, P450-oxidoreductase cytochrome deficiency

Overview

Cytochrome P450-oxidoreductase (POR) deficiency is a type of congenital adrenal hyperplasia that caused by mutations in the flavoprotein co-factor of the enzymes CYP17A1, CYP21A2, and CYP19A1 (aromatase). Severe Undervirilization in boys and severe virilization in girls and Antley-Bixler syndrome of craniofacial malformations are clinical finding of cytocrome P450-oxidoreductase deficiency. The mainstay of therapy for cytochrome P450-oxidoreductase deficiency is hydrocortisone to replace glucocorticoid deficiency.

Historical Perspective

In 1865, Luigi De Crecchio, an Italian pathologist was the first who discovered Congenital adrenal hyperplasia.^[1]

Classification

There is no established classification system for cytochrome P450-oxidoreductase deficiency.

Pathophysiology

The cytochrome P450 oxidoreductase (POR) enzyme serves as an electron donor enzyme for many enzymes such as steroid synthesis enzymes CYP17A1, and CYP21A2. Cytochrome P450-oxidoreductase deficiency is characterized by combined CYP17A1 and CYP21A2 deficiency.

CYP17A1 encodes17α-hydroxylase/17,20α-hydroxylase, a cytochrome P450 enzyme which acts upon:
- Pregnenolone and progesterone to add a hydroxyl (-OH) group at carbon 17 of the steroid D ring (the hydroxylase activity).
- 17-hydroxyprogesterone and 17-hydroxypregnenolone to split the side chain off the steroid nucleus.
CYP21A2 encodes steroid 21-hydroxylase, a cytochrome P450 enzyme which is involved with the biosynthesis of the steroid hormones aldosterone and cortisol.

Also, cytochrome P450 oxidoreductase enzyme serves as a co-factor for an enzyme called lanosterol de-methylase (CYP51A1), which is effective in de novo cholesterol synthesis. In this disease cholesterol loss may lead to craniofacial malformations and Antley-Bixler syndrome (ABS).^[2]^[3]^[4]^[5]^[6]

Causes

Cytochrome P450-oxidoreductase (POR) deficiency is caused by mutations in the flavoprotein that is a co-factor of the enzymes CYP17A1, CYP21A2, and CYP19A1 (aromatase).

Differentiating [disease name] from other Diseases

Cytochrome P450-oxidoreductase deficiency must be differentiated from other diseases that cause ambiguous genitalia such as: 21-hydroxylase deficiency, 11-β hydroxylase deficiency, 17 alpha-hydroxylase deficiency, and gestational hyperandrogenism.

Disease name	Steroid status		Important clinical findings
Disease name	Increased	Decreased	Important clinical findings
Classic type of 21-hydroxylase deficiency	17-hydroxyprogesterone Progesterone Androstenedione DHEA	Aldosterone Corticosterone (salt-wasting) Cortisol (virilization)	Ambiguous genitalia in female Virilization in female Salt-wasting Hypotension and hyperkalemia
11-β hydroxylase deficiency	Deoxycorticosterone 11-Deoxy-cortisol 17-hydroxyprogesterone (mild elevation)	Cortisol Corticosterone Aldosterone	Ambiguous genitalia in female Hypertension and hypokalemia Virilization
17-α hydroxylase deficiency	Deoxycorticosterone Corticosterone Progesterone	Cortisol Aldosterone	Ambiguous genitalia in male Hypertension Primary amenorrhea Absence of secondary sexual characteristics Minimal body hair
3 beta-hydroxysteroid dehydrogenase deficiency	Dehydroepiandrosterone 17-hydroxypregnenolone Pregnenolone	Cortisol Aldosterone	Vomiting, volume depletion, hyponatremia, and hyperkalemia 46-XY infants often show undervirilization, due to a block in testosterone synthesis
Gestational hyperandrogenism	Maternal serum androgen concentrations (usually testosterone and androstenedione) are high If virilization is caused by exogenous hormone administration, the values may be low because the offending hormone is usually a synthetic steroid not measured in assays for testosterone or other androgens		Androgen excess in mother History of androgen containing medication consumption during pregnancy in mother Virilization in a 46,XX individual with normal female internal anatomy Causes include maternal luteoma or theca-lutein cysts, and placental aromatase enzyme deficiency

Epidemiology and Demographics

Cytochrome P450-oxidoreductase (POR) deficiency is a rere disease with unknown prevalence.^[7]^[8]

Diagnosis

Symptoms and physical Examination

Severe Undervirilization in boys and severe virilization in girls but pubertal development in this disease is not studied enough.
Antley-Bixler syndrome (ABS): craniofacial malformations (midface hypoplasia with low set ears and pear-shaped nose), arachnodactyly, clinodactyly, and radio-humeral synostosis.^[3]^[4]^[5]^[6]

Laboratory Findings

Genetic testing is the gold standard of diagnosis. Pregnenolone, progesterone and 17-hydroxyprogesterone metabolites are increased and androgen metabolites are decreased.^[9]

Treatment

Medical Therapy

The mainstay of therapy for cytochrome P450-oxidoreductase deficiency is hydrocortisone to replace glucocorticoid deficiency. Gender-appropriate replacement of androgens or estrogens with progestins is necessary at the puberty time.

