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'{{Redirect|Adrenal hyperplasia|text=See also [[primary aldosteronism]] or [[Cushing's syndrome]]}} {{Use dmy dates|date=March 2020}}{{Infobox medical condition |name = Congenital adrenal hyperplasia |synonym = |image = |image_size = |image_thumbtime = |alt = |caption = |pronounce = |specialty = <!--from Wikidata; can be overwritten--> |symptoms = [[Natriuresis|Excessive urination of sodium]], [[virilism]], [[precocious puberty|early]], [[delayed puberty|delayed, or absent puberty]], [[hyperandrogenism]] |complications = |onset = [[Uterus|Before birth]] |duration = Lifetime |types = |causes = Variants in genes responsible the [[enzymes]] required for the [[Biosynthesis|synthesis]] of cortisol in the [[adrenal cortex]] |risks = |diagnosis = |differential = |prevention = |treatment = <!-- or |management = --> |medication = |prognosis = |frequency = |deaths = }}'''Congenital adrenal hyperplasia''' ('''CAH''') is a group of [[Genetic disorder#Autosomal recessive|autosomal recessive disorders]] characterized by impaired [[cortisol]] synthesis.<ref name="pmid28576284">{{cite journal | vauthors = El-Maouche D, Arlt W, Merke DP | title = Congenital adrenal hyperplasia | journal = Lancet | volume = 390 | issue = 10108 | pages = 2194–2210 | date = November 2017 | pmid = 28576284 | doi = 10.1016/S0140-6736(17)31431-9 | s2cid = 13737960 | url = http://pure-oai.bham.ac.uk/ws/files/41341465/THELANCET_D_16_08898R1_2.pdf}}</ref><ref name="pmid30272171">{{cite journal | name-list-style=vanc |pmid=30272171|year=2018|last1=Speiser|first1=P. W.|last2=Arlt|first2=W.|last3=Auchus|first3=R. J.|last4=Baskin|first4=L. S.|last5=Conway|first5=G. S.|last6=Merke|first6=D. P.|author7=Meyer-Bahlburg HFL|last8=Miller|first8=W. L.|last9=Murad|first9=M. H.|last10=Oberfield|first10=S. E.|last11=White|first11=P. C.|title=Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clinical Practice Guideline|journal=The Journal of Clinical Endocrinology and Metabolism|volume=103|issue=11|pages=4043–4088|doi=10.1210/jc.2018-01865|pmc=6456929}}</ref> It results from the deficiency of one of the five [[enzymes]] required for the [[Biosynthesis|synthesis]] of cortisol in the [[adrenal cortex]].<ref name="pmid12930931">{{cite journal | vauthors = Speiser PW, White PC | title = Congenital adrenal hyperplasia | journal = [[The New England Journal of Medicine]] | volume = 349 | issue = 8 | pages = 776–88 | date = August 2003 | pmid = 12930931 | doi = 10.1056/NEJMra021561}}</ref> Most of these disorders involve excessive or deficient production of [[hormone]]s such as [[glucocorticoid]]s, [[mineralocorticoid]]s, or [[sex steroid]]s,<ref>{{cite journal |last1=La |first1=Betty |last2=Tung |first2=Celestine |last3=Choi |first3=Eugene A. |last4=Nguyen |first4=Ha |title=A Gigantic Uterine Leiomyoma and Big Bilateral Adrenal Myelolipomas as a Result of Untreated Congenital Adrenal Hyperplasia |journal=AACE Clinical Case Reports |date=1 November 2021 |volume=7 |issue=6 |pages=342–345 |doi=10.1016/j.aace.2021.05.002 |pmid=34765728 |pmc=8573279 }}</ref><ref name="pmid30272171"/> and can alter development of [[primary sex characteristic|primary]] or [[secondary sex characteristic]]s in some affected [[infant]]s, children, or adults.<ref name="MilunskyMilunsky2010">{{cite book|author1=Aubrey Milunsky|author2=Jeff Milunsky|title=Genetic Disorders and the Fetus: Diagnosis, Prevention and Treatment|url=https://books.google.com/books?id=oKCmA4dOYtMC&pg=PA600|access-date=14 June 2010|date=29 January 2010|publisher=John Wiley and Sons|isbn=978-1-4051-9087-9|pages=600–}}</ref> It is one of the most common autosomal recessive disorders in humans.