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Cortisone reductase deficiency 1(CORTRD1)

MedGen UID:
764630
•Concept ID:
C3551716
•
Disease or Syndrome
Synonym: CORTRD1
 
Gene (location): H6PD (1p36.22)
 
Monarch Initiative: MONDO:0011503
OMIM®: 604931

Definition

Cortisone reductase deficiency (CRD) results from a failure to regenerate the active glucocorticoid cortisol from cortisone via the enzyme 11-beta-hydroxysteroid dehydrogenase (HSD11B1; 600713). The oxoreductase activity of 11-beta-HSD requires the NADPH-regenerating enzyme hexose-6-phosphate dehydrogenase (H6PD; 138090) within the endoplasmic reticulum. Lack of cortisol regeneration stimulates ACTH-mediated adrenal hyperandrogenism, with males manifesting in early life with precocious pseudopuberty and females presenting in midlife with hirsutism, oligomenorrhea, and infertility. Biochemically, CRD is diagnosed through the assessment of urinary cortisol and cortisone metabolites and consists of measuring the tetrahydrocortisol (THF) plus 5-alpha-THF/tetrahydrocortisone (THE) ratio, which in CRD patients is typically less than 0.1 (reference range, 0.7 to 1.2) (summary by Lavery et al., 2008). Genetic Heterogeneity of Cortisone Reductase Deficiency CORTRD2 (614662) is caused by mutation in the HSD11B1 gene (600713) on chromosome 1q32. [from OMIM]

Clinical features

From HPO
Infertility disorder
MedGen UID:
43876
•Concept ID:
C0021359
•
Finding
Inability to conceive for at least one year after trying and having unprotected sex. Causes of female infertility include endometriosis, fallopian tubes obstruction, and polycystic ovary syndrome. Causes of male infertility include abnormal sperm production or function, blockage of the epididymis, blockage of the ejaculatory ducts, hypospadias, exposure to pesticides, and health related issues.
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Oligomenorrhea
MedGen UID:
18159
•Concept ID:
C0028949
•
Pathologic Function
Infrequent menses (less than 6 per year or more than 35 days between cycles).
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Obesity
MedGen UID:
18127
•Concept ID:
C0028754
•
Disease or Syndrome
Accumulation of substantial excess body fat.
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Acne
MedGen UID:
152379
•Concept ID:
C0702166
•
Disease or Syndrome
A skin condition in which there is an increase in sebum secretion by the pilosebaceous apparatus associated with open comedones (blackheads), closed comedones (whiteheads), and pustular nodules (papules, pustules, and cysts).
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Alopecia
MedGen UID:
7982
•Concept ID:
C0002170
•
Finding
A noncongenital process of hair loss, which may progress to partial or complete baldness.
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Hirsutism
MedGen UID:
42461
•Concept ID:
C0019572
•
Disease or Syndrome
Abnormally increased hair growth referring to a male pattern of body hair (androgenic hair).
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Precocious puberty
MedGen UID:
18752
•Concept ID:
C0034013
•
Disease or Syndrome
The onset of secondary sexual characteristics before a normal age. Although it is difficult to define normal age ranges because of the marked variation with which puberty begins in normal children, precocious puberty can be defined as the onset of puberty before the age of 8 years in girls or 9 years in boys.
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Recent clinical studies

Etiology

Role of a disordered steroid metabolome in the elucidation of sterol and steroid biosynthesis.
Shackleton CH
Lipids 2012 Jan;47(1):1-12. Epub 2011 Aug 27 doi: 10.1007/s11745-011-3605-6. PMID: 21874273Free PMC Article
Premature adrenarche: novel lessons from early onset androgen excess.
Idkowiak J, Lavery GG, Dhir V, Barrett TG, Stewart PM, Krone N, Arlt W
Eur J Endocrinol 2011 Aug;165(2):189-207. Epub 2011 May 26 doi: 10.1530/EJE-11-0223. PMID: 21622478
Mutations of the hexose-6-phosphate dehydrogenase gene rarely cause hyperandrogenemic polycystic ovary syndrome.
Qin K, Rosenfield RL
Steroids 2011 Jan;76(1-2):135-9. Epub 2010 Nov 2 doi: 10.1016/j.steroids.2010.10.001. PMID: 21050867Free PMC Article
Hexose-6-phosphate dehydrogenase: a new risk gene for multiple sclerosis.
Alcina A, Ramagopalan SV, Fernández O, Catalá-Rabasa A, Fedetz M, Ndagire D, Leyva L, Arnal C, Delgado C, Lucas M, Izquierdo G, Ebers GC, Matesanz F
Eur J Hum Genet 2010 May;18(5):618-20. Epub 2009 Nov 25 doi: 10.1038/ejhg.2009.213. PMID: 19935835Free PMC Article
Genotypes at 11beta-hydroxysteroid dehydrogenase type 11B1 and hexose-6-phosphate dehydrogenase loci are not risk factors for apparent cortisone reductase deficiency in a large population-based sample.
White PC
J Clin Endocrinol Metab 2005 Oct;90(10):5880-3. Epub 2005 Aug 9 doi: 10.1210/jc.2005-0942. PMID: 16091483

