Cytochrome P450-oxidoreductase (POR) deficiency (ORD): Difference between revisions
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There is no established classification system for lipoid congenital adrenal hyperplasia. | There is no established classification system for lipoid congenital adrenal hyperplasia. | ||
==Pathophysiology== | ==Pathophysiology== | ||
The cytochrome P450 oxidoreductase (POR) enzyme serves as an electron donor enzyme for many enzymes such as steroid synthesis enzymes CYP17A1, CYP21A2. Presentation of Cytochrome P450-oxidoreductase deficiency is characterized by combined CYP17A1 and CYP21A2. | |||
Also,cytochrome P450 oxidoreductase enzyme serves as a co-factor for an enzyme called lanosterol demethylase (CYP51A1), which is effective in de novo cholesterol synthesis. In this disease cholesterol loss may lead to craniofacial malformations and Antley-Bixler syndrome (ABS).<ref name="pmid19258400">{{cite journal |vauthors=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 |title=Cytochrome P450 oxidoreductase deficiency: identification and characterization of biallelic mutations and genotype-phenotype correlations in 35 Japanese patients |journal=J. Clin. Endocrinol. Metab. |volume=94 |issue=5 |pages=1723–31 |year=2009 |pmid=19258400 |doi=10.1210/jc.2008-2816 |url=}}</ref><ref name="pmid2932643">{{cite journal |vauthors=Peterson RE, Imperato-McGinley J, Gautier T, Shackleton C |title=Male pseudohermaphroditism due to multiple defects in steroid-biosynthetic microsomal mixed-function oxidases. A new variant of congenital adrenal hyperplasia |journal=N. Engl. J. Med. |volume=313 |issue=19 |pages=1182–91 |year=1985 |pmid=2932643 |doi=10.1056/NEJM198511073131903 |url=}}</ref><ref name="pmid15793702">{{cite journal |vauthors=Huang N, Pandey AV, Agrawal V, Reardon W, Lapunzina PD, Mowat D, Jabs EW, Van Vliet G, Sack J, Flück CE, Miller WL |title=Diversity and function of mutations in p450 oxidoreductase in patients with Antley-Bixler syndrome and disordered steroidogenesis |journal=Am. J. Hum. Genet. |volume=76 |issue=5 |pages=729–49 |year=2005 |pmid=15793702 |pmc=1199364 |doi=10.1086/429417 |url=}}</ref><ref name="pmid12116245">{{cite journal |vauthors=Kelley RI, Kratz LE, Glaser RL, Netzloff ML, Wolf LM, Jabs EW |title=Abnormal sterol metabolism in a patient with Antley-Bixler syndrome and ambiguous genitalia |journal=Am. J. Med. Genet. |volume=110 |issue=2 |pages=95–102 |year=2002 |pmid=12116245 |doi=10.1002/ajmg.10510 |url=}}</ref><ref name="pmid15189162">{{cite journal |vauthors=Mann RK, Beachy PA |title=Novel lipid modifications of secreted protein signals |journal=Annu. Rev. Biochem. |volume=73 |issue= |pages=891–923 |year=2004 |pmid=15189162 |doi=10.1146/annurev.biochem.73.011303.073933 |url=}}</ref> | |||
==Causes== | ==Causes== | ||
Cytochrome P450-oxidoreductase (POR) deficiency is caused by mutations in the flavoprotein co-factor of the enzymes CYP17A1, CYP21A2, and CYP19A1 (aromatase). | |||
==Differentiating [disease name] from other Diseases== | ==Differentiating [disease name] from other Diseases== | ||
fibroblast growth factor receptor 2 (FGFR2) mutations, However, the FGFR2 gene in patients with ORD is normal [22,24,117] and patients with proven FGFR2 mutations do not present with disordered steroidogenesis or disordered sex development | |||
==Epidemiology and Demographics== | ==Epidemiology and Demographics== | ||
Cytochrome P450-oxidoreductase (POR) deficiency is a rear disease with unknown prevalence.<ref name="pmid14758361">{{cite journal |vauthors=Flück CE, Tajima T, Pandey AV, Arlt W, Okuhara K, Verge CF, Jabs EW, Mendonça BB, Fujieda K, Miller WL |title=Mutant P450 oxidoreductase causes disordered steroidogenesis with and without Antley-Bixler syndrome |journal=Nat. Genet. |volume=36 |issue=3 |pages=228–30 |year=2004 |pmid=14758361 |doi=10.1038/ng1300 |url=}}</ref><ref name="pmid18559916">{{cite journal |vauthors=Hershkovitz E, Parvari R, Wudy SA, Hartmann MF, Gomes LG, Loewental N, Miller WL |title=Homozygous mutation G539R in the gene for P450 oxidoreductase in a family previously diagnosed as having 17,20-lyase deficiency |journal=J. Clin. Endocrinol. Metab. |volume=93 |issue=9 |pages=3584–8 |year=2008 |pmid=18559916 |pmc=2567854 |doi=10.1210/jc.2008-0051 |url=}}</ref> | |||