Preferred regiemen: hydrocortisone oral, 15 to 25 mg/day in 2 to 3 divided doses.

Surgery

The reconstruction surgery for ambiguous genitalia in genetically male patients may be applied.^[10]

References

↑ Delle Piane L, Rinaudo PF, Miller WL (2015). “150 years of congenital adrenal hyperplasia: translation and commentary of De Crecchio’s classic paper from 1865”. Endocrinology. 156 (4): 1210–7. doi:10.1210/en.2014-1879. PMID 25635623.
↑ Fukami M, Nishimura G, Homma K, Nagai T, Hanaki K, Uematsu A, Ishii T, Numakura C, Sawada H, Nakacho M, Kowase T, Motomura K, Haruna H, Nakamura M, Ohishi A, Adachi M, Tajima T, Hasegawa Y, Hasegawa T, Horikawa R, Fujieda K, Ogata T (2009). “Cytochrome P450 oxidoreductase deficiency: identification and characterization of biallelic mutations and genotype-phenotype correlations in 35 Japanese patients”. J. Clin. Endocrinol. Metab. 94 (5): 1723–31. doi:10.1210/jc.2008-2816. PMID 19258400.
↑ ^3.0 ^3.1 Peterson RE, Imperato-McGinley J, Gautier T, Shackleton C (1985). “Male pseudohermaphroditism due to multiple defects in steroid-biosynthetic microsomal mixed-function oxidases. A new variant of congenital adrenal hyperplasia”. N. Engl. J. Med. 313 (19): 1182–91. doi:10.1056/NEJM198511073131903. PMID 2932643.
↑ ^4.0 ^4.1 Huang N, Pandey AV, Agrawal V, Reardon W, Lapunzina PD, Mowat D, Jabs EW, Van Vliet G, Sack J, Flück CE, Miller WL (2005). “Diversity and function of mutations in p450 oxidoreductase in patients with Antley-Bixler syndrome and disordered steroidogenesis”. Am. J. Hum. Genet. 76 (5): 729–49. doi:10.1086/429417. PMC 1199364. PMID 15793702.
↑ ^5.0 ^5.1 Kelley RI, Kratz LE, Glaser RL, Netzloff ML, Wolf LM, Jabs EW (2002). “Abnormal sterol metabolism in a patient with Antley-Bixler syndrome and ambiguous genitalia”. Am. J. Med. Genet. 110 (2): 95–102. doi:10.1002/ajmg.10510. PMID 12116245.
↑ ^6.0 ^6.1 Mann RK, Beachy PA (2004). “Novel lipid modifications of secreted protein signals”. Annu. Rev. Biochem. 73: 891–923. doi:10.1146/annurev.biochem.73.011303.073933. PMID 15189162.
↑ Flück CE, Tajima T, Pandey AV, Arlt W, Okuhara K, Verge CF, Jabs EW, Mendonça BB, Fujieda K, Miller WL (2004). “Mutant P450 oxidoreductase causes disordered steroidogenesis with and without Antley-Bixler syndrome”. Nat. Genet. 36 (3): 228–30. doi:10.1038/ng1300. PMID 14758361.
↑ Hershkovitz E, Parvari R, Wudy SA, Hartmann MF, Gomes LG, Loewental N, Miller WL (2008). “Homozygous mutation G539R in the gene for P450 oxidoreductase in a family previously diagnosed as having 17,20-lyase deficiency”. J. Clin. Endocrinol. Metab. 93 (9): 3584–8. doi:10.1210/jc.2008-0051. PMC 2567854. PMID 18559916.
↑ Shackleton C, Marcos J, Malunowicz EM, Szarras-Czapnik M, Jira P, Taylor NF, Murphy N, Crushell E, Gottschalk M, Hauffa B, Cragun DL, Hopkin RJ, Adachi M, Arlt W (2004). “Biochemical diagnosis of Antley-Bixler syndrome by steroid analysis”. Am. J. Med. Genet. A. 128A (3): 223–31. doi:10.1002/ajmg.a.30104. PMID 15216541.
↑ Schnitzer JJ, Donahoe PK (2001). “Surgical treatment of congenital adrenal hyperplasia”. Endocrinol. Metab. Clin. North Am. 30 (1): 137–54. PMID 11344932.