<ref name="pmid9556656">{{cite journal | vauthors = Speiser PW, Dupont B, Rubinstein P, Piazza A, Kastelan A, New MI | title = High frequency of nonclassical steroid 21-hydroxylase deficiency | journal = American Journal of Human Genetics | volume = 37 | issue = 4 | pages = 650–67 | date = July 1985 | pmid = 9556656 | pmc = 1684620}}</ref><ref name="pmid19500762">{{cite journal | vauthors = Krone N, Arlt W | title = Genetics of congenital adrenal hyperplasia | journal = Best Practice & Research. Clinical Endocrinology & Metabolism | volume = 23 | issue = 2 | pages = 181–92 | date = April 2009 | pmid = 19500762 | pmc = 5576025 | doi = 10.1016/j.beem.2008.10.014}}</ref><ref name="pmid26865584">{{cite journal | vauthors = Turcu AF, Nanba AT, Chomic R, Upadhyay SK, Giordano TJ, Shields JJ, Merke DP, Rainey WE, Auchus RJ | title = Adrenal-derived 11-oxygenated 19-carbon steroids are the dominant androgens in classic 21-hydroxylase deficiency | journal = European Journal of Endocrinology | volume = 174 | issue = 5 | pages = 601–9 | date = May 2016 | pmid = 26865584 | pmc = 4874183 | doi = 10.1530/EJE-15-1181}}</ref> ==Types== CAH can occur in various forms. The clinical presentation of each form is different and depends to a large extent on the underlying enzyme defect, its precursor retention, and deficient products.<ref name="pmid25905188">{{cite book | vauthors = Feingold KR, Anawalt B, Boyce A, Chrousos G, de Herder WW, Dungan K, Grossman A, Hershman JM, Hofland HJ, Kaltsas G, Koch C, Kopp P, Korbonits M, McLachlan R, Morley JE, New M, Purnell J, Singer F, Stratakis CA, Trence DL, Wilson DP, New M, Yau M, Lekarev O, Lin-Su K, Parsa A, Pina C, Yuen T, Khattab A | title = Congenital Adrenal Hyperplasia | url=https://www.ncbi.nlm.nih.gov/books/NBK278953/ | date = 15 March 2017 | publisher = MDText.com, Inc | pmid = 25905188}}</ref> Classical forms appear in infancy, and nonclassical forms appear in late childhood. The presentation in patients with classic CAH can be further subdivided into three forms: salt-wasting, simple-virilizing, and non-classic (NC) depending on whether mineralocorticoid deficiency presents or absents, respectively.<ref>{{Cite journal |last1=Speiser |first1=Phyllis W. |last2=Arlt |first2=Wiebke |last3=Auchus |first3=Richard J. |last4=Baskin |first4=Laurence S. |last5=Conway |first5=Gerard S. |last6=Merke |first6=Deborah P. |last7=Meyer-Bahlburg |first7=Heino F. L. |last8=Miller |first8=Walter L. |last9=Murad |first9=M. Hassan |last10=Oberfield |first10=Sharon E. |last11=White |first11=Perrin C. |date=2018-11-01 |title=Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clinical Practice Guideline |journal=The Journal of Clinical Endocrinology and Metabolism |volume=103 |issue=11 |pages=4043–4088 |doi=10.1210/jc.2018-01865 |issn=1945-7197 |pmc=6456929 |pmid=30272171}}</ref><ref name=pmid35799332>{{Cite journal |last1=Nordenström |first1=Anna |last2=Lajic |first2=Svetlana |last3=Falhammar |first3=Henrik |date=2022-07-08 |title=Long-Term Outcomes of Congenital Adrenal Hyperplasia |journal=Endocrinology and Metabolism |language=English |volume=37 |issue=4 |pages=587–598 |doi=10.3803/EnM.2022.1528 |issn=2093-596X |pmc=9449109 |pmid=35799332}}</ref><ref name = "pmid20558634">{{cite journal | name-list-style=vanc |pmid=20558634|year=2010|last1=Dauber|first1=A.|last2=Kellogg|first2=M.|last3=Majzoub|first3=J. A.|title=Monitoring of therapy in congenital adrenal hyperplasia|journal=Clinical Chemistry|volume=56|issue=8|pages=1245–51|doi=10.1373/clinchem.2010.146035|doi-access=free}}</ref> This subtyping is often not clinically meaningful, though, because all patients lose salt to some degree, and clinical presentations may overlap.<ref name="pmid32966723">{{cite journal | vauthors = Merke DP, Auchus RJ | title = Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency | journal = The New England Journal of Medicine | volume = 383 | issue = 13 | pages = 1248–1261 | date = September 2020 | pmid = 32966723 | doi = 10.1056/NEJMra1909786 | s2cid = 221884108 }}</ref> === Classic === ====Salt-wasting==== In 75% of cases of severe enzyme deficiency, insufficient [[aldosterone]] production can lead to salt wasting, failure to thrive, and potentially fatal [[hypovolemia]] and shock. A missed diagnosis of salt-loss CAH is related to the increased risk of early [[neonatal]] morbidity and death.<ref name="pmid30272171"/> ====Simple-virilizing==== The main feature of CAH in newborn females is the abnormal development of the external genitalia, which has varying degrees of [[virilization]]. According to clinical practice guidelines, for newborns found to have bilateral inaccessible gonads, CAH evaluation should be considered. If virilizing CAH cannot be identified and treated, both boys and girls may undergo rapid postnatal growth and virilization.