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Congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiency

MedGen UID:
348008
Concept ID:
C1860042
Disease or Syndrome
Synonyms: Congenital Adrenal Hyperplasia due to Apparent Combined P450c17 and P450c21 Deficiency; Disordered steroidogenesis due to cytochrome p450 oxidoreductase deficiency; DISORDERED STEROIDOGENESIS DUE TO POR DEFICIENCY
SNOMED CT: Congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiency (715733000)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
 
Gene (location): POR (7q11.23)
 
Monarch Initiative: MONDO:0013310
OMIM®: 613571
Orphanet: ORPHA95699

Disease characteristics

Excerpted from the GeneReview: Cytochrome P450 Oxidoreductase Deficiency
Cytochrome P450 oxidoreductase deficiency (PORD) is a disorder of steroidogenesis with a broad phenotypic spectrum including cortisol deficiency, altered sex steroid synthesis, disorders of sex development (DSD), and skeletal malformations of the Antley-Bixler syndrome (ABS) phenotype. Cortisol deficiency is usually partial, with some baseline cortisol production but failure to mount an adequate cortisol response in stress. Mild mineralocorticoid excess can be present and causes arterial hypertension, usually presenting in young adulthood. Manifestations of altered sex steroid synthesis include ambiguous genitalia/DSD in both males and females, large ovarian cysts in females, poor masculinization and delayed puberty in males, and maternal virilization during pregnancy with an affected fetus. Skeletal malformations can manifest as craniosynostosis, mid-face retrusion with proptosis and choanal stenosis or atresia, low-set dysplastic ears with stenotic external auditory canals, hydrocephalus, radiohumeral synostosis, neonatal fractures, congenital bowing of the long bones, joint contractures, arachnodactyly, and clubfeet; other anomalies observed include urinary tract anomalies (renal pelvic dilatation, vesicoureteral reflux). Cognitive impairment is of minor concern and likely associated with the severity of malformations; studies of developmental outcomes are lacking. [from GeneReviews]
Authors:
Jan Idkowiak  |  Deborah Cragun  |  Robert J Hopkin, et. al.   view full author information

Additional descriptions

From OMIM
This rare variant of congenital adrenal hyperplasia, caused by mutations in the POR gene, results in apparent combined deficiency of P450C17 (609300) and P450C21 (613815) and accumulation of steroid metabolites. The most striking phenotypic feature is that affected girls are born with ambiguous genitalia, indicating intrauterine androgen excess. After birth, however, virilization does not progress and amounts of circulating androgens are low or normal. Affected boys are sometimes born undermasculinized. Boys and girls can present with bone malformations, sometimes suggesting the pattern seen in patients with Antley-Bixler syndrome (see 207410) (summary by Arlt et al., 2004).  http://www.omim.org/entry/613571
From MedlinePlus Genetics
Cytochrome P450 oxidoreductase deficiency is a disorder of hormone production. This condition specifically affects steroid hormones, which are needed for normal development and reproduction. The hormonal changes associated with cytochrome P450 oxidoreductase deficiency can affect the development of the reproductive system, skeleton, and other parts of the body. These signs and symptoms are usually present at birth or become apparent in early childhood.

The signs and symptoms of cytochrome P450 oxidoreductase deficiency vary from mild to severe. Signs and symptoms of mild cases can include a failure to begin menstruation by age 16 (primary amenorrhea), an inability to have biological children (infertility) in both men and women, and a condition called polycystic ovarian syndrome (PCOS). PCOS is characterized by a hormonal imbalance in women that can lead to irregular menstruation, acne, excess body hair (hirsutism), and weight gain.

People with moderate cases of cytochrome P450 oxidoreductase deficiency may have external genitalia that do not look clearly male or female, and they may have infertility. People with moderate cytochrome P450 oxidoreductase deficiency usually do not have skeletal abnormalities.

The severe form of cytochrome P450 oxidoreductase deficiency is sometimes called Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis. Hormonal changes in affected males and females lead to the development of genital differences, as well as infertility. Severe cases are also characterized by skeletal abnormalities, particularly involving bones of the head and face. These include premature fusion of the skull bones (craniosynostosis), a flattened mid-face, a prominent forehead, and low-set ears. Other skeletal abnormalities can include joint deformities (contractures) that limit movement; unusually long, slender fingers (arachnodactyly); bowing of the thigh bones; and radiohumeral synostosis, which is a bone abnormality that locks the elbows in a bent position. A blockage of the nasal passages (choanal atresia), intellectual disability, and delayed development are also associated with the severe form of the disorder.

