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21-hydroxylase deficiency

MedGen UID:
468578
Concept ID:
C0852654
Disease or Syndrome
Synonyms: 21-Hydroxylase-Deficient Congenital Adrenal Hyperplasia; ADRENAL HYPERPLASIA III; Adrenal hyperplasia, congenital, due to 21-hydroxylase deficiency; CYP21 deficiency
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Sources: HPO, OMIM, 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 homozygotes. In the context of medical genetics, autosomal recessive disorders manifest in homozygotes (with two copies of the mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
Autosomal recessive inheritance (HPO, OMIM, Orphanet)
 
Gene (location): CYP21A2 (6p21.33)
OMIM®: 201910

Disease characteristics

21-hydroxylase deficiency (21-OHD) is the most common cause of congenital adrenal hyperplasia (CAH), a family of autosomal recessive disorders involving impaired synthesis of cortisol from cholesterol by the adrenal cortex. In 21-OHD CAH, excessive adrenal androgen biosynthesis results in virilization in all individuals and salt wasting in some individuals. A classic form with severe enzyme deficiency and prenatal onset of virilization is distinguished from a non-classic form with mild enzyme deficiency and postnatal onset. The classic form is further divided into the simple virilizing form (~25% of affected individuals) and the salt-wasting form, in which aldosterone production is inadequate (≥75% of individuals). Newborns with salt-wasting 21-OHD CAH are at risk for life-threatening salt-wasting crises. Individuals with the non-classic form of 21-OHD CAH present postnatally with signs of hyperandrogenism; females with the non-classic form are not virilized at birth. [from GeneReviews]
Authors:
Saroj Nimkarn  |  Prasanna K Gangishetti  |  Mabel Yau, et. al.   view full author information

Additional descriptions

From OMIM
Congenital adrenal hyperplasia (CAH) results from a deficiency in one or another of the enzymes of cortisol biosynthesis. In about 95% of cases, 21-hydroxylation is impaired in the zona fasciculata of the adrenal cortex so that 17-hydroxyprogesterone (17-OHP) is not converted to 11-deoxycortisol. Because of defective cortisol synthesis, ACTH levels increase, resulting in overproduction and accumulation of cortisol precursors, particularly 17-OHP, proximal to the block. This causes excessive production of androgens, resulting in virilization. Slominski et al. (1996) presented evidence that the CYP21A2, CYP11A1 (118485), CYP17 (609300), and ACTHR (202200) genes are expressed in skin (see 202200). The authors suggested that expression of these genes may play a role in skin physiology and pathology and that cutaneous proopiomelanocortin activity may be autoregulated by a feedback mechanism involving glucocorticoids synthesized locally.  http://www.omim.org/entry/201910
From GHR
21-hydroxylase deficiency is an inherited disorder that affects the adrenal glands. The adrenal glands are located on top of the kidneys and produce a variety of hormones that regulate many essential functions in the body. In people with 21-hydroxylase deficiency, the adrenal glands produce excess androgens, which are male sex hormones.There are three types of 21-hydroxylase deficiency. Two types are classic forms, known as the salt-wasting and simple virilizing types. The third type is called the non-classic type. The salt-wasting type is the most severe, the simple virilizing type is less severe, and the non-classic type is the least severe form.Males and females with either classic form of 21-hydroxylase deficiency tend to have an early growth spurt, but their final adult height is usually shorter than others in their family. Additionally, affected individuals may have a reduced ability to have biological children (decreased fertility). Females may also develop excessive body hair growth (hirsutism), male pattern baldness, and irregular menstruation.Approximately 75 percent of individuals with classic 21-hydroxylase deficiency have the salt-wasting type. Hormone production is extremely low in this form of the disorder. Affected individuals lose large amounts of sodium in their urine, which can be life-threatening in early infancy. Babies with the salt-wasting type can experience poor feeding, weight loss, dehydration, and vomiting. Individuals with the simple virilizing form do not experience salt loss.In both the salt-wasting and simple virilizing forms of this disorder, females typically have external genitalia that do not look clearly male or female (ambiguous genitalia). Males usually have normal genitalia, but the testes may be small.Females with the non-classic type of 21-hydroxylase deficiency have normal female genitalia. As affected females get older, they may experience hirsutism, male pattern baldness, irregular menstruation, and decreased fertility. Males with the non-classic type may have early beard growth and small testes. Some individuals with this type of 21-hydroxylase deficiency have no symptoms of the disorder.  https://ghr.nlm.nih.gov/condition/21-hydroxylase-deficiency