<ref name="pmid30272171"/> ===Nonclassic=== {{Main|Late onset congenital adrenal hyperplasia}}In addition to the salt-wasting and simple-virilizing forms of CAH diagnosed in infancy, a mild or "nonclassic" form exists, which is characterized by varying degrees of postnatal androgen excess, but is sometimes asymptomatic <ref>{{cite journal<ref>{{cite journal |last1=Adriaansen |first1=Bas P. H. |last2=Schröder |first2=Mariska A. M. |last3=Span |first3=Paul N. |last4=Sweep |first4=Fred C. G. J. |last5=van Herwaarden |first5=Antonius E. |last6=Claahsen-van der Grinten |first6=Hedi L. |title=Challenges in treatment of patients with non-classic congenital adrenal hyperplasia |journal=Frontiers in Endocrinology |date=12 December 2022 |volume=13 |doi=10.3389/fendo.2022.1064024}}</ref>. The nonclassic form may be noticed in late childhood and may lead to signs of hyperandrogenism such as accelerated growth, [[acne]], hirsutism, premature pubarche, menstrual irregularities<ref>{{cite journal |last1=Adriaansen |first1=Bas P. H. |last2=Schröder |first2=Mariska A. M. |last3=Span |first3=Paul N. |last4=Sweep |first4=Fred C. G. J. |last5=van Herwaarden |first5=Antonius E. |last6=Claahsen-van der Grinten |first6=Hedi L. |title=Challenges in treatment of patients with non-classic congenital adrenal hyperplasia |journal=Frontiers in Endocrinology |date=12 December 2022 |volume=13 |doi=10.3389/fendo.2022.1064024}}</ref>, and secondary [[polycystic ovary syndrome]].<ref name="NBK279085"/> In adult males, early balding <ref>{{cite journal |last1=Adriaansen |first1=Bas P. H. |last2=Schröder |first2=Mariska A. M. |last3=Span |first3=Paul N. |last4=Sweep |first4=Fred C. G. J. |last5=van Herwaarden |first5=Antonius E. |last6=Claahsen-van der Grinten |first6=Hedi L. |title=Challenges in treatment of patients with non-classic congenital adrenal hyperplasia |journal=Frontiers in Endocrinology |date=12 December 2022 |volume=13 |doi=10.3389/fendo.2022.1064024}}</ref> and infertility may suggest the diagnosis.|url=https://www.ncbi.nlm.nih.gov/books/NBK279085/ |title=Congenital Adrenal Hyperplasia: Diagnosis and Emergency Treatment|year=2000|publisher=MDText.com|pmid=25905311 |last1=Yau |first1=M. |last2=Gujral |first2=J. |last3=New |first3=M. I. |last4=Feingold |first4=K. R. |last5=Anawalt |first5=B. |last6=Boyce |first6=A. |last7=Chrousos |first7=G. |last8=De Herder |first8=W. W. |last9=Dhatariya |first9=K. |last10=Dungan |first10=K. |last11=Hershman |first11=J. M. |last12=Hofland |first12=J. |last13=Kalra |first13=S. |last14=Kaltsas |first14=G. |last15=Koch |first15=C. |last16=Kopp |first16=P. |last17=Korbonits |first17=M. |last18=Kovacs |first18=C. S. |last19=Kuohung |first19=W. |last20=Laferrère |first20=B. |last21=Levy |first21=M. |last22=McGee |first22=E. A. |last23=McLachlan |first23=R. |last24=Morley |first24=J. E. |last25=New |first25=M. |last26=Purnell |first26=J. |last27=Sahay |first27=R. |last28=Singer |first28=F. |last29=Sperling |first29=M. A. |last30=Stratakis |first30=C. A. |display-authors=1 }}</ref> The nonclassic form is characterized by mild subclinical impairment of cortisol synthesis <ref>{{cite journal |last1=Adriaansen |first1=Bas P. H. |last2=Schröder |first2=Mariska A. M. |last3=Span |first3=Paul N. |last4=Sweep |first4=Fred C. G. J. |last5=van Herwaarden |first5=Antonius E. |last6=Claahsen-van der Grinten |first6=Hedi L. |title=Challenges in treatment of patients with non-classic congenital adrenal hyperplasia |journal=Frontiers in Endocrinology |date=12 December 2022 |volume=13 |doi=10.3389/fendo.2022.1064024}}</ref>, serum cortisol concentration is usually normal <ref>{{cite journal |last1=Adriaansen |first1=Bas P. H. |last2=Schröder |first2=Mariska A. M. |last3=Span |first3=Paul N. |last4=Sweep |first4=Fred C. G. J. |last5=van Herwaarden |first5=Antonius E. |last6=Claahsen-van der Grinten |first6=Hedi L. |title=Challenges in treatment of patients with non-classic congenital adrenal hyperplasia |journal=Frontiers in Endocrinology |date=12 December 2022 |volume=13 |doi=10.3389/fendo.2022.1064024}}</ref>. ==Signs and symptoms== The symptoms of CAH vary depending upon the form of CAH and the sex of the patient. Symptoms can include: Due to inadequate [[mineralocorticoid]]s:{{citation needed|date=August 2020}} * [[Vomiting]] due to [[natriuresis|salt-wasting]], leading to [[dehydration]] and death Due to excess androgens: * In extreme [[virilization]], an elongated clitoris with a phallic-like structure is seen.