Diagnosis

Estimation of reference curves for the urinary steroid metabolome in the first year of life in healthy children: Tracing the complexity of human postnatal steroidogenesis.
Dhayat NA, Frey AC, Frey BM, d'Uscio CH, Vogt B, Rousson V, Dick B, Flück CE
J Steroid Biochem Mol Biol 2015 Nov;154:226-36. Epub 2015 Aug 19 doi: 10.1016/j.jsbmb.2015.07.024. PMID: 26297192
Premature adrenarche: novel lessons from early onset androgen excess.
Idkowiak J, Lavery GG, Dhir V, Barrett TG, Stewart PM, Krone N, Arlt W
Eur J Endocrinol 2011 Aug;165(2):189-207. Epub 2011 May 26 doi: 10.1530/EJE-11-0223. PMID: 21622478
Gas chromatography/mass spectrometry (GC/MS) remains a pre-eminent discovery tool in clinical steroid investigations even in the era of fast liquid chromatography tandem mass spectrometry (LC/MS/MS).
Krone N, Hughes BA, Lavery GG, Stewart PM, Arlt W, Shackleton CH
J Steroid Biochem Mol Biol 2010 Aug;121(3-5):496-504. Epub 2010 Apr 22 doi: 10.1016/j.jsbmb.2010.04.010. PMID: 20417277Free PMC Article
Physiological roles of 11 beta-hydroxysteroid dehydrogenase type 1 and hexose-6-phosphate dehydrogenase.
White PC, Rogoff D, McMillan DR
Curr Opin Pediatr 2008 Aug;20(4):453-7. doi: 10.1097/MOP.0b013e328305e439. PMID: 18622204
11beta-hydroxysteroid dehydrogenase type 1 deficiency ('apparent cortisone reductase deficiency') in a 6-year-old boy.
Małunowicz EM, Romer TE, Urban M, Bossowski A
Horm Res 2003;59(4):205-10. doi: 10.1159/000069326. PMID: 12649576

Therapy

A follow-up history of young man with apparent cortisone reductase deficiency (ACRD) - several years after diagnosis.
Zajkowska A, Rydzewska M, Wojtkielewicz K, Pomaski J, Romer T, Bossowski A
Pediatr Endocrinol Diabetes Metab 2017;23(1):42-48. doi: 10.18544/PEDM-23.01.0073. PMID: 29073307
11beta-hydroxysteroid dehydrogenase type 1 deficiency ('apparent cortisone reductase deficiency') in a 6-year-old boy.
Małunowicz EM, Romer TE, Urban M, Bossowski A
Horm Res 2003;59(4):205-10. doi: 10.1159/000069326. PMID: 12649576
Apparent cortisone reductase deficiency: a functional defect in 11beta-hydroxysteroid dehydrogenase type 1.
Jamieson A, Wallace AM, Andrew R, Nunez BS, Walker BR, Fraser R, White PC, Connell JM
J Clin Endocrinol Metab 1999 Oct;84(10):3570-4. doi: 10.1210/jcem.84.10.6031. PMID: 10522997

Prognosis

A follow-up history of young man with apparent cortisone reductase deficiency (ACRD) - several years after diagnosis.
Zajkowska A, Rydzewska M, Wojtkielewicz K, Pomaski J, Romer T, Bossowski A
Pediatr Endocrinol Diabetes Metab 2017;23(1):42-48. doi: 10.18544/PEDM-23.01.0073. PMID: 29073307
Genetic variation in 11beta-hydroxysteroid dehydrogenase type 1 predicts adrenal hyperandrogenism among lean women with polycystic ovary syndrome.
Gambineri A, Vicennati V, Genghini S, Tomassoni F, Pagotto U, Pasquali R, Walker BR
J Clin Endocrinol Metab 2006 Jun;91(6):2295-302. Epub 2006 Mar 21 doi: 10.1210/jc.2005-2222. PMID: 16551740

Clinical prediction guides

Mutations of the hexose-6-phosphate dehydrogenase gene rarely cause hyperandrogenemic polycystic ovary syndrome.
Qin K, Rosenfield RL
Steroids 2011 Jan;76(1-2):135-9. Epub 2010 Nov 2 doi: 10.1016/j.steroids.2010.10.001. PMID: 21050867Free PMC Article
Hexose-6-phosphate dehydrogenase: a new risk gene for multiple sclerosis.
Alcina A, Ramagopalan SV, Fernández O, Catalá-Rabasa A, Fedetz M, Ndagire D, Leyva L, Arnal C, Delgado C, Lucas M, Izquierdo G, Ebers GC, Matesanz F
Eur J Hum Genet 2010 May;18(5):618-20. Epub 2009 Nov 25 doi: 10.1038/ejhg.2009.213. PMID: 19935835Free PMC Article
Lack of Association of the 11beta-hydroxysteroid dehydrogenase type 1 gene 83,557insA and hexose-6-phosphate dehydrogenase gene R453Q polymorphisms with body composition, adrenal androgen production, blood pressure, glucose metabolism, and dementia.
Smit P, Dekker MJ, de Jong FJ, van den Beld AW, Koper JW, Pols HA, Brinkmann AO, de Jong FH, Breteler MM, Lamberts SW
J Clin Endocrinol Metab 2007 Jan;92(1):359-62. Epub 2006 Oct 24 doi: 10.1210/jc.2006-1349. PMID: 17062770
Genetic variation in 11beta-hydroxysteroid dehydrogenase type 1 predicts adrenal hyperandrogenism among lean women with polycystic ovary syndrome.
Gambineri A, Vicennati V, Genghini S, Tomassoni F, Pagotto U, Pasquali R, Walker BR
J Clin Endocrinol Metab 2006 Jun;91(6):2295-302. Epub 2006 Mar 21 doi: 10.1210/jc.2005-2222. PMID: 16551740
11beta-hydroxysteroid dehydrogenase and the pre-receptor regulation of corticosteroid hormone action.
Draper N, Stewart PM
J Endocrinol 2005 Aug;186(2):251-71. doi: 10.1677/joe.1.06019. PMID: 16079253

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