Clinical features

Fever
MedGen UID:
5169
Concept ID:
C0015967
Sign or Symptom
A condition characterized by an abnormally high body temperature. In a hyperthermic state, the hypothalamic set-point is normal but body temperature increases and overrides the ability to lose heat, resulting from exogenous heat exposure or endogenous heat production.
Gynecomastia
MedGen UID:
6694
Concept ID:
C0018418
Disease or Syndrome
Abnormal development of large mammary glands in males resulting in breast enlargement.
Hypertension
MedGen UID:
6969
Concept ID:
C0020538
Disease or Syndrome
Blood pressure that is abnormally high.
Hypoglycemia
MedGen UID:
6979
Concept ID:
C0020615
Disease or Syndrome
A decreased concentration of glucose in the blood.
Growth abnormality
MedGen UID:
808205
Concept ID:
C0262361
Finding
Adrenogenital syndrome
MedGen UID:
86215
Concept ID:
C0302280
Disease or Syndrome
Abnormal SEX DIFFERENTIATION or congenital DISORDERS OF SEX DEVELOPMENT caused by abnormal levels of steroid hormones expressed by the GONADS or the ADRENAL GLANDS, such as in CONGENITAL ADRENAL HYPERPLASIA and ADRENAL CORTEX NEOPLASMS. Due to abnormal steroid biosynthesis, clinical features include VIRILISM in females; FEMINIZATION in males; or precocious sexual development in children.
Adrenal hyperplasia
MedGen UID:
301220
Concept ID:
C1621895
Disease or Syndrome
A congenital or acquired hyperplasia of the cells of the adrenal cortex or medulla.
Hypospadias
MedGen UID:
305577
Concept ID:
C1691215
Congenital Abnormality
Abnormal position of urethral meatus on the ventral penile shaft (underside) characterized by displacement of the urethral meatus from the tip of the glans penis to the ventral surface of the penis, scrotum, or perineum.
Renal salt wasting
MedGen UID:
375868
Concept ID:
C1846347
Finding
A high concentration of one or more electrolytes in the urine in the presence of low serum concentrations of the electrolyte(s).
Abnormality of the thorax
MedGen UID:
867424
Concept ID:
C4021797
Anatomical Abnormality
Any abnormality of the thorax (the region of the body formed by the sternum, the thoracic vertebrae and the ribs).

Professional guidelines

PubMed

Speiser PW, Azziz R, Baskin LS, Ghizzoni L, Hensle TW, Merke DP, Meyer-Bahlburg HF, Miller WL, Montori VM, Oberfield SE, Ritzen M, White PC; Endocrine Society.
J Clin Endocrinol Metab 2010 Sep;95(9):4133-60. doi: 10.1210/jc.2009-2631. PMID: 20823466Free PMC Article

External

American College of Medical Genetics ACT SHEET, Congenital Adrenal Hyperplasia, 2011

American College of Medical Genetics Algorithm, Congenital Adrenal Hyperplasia, 2009