<ref>{{Cite web|last=Philadelphia|first=The Children's Hospital of|date=2019-11-19|title=Classic congenital Adrenal Hyperplasia Diagnosed in the Newborn Period|url=https://www.chop.edu/news/classic-congenital-adrenal-hyperplasia-diagnosed-newborn-period|access-date=2020-09-05|website=www.chop.edu|language=en}}</ref><ref>{{Cite web|last1=New|first1=Maria|last2=Yau|first2=Mabel|last3=Lekarev|first3=Oksana|last4=Lin-Su|first4=Karen|last5=Parsa|first5=Alan|last6=Pina|first6=Christian|last7=Yuen|first7=Tony|last8=Khattab|first8=Ahmed|date=2017-03-15|title=Figure 2, [Different degrees of virilization according...].|url=https://www.ncbi.nlm.nih.gov/books/NBK278953/figure/congn-adren-hyprplsa_f_congn-adren-hyprplsa_etx-ped-ch8-fig2/|access-date=2020-09-05|website=www.ncbi.nlm.nih.gov|language=en}}</ref><ref>{{Cite web|title=Genital Birth Defects - Children's Health Issues|url=https://www.merckmanuals.com/home/children-s-health-issues/birth-defects-of-the-urinary-tract-and-genitals/genital-birth-defects|access-date=2020-09-05|website=Merck Manuals Consumer Version|language=en-US}}</ref> * [[Ambiguous genitalia]], in some infants, occurs such that initially identifying external genitalia as "male" or "female" is difficult. * Early [[pubarche|pubic hair]] and rapid growth occurs in childhood. * [[Precocious puberty]] or failure of [[puberty]] to occur ([[sexual infantilism]]: absent or [[delayed puberty]]) * [[Hirsutism|Excessive facial hair]], virilization, and/or [[menstrual cycle|menstrual irregularity]] in adolescence * [[Infertility]] due to [[anovulation]] * [[Clitoromegaly]], enlarged [[clitoris]] and shallow [[vagina]]<ref>Richard D. McAnulty, M. Michele Burnette (2006) ''[https://books.google.com/books?id=KBi9aG0pQAkC&pg=PA165&q=%22Digit%20ratio%22%20clitoris Sex and sexuality, Volume 1]'', [[Greenwood Publishing Group]], p.165</ref> Due to insufficient androgens and estrogens:{{citation needed|date=October 2016}} * [[Undervirilization]] in XY males can result in apparently female external genitalia. * [[Intersex|Ambiguous genitalia]] in XY males with 3β-hydroxysteroid dehydrogenase deficiency ([[Congenital adrenal hyperplasia due to 3β-hydroxysteroid dehydrogenase deficiency|3β-HSD2D]]). * In females, [[hypogonadism]] can cause [[sexual infantilism]] or abnormal pubertal development, [[infertility]], and other reproductive system abnormalities. ==Genetics== CAH results from [[mutation]]s of [[gene]]s for [[enzyme]]s mediating the biochemical steps of production of [[mineralocorticoids]], [[glucocorticoids]], or [[sex steroids]] from [[cholesterol]] by the [[adrenal gland]]s ([[steroidogenesis]]).<ref name="Warrell2005">{{cite book|author=David A. Warrell|title=Oxford textbook of medicine: Sections 18-33|url=https://books.google.com/books?id=hL1NKQJlY1IC&pg=PA261|access-date=14 June 2010|year=2005|publisher=Oxford University Press|isbn=978-0-19-856978-7|pages=261–}}</ref> Each form of CAH is associated with a specific defective gene. The most common type (95% of cases)<ref name="pmid30272171"/><ref name=pmid35799332/>involves the gene for [[21-hydroxylase]], which is found on 6p21.3 as part of the HLA complex; 21-hydroxylase deficiency results from a unique mutation with two highly homologous near-copies in series consisting of an active gene (''CYP21A2'') and an inactive pseudogene (''CYP21A1P'').<ref>{{Cite journal |last1=Gidlöf |first1=Sebastian |last2=Falhammar |first2=Henrik |last3=Thilén |first3=Astrid |last4=Döbeln |first4=Ulrika von |last5=Ritzén |first5=Martin |last6=Wedell |first6=Anna |last7=Nordenström |first7=Anna |date=2013-09-01 |title=One hundred years of congenital adrenal hyperplasia in Sweden: a retrospective, population-based cohort study |url=https://www.thelancet.com/journals/landia/article/PIIS2213-8587(13)70007-X/fulltext |journal=The Lancet Diabetes & Endocrinology |language=English |volume=1 |issue=1 |pages=35–42 |doi=10.1016/S2213-8587(13)70007-X |pmid=24622265 |issn=2213-8587}}</ref><ref>{{Cite journal |last1=Arlt |first1=Wiebke |last2=Willis |first2=Debbie S. |last3=Wild |first3=Sarah H. |last4=Krone |first4=Nils |last5=Doherty |first5=Emma J. |last6=Hahner |first6=Stefanie |last7=Han |first7=Thang S. |last8=Carroll |first8=Paul V. |last9=Conway |first9=Gerry S. |last10=Rees |first10=D. Aled |last11=Stimson |first11=Roland H. |last12=Walker |first12=Brian R. |last13=Connell |first13=John M. C. |last14=Ross |first14=Richard J. |date=2010-08-18 |title=Health Status of Adults with Congenital Adrenal Hyperplasia: A Cohort Study of 203 Patients |journal=The Journal of Clinical Endocrinology & Metabolism |language=en |volume=95 |issue=11 |pages=5110–5121 |doi=10.1210/jc.2010-0917 |issn=0021-972X |pmc=3066446 |pmid=20719839}}</ref><ref>{{Cite journal |last1=Strömer |first1=H. |last2=Cittadini |first2=A. |last3=Douglas |first3=P. S. |last4=Morgan |first4=J. P. |date=2022-01-12 |title=Exogenously administered growth hormone and insulin-like growth factor-I alter intracellular Ca2+ handling and enhance cardiac performance. In vitro evaluation in the isolated isovolumic buffer-perfused rat heart |url=https://pubmed.ncbi.nlm.nih.gov/8755999 |journal=Circulation Research |volume=79 |issue=2 |pages=227–236 |doi=10.1161/01.res.79.2.227 |issn=0009-7330 |pmid=8755999}}</ref> Mutant alleles result from recombination between the active and pseudogenes (gene conversion).<ref name="DeMais">{{cite book|last=Mais|first=Daniel D.|title=Quick compendium of clinical pathology|year=2008|publisher=ASCP Press|location=Chicago|isbn=978-0891895671|edition=2nd|url-access=registration|url=https://archive.org/details/quickcompendiumo0000mais}}</ref> About 5% of cases of CAH are due to defects in the gene encoding [[11β-hydroxylase]] and consequent [[11β-hydroxylase deficiency]]. Other, more rare forms of CAH are caused by mutations in genes, including ''[[HSD3B2]]'' (3β-hydroxysteroid dehydrogenase 2), ''[[CYP17A1]]'' (17α-hydroxylase/17,20-lyase),<ref name="Miller_2012">{{cite journal | vauthors = Miller WL | title = The syndrome of 17,20 lyase deficiency | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 97 | issue = 1 | pages = 59–67 | date = January 2012 | pmid = 22072737 | pmc = 3251937 | doi = 10.1210/jc.2011-2161 }}</ref>'' [[CYP11A1]]'' (P450scc; cholesterol side-chain cleavage enzyme), [[STAR (gene)|''STAR'']] ([[steroidogenic acute regulatory protein]]; StAR), ''[[CYB5A]]'' ([[cytochrome b5|cytochrome b₅]]), and ''CYPOR ''([[cytochrome P450 oxidoreductase]]; POR).{{citation needed|date=August 2020}} ===Expressivity=== Further variability is introduced by the degree of enzyme inefficiency produced by the specific [[allele]]s each patient has. Some alleles result in more severe degrees of enzyme inefficiency. In general, severe degrees of inefficiency produce changes in the fetus and problems in prenatal or perinatal life. Milder degrees of inefficiency are usually associated with excessive or deficient [[sex steroid|sex hormone]] effects in childhood or adolescence, while the mildest forms of CAH interfere with ovulation and fertility in adults.{{citation needed|date=March 2019}} ==Diagnosis== {{More citations needed section|date=October 2020}} ===Clinical evaluation=== Female infants with classic CAH have ambiguous genitalia due to exposure to high concentrations of androgens ''in utero''.<ref>{{Cite journal |last1=White |first1=P. C. |last2=Speiser |first2=P. W. |date=2000-06-01 |title=Congenital adrenal hyperplasia due to 21-hydroxylase deficiency |journal=Endocrine Reviews |volume=21 |issue=3 |pages=245–291 |doi=10.1210/edrv.21.3.0398 |issn=0163-769X |pmid=10857554|doi-access=free }}</ref> [[Congenital adrenal hyperplasia due to 21-hydroxylase deficiency|CAH due to 21-hydroxylase deficiency]] is the most common cause of ambiguous genitalia in genotypically normal female infants (46XX). Less severely affected females may present with early [[pubarche]]. Young women may present with symptoms of [[polycystic ovarian syndrome]] ([[oligomenorrhea]], polycystic ovaries, [[hirsutism]]).{{Medical citation needed|date=September 2020}} Males with classic CAH generally have no signs of CAH at birth. Some may present with [[hyperpigmentation]], due to co-secretion with melanocyte-stimulating hormone, and possible penile enlargement. Age of diagnosis of males with CAH varies and depends on the severity of [[aldosterone]] deficiency. Boys with salt-wasting disease present early with symptoms of [[hyponatremia]] and [[hypovolemia]]. Boys with non-salt-wasting disease present later with signs of virilization.