Some women who are pregnant with fetuses affected by cytochrome P450 oxidoreductase deficiency experience mild symptoms of the disorder even though they themselves do not have the disorder. They may develop excessive body hair growth (hirsutism), acne, and a deep voice. These changes go away soon after delivery.  https://medlineplus.gov/genetics/condition/cytochrome-p450-oxidoreductase-deficiency

Clinical features

From HPO
Ambiguous genitalia
MedGen UID:
78596
Concept ID:
C0266362
Congenital Abnormality
A genital phenotype that is not clearly assignable to a single gender. Ambiguous genitalia can be evaluated using the Prader scale
Congenital adrenal hyperplasia
MedGen UID:
7900
Concept ID:
C0001627
Disease or Syndrome
A type of adrenal hyperplasia with congenital onset.
Increased circulating ACTH level
MedGen UID:
867375
Concept ID:
C4021740
Finding
An abnormal increased in the concentration of corticotropin, also known as adrenocorticotropic hormone (ACTH), in the blood.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVCongenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiency

Professional guidelines

PubMed

Wang C, Tian Q
Front Endocrinol (Lausanne) 2023;14:1226387. Epub 2023 Aug 11 doi: 10.3389/fendo.2023.1226387. PMID: 37635957Free PMC Article
Dean B, Chrisp GL, Quartararo M, Maguire AM, Hameed S, King BR, Munns CF, Torpy DJ, Falhammar H, Rushworth RL
J Clin Endocrinol Metab 2020 Mar 1;105(3) doi: 10.1210/clinem/dgz255. PMID: 31825489
Fan L, Ren X, Song Y, Su C, Fu J, Gong C
Orphanet J Rare Dis 2019 Dec 30;14(1):299. doi: 10.1186/s13023-019-1283-2. PMID: 31888681Free PMC Article

Recent clinical studies

Etiology

Guo X, Zhang Y, Yu Y, Zhang L, Ullah K, Ji M, Jin B, Shu J
Front Endocrinol (Lausanne) 2022;13:982953. Epub 2022 Aug 31 doi: 10.3389/fendo.2022.982953. PMID: 36120452Free PMC Article
Fan L, Ren X, Song Y, Su C, Fu J, Gong C
Orphanet J Rare Dis 2019 Dec 30;14(1):299. doi: 10.1186/s13023-019-1283-2. PMID: 31888681Free PMC Article
Krone N, Arlt W
Best Pract Res Clin Endocrinol Metab 2009 Apr;23(2):181-92. doi: 10.1016/j.beem.2008.10.014. PMID: 19500762Free PMC Article
Scott RR, Miller WL
Horm Res 2008;69(5):266-75. Epub 2008 Feb 6 doi: 10.1159/000114857. PMID: 18259105
Krone N, Dhir V, Ivison HE, Arlt W
Clin Endocrinol (Oxf) 2007 Feb;66(2):162-72. doi: 10.1111/j.1365-2265.2006.02740.x. PMID: 17223983

Diagnosis

Zhang J, Woo KL, Hai Y, Wang S, Lin Y, Huang Y, Peng X, Wu H, Zhang S, Yan L, Li Y
Front Endocrinol (Lausanne) 2022;13:1020880. Epub 2022 Nov 28 doi: 10.3389/fendo.2022.1020880. PMID: 36518257Free PMC Article
Fukami M, Ogata T
Pediatr Int 2014 Dec;56(6):805-808. doi: 10.1111/ped.12518. PMID: 25294558
Flück CE, Pandey AV
Endocr Dev 2011;20:63-79. Epub 2010 Dec 16 doi: 10.1159/000321221. PMID: 21164260
Krone N, Arlt W
Best Pract Res Clin Endocrinol Metab 2009 Apr;23(2):181-92. doi: 10.1016/j.beem.2008.10.014. PMID: 19500762Free PMC Article
Scott RR, Miller WL
Horm Res 2008;69(5):266-75. Epub 2008 Feb 6 doi: 10.1159/000114857. PMID: 18259105