Recent clinical studies

Etiology

Carmina E, Dewailly D, Escobar-Morreale HF, Kelestimur F, Moran C, Oberfield S, Witchel SF, Azziz R
Hum Reprod Update 2017 Sep 1;23(5):580-599. doi: 10.1093/humupd/dmx014. PMID: 28582566
Zhang B, Lu L, Lu Z
J Int Med Res 2017 Apr;45(2):481-492. Epub 2017 Feb 2 doi: 10.1177/0300060516685204. PMID: 28415939Free PMC Article
Kamrath C, Wettstaedt L, Boettcher C, Hartmann MF, Wudy SA
J Steroid Biochem Mol Biol 2017 Jan;165(Pt B):396-406. Epub 2016 Aug 17 doi: 10.1016/j.jsbmb.2016.08.006. PMID: 27544322
Dumic KK, Grubic Z, Yuen T, Wilson RC, Kusec V, Barisic I, Stingl K, Sansovic I, Skrabic V, Dumic M, New MI
J Steroid Biochem Mol Biol 2017 Jan;165(Pt A):51-56. Epub 2016 Mar 31 doi: 10.1016/j.jsbmb.2016.03.035. PMID: 27041116
Wang R, Yu Y, Ye J, Han L, Qiu W, Zhang H, Liang L, Gong Z, Wang L, Gu X
Steroids 2016 Apr;108:47-55. Epub 2016 Jan 21 doi: 10.1016/j.steroids.2016.01.007. PMID: 26804566

Diagnosis

Carmina E, Dewailly D, Escobar-Morreale HF, Kelestimur F, Moran C, Oberfield S, Witchel SF, Azziz R
Hum Reprod Update 2017 Sep 1;23(5):580-599. doi: 10.1093/humupd/dmx014. PMID: 28582566
Concolino P, Rizza R, Costella A, Carrozza C, Zuppi C, Capoluongo E
Metabolism 2017 Jun;71:46-51. Epub 2017 Mar 9 doi: 10.1016/j.metabol.2017.03.003. PMID: 28521877
Zhang B, Lu L, Lu Z
J Int Med Res 2017 Apr;45(2):481-492. Epub 2017 Feb 2 doi: 10.1177/0300060516685204. PMID: 28415939Free PMC Article
Dumic KK, Grubic Z, Yuen T, Wilson RC, Kusec V, Barisic I, Stingl K, Sansovic I, Skrabic V, Dumic M, New MI
J Steroid Biochem Mol Biol 2017 Jan;165(Pt A):51-56. Epub 2016 Mar 31 doi: 10.1016/j.jsbmb.2016.03.035. PMID: 27041116
Wang R, Yu Y, Ye J, Han L, Qiu W, Zhang H, Liang L, Gong Z, Wang L, Gu X
Steroids 2016 Apr;108:47-55. Epub 2016 Jan 21 doi: 10.1016/j.steroids.2016.01.007. PMID: 26804566

Therapy

Carmina E, Dewailly D, Escobar-Morreale HF, Kelestimur F, Moran C, Oberfield S, Witchel SF, Azziz R
Hum Reprod Update 2017 Sep 1;23(5):580-599. doi: 10.1093/humupd/dmx014. PMID: 28582566
Bachelot A, Grouthier V, Courtillot C, Dulon J, Touraine P
Eur J Endocrinol 2017 Apr;176(4):R167-R181. Epub 2017 Jan 23 doi: 10.1530/EJE-16-0888. PMID: 28115464
Kamrath C, Wettstaedt L, Boettcher C, Hartmann MF, Wudy SA
J Steroid Biochem Mol Biol 2017 Jan;165(Pt B):396-406. Epub 2016 Aug 17 doi: 10.1016/j.jsbmb.2016.08.006. PMID: 27544322
Kashimada K, Ishii T, Nagasaki K, Ono M, Tajima T, Yokota I, Hasegawa Y
Endocr J 2015;62(3):277-82. Epub 2015 Jan 21 doi: 10.1507/endocrj.EJ14-0377. PMID: 25736066
Eyal O, Tenenbaum-Rakover Y, Shalitin S, Israel S, Weintrob N
Acta Paediatr 2013 Apr;102(4):419-23. Epub 2013 Jan 28 doi: 10.1111/apa.12147. PMID: 23298233