<ref name="DeMais" /> In rarer forms of CAH, males are undermasculinized <ref>{{cite web|title=3-beta-hydroxysteroid dehydrogenase deficiency|url=https://medlineplus.gov/genetics/condition/3-beta-hydroxysteroid-dehydrogenase-deficiency/|url-status=live|access-date=2 June 2021|website=MedlinePlus|archive-url=https://web.archive.org/web/20200928130801/https://medlineplus.gov/genetics/condition/3-beta-hydroxysteroid-dehydrogenase-deficiency/ |archive-date=28 September 2020 }}</ref> and females generally have no signs or symptoms at birth.{{Medical citation needed|date=September 2020}} ===Laboratory studies=== Genetic analysis can be helpful to confirm a diagnosis of CAH, but it is not necessary if classic clinical and laboratory findings are present. In classic 21-hydroxylase deficiency, laboratory studies will show: :*'''Hypoglycemia''' (due to hypocortisolism) - One of cortisol's many functions is to increase blood glucose levels. This occurs via a combination of several mechanisms, including (a) the stimulation of gluconeogesis (i.e. the creation of new glucose) in the liver, (b) the promotion of glycogenolysis (i.e. the breakdown of glycogen into glucose), and (c) the prevention of glucose leaving the bloodstream via the downregulation of GLUT-4 receptors (which normally promote movement of glucose from the bloodstream into adipose and muscle tissues). Therefore, when cortisol is deficient, these processes (effectively) occur in the reverse direction. Although there are compensatory mechanisms that mitigate the impact of hypocortisolism, they are limited in their extent and the net effect is still hypoglycemia. :*'''Hyponatremia''' (due to hypoaldosteronism) - Aldosterone is the end product of the renin-angiotensin-aldosterone system that regulates blood pressure via blood pressure surveillance in the Kidney Juxtaglomerular apparatus. Aldosterone normally functions to increase sodium retention (which brings water as well) in exchange for potassium. Thus, lack of aldosterone causes hyperkalemia and hyponatremia. In fact, this is a distinguishing point from 11-hydroxylase deficiency, in which one of the increased products is 11-deoxycorticosterone that has weak mineralocorticoid activity. In 11-hydroxylase deficiency, 11-deoxycorticosterone is produced in such excess that it acts to retain sodium at the expense of potassium. It is this reason that patients with 11-hydroxylase deficiency do not show salt wasting (although sometimes they do in infancy), and instead have hypertension/water retention and sometimes hypokalemia. :*'''Hyperkalemia''' (due to hypoaldosteronism) :* Elevated [[17α-hydroxyprogesterone]] Classic 21-hydroxylase deficiency typically causes 17α-hydroxyprogesterone blood levels >242 nmol/L.{{Medical citation needed|date=September 2020}} (For comparison, a full-term infant at three days of age should have <3 nmol/L. Many neonatal screening programs have specific reference ranges by weight and gestational age because high levels may be seen in premature infants without CAH.) Salt-wasting patients tend to have higher 17α-hydroxyprogesterone levels than non-salt-wasting patients. In mild cases, 17α-hydroxyprogesterone may not be elevated in a particular random blood sample, but it will rise during a [[ACTH stimulation test|corticotropin stimulation test]]. ===Classification=== Cortisol is an adrenal steroid hormone required for normal endocrine function. Production begins in the second month of fetal life. Poor cortisol production is a hallmark of most forms of CAH. Inefficient cortisol production results in rising levels of [[adrenocorticotropic hormone|ACTH]], because cortisol feeds back to inhibit ACTH production, so loss of cortisol results in increased ACTH.<ref>{{Cite book|title=Robbins and Cotran pathologic basis of disease|others=Kumar, Vinay, 1944-, Abbas, Abul K.,, Aster, Jon C.,, Perkins, James A.|year=2014|isbn=9781455726134|edition=Ninth|location=Philadelphia, PA|pages=1128|oclc=879416939|last1 = Kumar|first1 = Vinay|last2 = Abbas|first2 = Abul K.|last3 = Aster|first3 = Jon C.}}</ref> This increased ACTH stimulation induces overgrowth (''hyperplasia'') and overactivity of the steroid-producing cells of the adrenal cortex. The defects causing adrenal hyperplasia are congenital (i.e. present at birth). [[File:Steroidogenesis.svg|thumb|400px|[[Steroidogenesis]]: The enzymes affected in CAH are represented by one red and four green bars on the top half of the diagram (for example, "21α-hydroxylase" is visible near the top center. "17α-hydroxylase" and "17,20 lyase" are carried out by a single enzyme).