Therapy

Guo X, Zhang Y, Yu Y, Zhang L, Ullah K, Ji M, Jin B, Shu J
Front Endocrinol (Lausanne) 2022;13:982953. Epub 2022 Aug 31 doi: 10.3389/fendo.2022.982953. PMID: 36120452Free PMC Article
Auchus RJ
J Steroid Biochem Mol Biol 2017 Jan;165(Pt A):71-78. Epub 2016 Feb 6 doi: 10.1016/j.jsbmb.2016.02.002. PMID: 26862015Free PMC Article
Gençay I, Vargel I, Büyükkoçak U, Yazc I, Apan A
J Craniofac Surg 2013 Jan;24(1):e21-3. doi: 10.1097/SCS.0b013e318267be0f. PMID: 23348324
Horvat S, McWhir J, Rozman D
Drug Metab Rev 2011 Feb;43(1):69-90. doi: 10.3109/03602532.2010.540580. PMID: 21247357
Idkowiak J, O'Riordan S, Reisch N, Malunowicz EM, Collins F, Kerstens MN, Köhler B, Graul-Neumann LM, Szarras-Czapnik M, Dattani M, Silink M, Shackleton CH, Maiter D, Krone N, Arlt W
J Clin Endocrinol Metab 2011 Mar;96(3):E453-62. Epub 2010 Dec 29 doi: 10.1210/jc.2010-1607. PMID: 21190981Free PMC Article

Prognosis

Wang C, Tian Q
Front Endocrinol (Lausanne) 2023;14:1226387. Epub 2023 Aug 11 doi: 10.3389/fendo.2023.1226387. PMID: 37635957Free PMC Article
Pecori Giraldi F, Einaudi S, Sesta A, Verna F, Messina M, Manieri C, Menegatti E, Ghizzoni L
J Endocrinol Invest 2021 Oct;44(10):2219-2226. Epub 2021 Mar 5 doi: 10.1007/s40618-021-01527-2. PMID: 33666875Free PMC Article
Miller WL
Sci Signal 2012 Oct 23;5(247):pt11. doi: 10.1126/scisignal.2003318. PMID: 23092891
Tomalik-Scharte D, Maiter D, Kirchheiner J, Ivison HE, Fuhr U, Arlt W
Eur J Endocrinol 2010 Dec;163(6):919-24. Epub 2010 Sep 15 doi: 10.1530/EJE-10-0764. PMID: 20844025Free PMC Article
Scott RR, Miller WL
Horm Res 2008;69(5):266-75. Epub 2008 Feb 6 doi: 10.1159/000114857. PMID: 18259105

Clinical prediction guides

Nurhafizuddin M, Azizi A, Ming LC, Shafqat N
Molecules 2022 Jul 21;27(14) doi: 10.3390/molecules27144646. PMID: 35889519Free PMC Article
Dean B, Chrisp GL, Quartararo M, Maguire AM, Hameed S, King BR, Munns CF, Torpy DJ, Falhammar H, Rushworth RL
J Clin Endocrinol Metab 2020 Mar 1;105(3) doi: 10.1210/clinem/dgz255. PMID: 31825489
Miller WL
Sci Signal 2012 Oct 23;5(247):pt11. doi: 10.1126/scisignal.2003318. PMID: 23092891
Krone N, Arlt W
Best Pract Res Clin Endocrinol Metab 2009 Apr;23(2):181-92. doi: 10.1016/j.beem.2008.10.014. PMID: 19500762Free PMC Article
Krone N, Dhir V, Ivison HE, Arlt W
Clin Endocrinol (Oxf) 2007 Feb;66(2):162-72. doi: 10.1111/j.1365-2265.2006.02740.x. PMID: 17223983

Recent systematic reviews

Guo X, Zhang Y, Yu Y, Zhang L, Ullah K, Ji M, Jin B, Shu J
Front Endocrinol (Lausanne) 2022;13:982953. Epub 2022 Aug 31 doi: 10.3389/fendo.2022.982953. PMID: 36120452Free PMC Article
Dean B, Chrisp GL, Quartararo M, Maguire AM, Hameed S, King BR, Munns CF, Torpy DJ, Falhammar H, Rushworth RL
J Clin Endocrinol Metab 2020 Mar 1;105(3) doi: 10.1210/clinem/dgz255. PMID: 31825489

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