Prognosis

Savaş-Erdeve Ş, Çetinkaya S, Abalı ZY, Poyrazoğlu Ş, Baş F, Berberoğlu M, Sıklar Z, Korkmaz Ö, Buluş D, Akbaş ED, Güran T, Böber E, Akın O, Yılmaz GC, Aycan Z
J Pediatr Endocrinol Metab 2017 Jul 26;30(7):759-766. doi: 10.1515/jpem-2017-0088. PMID: 28672743
Zhang B, Lu L, Lu Z
J Int Med Res 2017 Apr;45(2):481-492. Epub 2017 Feb 2 doi: 10.1177/0300060516685204. PMID: 28415939Free PMC Article
Kim JH, Choi JH, Kang E, Kim YM, Lee BH, Yoo HW
Exp Clin Endocrinol Diabetes 2017 Mar;125(3):196-201. Epub 2017 Jan 10 doi: 10.1055/s-0042-123037. PMID: 28073127
Wang R, Yu Y, Ye J, Han L, Qiu W, Zhang H, Liang L, Gong Z, Wang L, Gu X
Steroids 2016 Apr;108:47-55. Epub 2016 Jan 21 doi: 10.1016/j.steroids.2016.01.007. PMID: 26804566
Kamrath C, Hartmann MF, Wudy SA
J Steroid Biochem Mol Biol 2014 Sep;143:386-91. Epub 2014 May 23 doi: 10.1016/j.jsbmb.2014.05.008. PMID: 24861266

Clinical prediction guides

Zhang B, Lu L, Lu Z
J Int Med Res 2017 Apr;45(2):481-492. Epub 2017 Feb 2 doi: 10.1177/0300060516685204. PMID: 28415939Free PMC Article
Dumic KK, Grubic Z, Yuen T, Wilson RC, Kusec V, Barisic I, Stingl K, Sansovic I, Skrabic V, Dumic M, New MI
J Steroid Biochem Mol Biol 2017 Jan;165(Pt A):51-56. Epub 2016 Mar 31 doi: 10.1016/j.jsbmb.2016.03.035. PMID: 27041116
Wang R, Yu Y, Ye J, Han L, Qiu W, Zhang H, Liang L, Gong Z, Wang L, Gu X
Steroids 2016 Apr;108:47-55. Epub 2016 Jan 21 doi: 10.1016/j.steroids.2016.01.007. PMID: 26804566
Coeli-Lacchini FB, Turatti W, Elias PC, Elias LL, Martinelli CE Jr, Moreira AC, Antonini SR, de Castro M
Gene 2013 Sep 10;526(2):239-45. Epub 2013 Apr 6 doi: 10.1016/j.gene.2013.03.082. PMID: 23570880
Gonçalves EM, Silva AM, Matias CN, Lemos-Marini SH, Santos AO, Guerra-Júnior G
Clin Nutr 2013 Feb;32(1):45-50. Epub 2012 May 29 doi: 10.1016/j.clnu.2012.05.007. PMID: 22647418

Recent systematic reviews

Carmina E, Dewailly D, Escobar-Morreale HF, Kelestimur F, Moran C, Oberfield S, Witchel SF, Azziz R
Hum Reprod Update 2017 Sep 1;23(5):580-599. doi: 10.1093/humupd/dmx014. PMID: 28582566
Houben CH, Tsui SY, Mou JW, Chan KW, Tam YH, Lee KH
Hong Kong Med J 2014 Dec;20(6):481-5. Epub 2014 Jul 18 doi: 10.12809/hkmj144227. PMID: 25045882
Gomes LG, Madureira G, Mendonca BB, Bachega TA
Clinics (Sao Paulo) 2013;68(2):147-52. PMID: 23525308Free PMC Article
Speiser PW, Azziz R, Baskin LS, Ghizzoni L, Hensle TW, Merke DP, Meyer-Bahlburg HF, Miller WL, Montori VM, Oberfield SE, Ritzen M, White PC; Endocrine Society.
J Clin Endocrinol Metab 2010 Sep;95(9):4133-60. doi: 10.1210/jc.2009-2631. PMID: 20823466Free PMC Article
Merke DP, Bornstein SR, Avila NA, Chrousos GP
Ann Intern Med 2002 Feb 19;136(4):320-34. PMID: 11848730

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