<ref name="HäggströmRichfield2014">{{cite journal|last2=Richfield|first2=David|year=2014|title=Diagram of the pathways of human steroidogenesis|journal=WikiJournal of Medicine|volume=1|issue=1|doi=10.15347/wjm/2014.005|issn=2002-4436|last1=Häggström|first1=Mikael|doi-access=free}}</ref> Depending upon which enzyme is unavailable, production of [[androgen]]s (lower left) or [[mineralocorticoid]]s (upper right) is reduced. This, in turn, can lead to increased production of other molecules, due to a buildup of precursors.]] Cortisol deficiency in CAH is usually partial, and not the most serious problem for an affected person. Synthesis of cortisol shares steps with synthesis of mineralocorticoids such as aldosterone, [[androgen]]s such as [[testosterone]], and [[estrogen]]s such as [[estradiol]]. The resulting excessive or deficient production of these three classes of hormones produce the most important problems for people with CAH. Specific enzyme inefficiencies are associated with characteristic patterns of over- or underproduction of mineralocorticoids or sex steroids. Since the 1960s, most endocrinologists have referred to the forms of CAH by the traditional names in the left column, which generally correspond to the deficient enzyme activity. As exact structures and genes for the enzymes were identified in the 1980s, most of the enzymes were found to be [[cytochrome P450 oxidase]]s and were renamed to reflect this. In some cases, more than one enzyme was found to participate in a reaction, and in other cases, a single enzyme mediated in more than one reaction. Variation in different tissues and mammalian species also was found. In all its forms, congenital adrenal hyperplasia due to 21-hydroxylase deficiency accounts for about 95% of diagnosed cases of CAH.<ref name="pmid30272171"/> Unless another specific enzyme is mentioned, "CAH" in nearly all contexts refers to 21-hydroxylase deficiency. (The terms "salt-wasting CAH", and "simple virilizing CAH" usually refer to subtypes of this condition.) CAH due to deficiencies of enzymes other than 21-hydroxylase present many of the same management challenges, as 21-hydroxylase deficiency, but some involve mineralocorticoid excess or sex steroid deficiency. {| class="wikitable" |- ! Common medical term ! % ! [[OMIM]] ! Enzyme(s) ! [[Locus (genetics)|Locus]] ! Substrate(s) ! Product(s) ! Mineralocorticoids ! Androgens |- | [[Congenital adrenal hyperplasia due to 21-hydroxylase deficiency|21-Hydroxylase CAH]] | 95%<ref name="pmid30272171"/> | {{OMIM|201910||none}} | [[P450c21]] | 6p21.3 | [[17-Hydroxyprogesterone|17-OH-Progesterone]]→<br />[[Progesterone]]→ | [[11-Deoxycortisol]]<br />[[11-Deoxycorticosterone|DOC]] | ↓ | ↑ |- | [[Congenital adrenal hyperplasia due to 11β-hydroxylase deficiency|11β-Hydroxylase CAH]] | 5% | {{OMIM|202010||none}} | [[P450c11β]] | 8q21-22 | 11-Deoxycortisol→<br />DOC→ | [[Cortisol]]<br />[[Corticosterone]] | ↑ | ↑ |- | [[Congenital adrenal hyperplasia due to 3β-hydroxysteroid dehydrogenase deficiency|3β-HSD CAH]] | Very rare | {{OMIM|201810||none}} | [[3βHSD2]] | 1p13 | [[Pregnenolone]]→<br />[[17-OH-Pregnenolone]]→<br />[[DHEA]]→ | [[Progesterone]]<br />17-OH-Progesterone<br />[[Androstenedione]] | ↓ | ↓ |- | [[Congenital adrenal hyperplasia due to 17α-hydroxylase deficiency|17α-Hydroxylase CAH]] | Very rare | {{OMIM|202110||none}} | [[CYP17A1]] | 10q24.3 | [[Pregnenolone]]→<br />[[Progesterone]]→<br />17-OH-Pregnenolone→ | 17-OH-Pregnenolone<br />17-OH-Progesterone<br />[[DHEA]] | ↑ | ↓ |- | [[Lipoid congenital adrenal hyperplasia|Lipoid CAH]]<br />(20,22-desmolase) | Very rare | {{OMIM|201710||none}} | [[StAR]]<br />[[P450scc]] | 8p11.2<br />15q23-q24 | Transport of [[cholesterol]]<br />[[Cholesterol]]→ | Into mitochondria<br />[[Pregnenolone]] | ↓ | ↓ |} ==Screening== Currently, in the United States and over 40 other countries, every child born is screened for 21-hydroxylase CAH at birth. This test detects elevated levels of [[17α-hydroxyprogesterone]] (17-OHP). Detecting high levels of 17-OHP enables early detection of CAH. Newborns detected early enough can be placed on medication and live relatively normal lives.