== Diagnosis == | == Diagnosis == | ||
=== Symptoms and physical Examination === | |||
=== Symptoms === | *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 radiohumeral synostosis. Other features are bowed femora, neonatal fractures and choanal atresia.<ref name="pmid2932643">{{cite journal |vauthors=Peterson RE, Imperato-McGinley J, Gautier T, Shackleton C |title=Male pseudohermaphroditism due to multiple defects in steroid-biosynthetic microsomal mixed-function oxidases. A new variant of congenital adrenal hyperplasia |journal=N. Engl. J. Med. |volume=313 |issue=19 |pages=1182–91 |year=1985 |pmid=2932643 |doi=10.1056/NEJM198511073131903 |url=}}</ref><ref name="pmid15793702">{{cite journal |vauthors=Huang N, Pandey AV, Agrawal V, Reardon W, Lapunzina PD, Mowat D, Jabs EW, Van Vliet G, Sack J, Flück CE, Miller WL |title=Diversity and function of mutations in p450 oxidoreductase in patients with Antley-Bixler syndrome and disordered steroidogenesis |journal=Am. J. Hum. Genet. |volume=76 |issue=5 |pages=729–49 |year=2005 |pmid=15793702 |pmc=1199364 |doi=10.1086/429417 |url=}}</ref><ref name="pmid12116245">{{cite journal |vauthors=Kelley RI, Kratz LE, Glaser RL, Netzloff ML, Wolf LM, Jabs EW |title=Abnormal sterol metabolism in a patient with Antley-Bixler syndrome and ambiguous genitalia |journal=Am. J. Med. Genet. |volume=110 |issue=2 |pages=95–102 |year=2002 |pmid=12116245 |doi=10.1002/ajmg.10510 |url=}}</ref><ref name="pmid15189162">{{cite journal |vauthors=Mann RK, Beachy PA |title=Novel lipid modifications of secreted protein signals |journal=Annu. Rev. Biochem. |volume=73 |issue= |pages=891–923 |year=2004 |pmid=15189162 |doi=10.1146/annurev.biochem.73.011303.073933 |url=}}</ref> | ||
=== | |||
=== Laboratory Findings === | === Laboratory Findings === | ||
Genetic testing is the gold standard of diagnosis. Pregnenolone, progesterone and 17-hydroxyprogesterone metabolites are increased and androgen metabolites are decreased.<ref name="pmid15216541">{{cite journal |vauthors=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 |title=Biochemical diagnosis of Antley-Bixler syndrome by steroid analysis |journal=Am. J. Med. Genet. A |volume=128A |issue=3 |pages=223–31 |year=2004 |pmid=15216541 |doi=10.1002/ajmg.a.30104 |url=}}</ref> | |||
===Imaging Findings=== | ===Imaging Findings=== | ||
== Treatment == | == Treatment == | ||
Revision as of 16:53, 14 August 2017
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mehrian Jafarizade, M.D [2]
Synonyms and keywords:
Overview
Historical Perspective
Congenital adrenal hyperplasia was first discovered by Luigi De Crecchio, an Italian pathologist in 1865.[1]
Classification
There is no established classification system for lipoid congenital adrenal hyperplasia.
Pathophysiology
The cytochrome P450 oxidoreductase (POR) enzyme serves as an electron donor enzyme for many enzymes such as steroid synthesis enzymes CYP17A1, CYP21A2. Presentation of Cytochrome P450-oxidoreductase deficiency is characterized by combined CYP17A1 and CYP21A2. Also,cytochrome P450 oxidoreductase enzyme serves as a co-factor for an enzyme called lanosterol demethylase (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 co-factor of the enzymes CYP17A1, CYP21A2, and CYP19A1 (aromatase).
Differentiating [disease name] from other Diseases
fibroblast growth factor receptor 2 (FGFR2) mutations, However, the FGFR2 gene in patients with ORD is normal [22,24,117] and patients with proven FGFR2 mutations do not present with disordered steroidogenesis or disordered sex development
Epidemiology and Demographics
Cytochrome P450-oxidoreductase (POR) deficiency is a rear 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 radiohumeral synostosis. Other features are bowed femora, neonatal fractures and choanal atresia.[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]
Imaging Findings
Treatment
Medical Therapy
Surgery
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.