Template:WS Template:WH

[pmid25635623-1] Delle Piane L, Rinaudo PF, Miller WL (2015). “150 years of congenital adrenal hyperplasia: translation and commentary of De Crecchio’s classic paper from 1865”. Endocrinology. 156 (4): 1210–7. doi:10.1210/en.2014-1879. PMID 25635623.

[pmid19258400-2] Fukami M, Nishimura G, Homma K, Nagai T, Hanaki K, Uematsu A, Ishii T, Numakura C, Sawada H, Nakacho M, Kowase T, Motomura K, Haruna H, Nakamura M, Ohishi A, Adachi M, Tajima T, Hasegawa Y, Hasegawa T, Horikawa R, Fujieda K, Ogata T (2009). “Cytochrome P450 oxidoreductase deficiency: identification and characterization of biallelic mutations and genotype-phenotype correlations in 35 Japanese patients”. J. Clin. Endocrinol. Metab. 94 (5): 1723–31. doi:10.1210/jc.2008-2816. PMID 19258400.

[pmid2932643-3] 3.0 ^3.1 Peterson RE, Imperato-McGinley J, Gautier T, Shackleton C (1985). “Male pseudohermaphroditism due to multiple defects in steroid-biosynthetic microsomal mixed-function oxidases. A new variant of congenital adrenal hyperplasia”. N. Engl. J. Med. 313 (19): 1182–91. doi:10.1056/NEJM198511073131903. PMID 2932643.

[pmid15793702-4] 4.0 ^4.1 Huang N, Pandey AV, Agrawal V, Reardon W, Lapunzina PD, Mowat D, Jabs EW, Van Vliet G, Sack J, Flück CE, Miller WL (2005). “Diversity and function of mutations in p450 oxidoreductase in patients with Antley-Bixler syndrome and disordered steroidogenesis”. Am. J. Hum. Genet. 76 (5): 729–49. doi:10.1086/429417. PMC 1199364. PMID 15793702.

[pmid12116245-5] 5.0 ^5.1 Kelley RI, Kratz LE, Glaser RL, Netzloff ML, Wolf LM, Jabs EW (2002). “Abnormal sterol metabolism in a patient with Antley-Bixler syndrome and ambiguous genitalia”. Am. J. Med. Genet. 110 (2): 95–102. doi:10.1002/ajmg.10510. PMID 12116245.

[pmid15189162-6] 6.0 ^6.1 Mann RK, Beachy PA (2004). “Novel lipid modifications of secreted protein signals”. Annu. Rev. Biochem. 73: 891–923. doi:10.1146/annurev.biochem.73.011303.073933. PMID 15189162.

[pmid14758361-7] Flück CE, Tajima T, Pandey AV, Arlt W, Okuhara K, Verge CF, Jabs EW, Mendonça BB, Fujieda K, Miller WL (2004). “Mutant P450 oxidoreductase causes disordered steroidogenesis with and without Antley-Bixler syndrome”. Nat. Genet. 36 (3): 228–30. doi:10.1038/ng1300. PMID 14758361.

[pmid18559916-8] Hershkovitz E, Parvari R, Wudy SA, Hartmann MF, Gomes LG, Loewental N, Miller WL (2008). “Homozygous mutation G539R in the gene for P450 oxidoreductase in a family previously diagnosed as having 17,20-lyase deficiency”. J. Clin. Endocrinol. Metab. 93 (9): 3584–8. doi:10.1210/jc.2008-0051. PMC 2567854. PMID 18559916.

[pmid15216541-9] Shackleton C, Marcos J, Malunowicz EM, Szarras-Czapnik M, Jira P, Taylor NF, Murphy N, Crushell E, Gottschalk M, Hauffa B, Cragun DL, Hopkin RJ, Adachi M, Arlt W (2004). “Biochemical diagnosis of Antley-Bixler syndrome by steroid analysis”. Am. J. Med. Genet. A. 128A (3): 223–31. doi:10.1002/ajmg.a.30104. PMID 15216541.

[pmid11344932-10] Schnitzer JJ, Donahoe PK (2001). “Surgical treatment of congenital adrenal hyperplasia”. Endocrinol. Metab. Clin. North Am. 30 (1): 137–54. PMID 11344932.

[1]

[2]

[3]

[4]

[5]

[6]

[7]

[8]

[9]

[10]