{{citation needed|date=August 2020}} The screening process, however, is characterized by a high false-positive rate. In one study,<ref name="Pass & Neto">{{cite book|author1=Kenneth A. Pass|author2=Eurico Carmago Neto|title=Update: Newborn Screening for Endocrinopathies|url=http://pediatrics.evms.edu/residency/resgoals/ENDO/ENDORef-newborn-screening.pdf|access-date=12 December 2013|year=2005|pages=831–834|archive-url=https://web.archive.org/web/20140101065427/http://pediatrics.evms.edu/residency/resgoals/ENDO/ENDORef-newborn-screening.pdf|archive-date=1 January 2014|url-status=dead}}</ref> CAH screening had the lowest [[positive predictive value]] (111 true-positive cases among 20,647 abnormal screening results in a 2-year period, or 0.53%, compared with 6.36% for biotinidase deficiency, 1.84% for congenital hypo-thyroidism, 0.56% for classic galactosemia, and 2.9% for phenylketonuria). According to this estimate, 200 unaffected newborns required clinical and laboratory follow-up for every true case of CAH.{{Primary source inline|date=September 2020}} In 2020, Wael AbdAlmageed from [[University of Southern California|USC]] [[Information Sciences Institute]] and Mimi Kim from USC [[Keck School of Medicine of USC|Keck School Of Medicine]] led a joint study in which they used [[deep learning]] technology to analyze the facial morphology and features of CAH patients compared to control. In this cross-sectional study <ref>{{Cite journal |last1=AbdAlmageed |first1=Wael |last2=Mirzaalian |first2=Hengameh |last3=Guo |first3=Xiao |last4=Randolph |first4=Linda M. |last5=Tanawattanacharoen |first5=Veeraya K. |last6=Geffner |first6=Mitchell E. |last7=Ross |first7=Heather M. |last8=Kim |first8=Mimi S. |date=2020-11-18 |title=Assessment of Facial Morphologic Features in Patients With Congenital Adrenal Hyperplasia Using Deep Learning |url=https://doi.org/10.1001/jamanetworkopen.2020.22199 |journal=JAMA Network Open |volume=3 |issue=11 |pages=e2022199 |doi=10.1001/jamanetworkopen.2020.22199 |pmid=33206189 |pmc=7675110 |issn=2574-3805}}</ref> of 102 patients with CAH and 144 control participants, deep learning methods achieved a mean area under the receiver operating characteristic curve of 92% for predicting CAH from facial images. Facial features distinguished patients with CAH from controls, and analyses of facial regions found that the nose and upper face were most contributory. The findings suggest that facial morphologic features, as analyzed by deep neural network techniques, can be used as a [[Phenotype|phenotypic]] biomarker to predict CAH. ==Treatment== Since the clinical manifestations of each form of CAH are unique and depend to a large extent on the underlying enzyme defects, their precursor retention and defective products, the therapeutic goal of CAH is to replenish insufficient adrenal hormones and suppress excess of precursors.<ref name="pmid25905188"/> Treatment of all forms of CAH may include any of: # Supplying enough glucocorticoid to reduce hyperplasia and overproduction of androgens or mineralocorticoids{{citation needed|date=September 2020}} # Providing replacement mineralocorticoid and extra salt if the person is deficient<ref name="pmid30272171"/> # Providing replacement testosterone or estrogens at puberty if the person is deficient{{citation needed|date=September 2020}} # Additional treatments to optimize growth by delaying puberty or delaying [[bone maturation]]{{citation needed|date=September 2020}} If CAH is caused by the deficiency of the 21-hydroxylase enzyme, then treatment aims to normalize levels of androstenedione, but normalization of 17α-hydroxyprogesterone is a sign of overtreatment.<ref name=":0">{{Cite journal |last1=Adriaansen |first1=Bas P. H. |last2=Kamphuis |first2=Johannes S. |last3=Schröder |first3=Mariska A. M. |last4=Olthaar |first4=André J. |last5=Bock |first5=Carina |last6=Brandt |first6=André |last7=Stikkelbroeck |first7=Nike M. M. L. |last8=Lentjes |first8=Eef G. W. M. |last9=Span |first9=Paul N. |last10=Sweep |first10=Fred C. G. J. |last11=Claahsen‐van der Grinten |first11=Hedi L. |last12=van Herwaarden |first12=Antonius E. |date=2022 |title=Diurnal salivary androstenedione and 17‐hydroxyprogesterone levels in healthy volunteers for monitoring treatment efficacy of patients with congenital adrenal hyperplasia |journal=Clinical Endocrinology |language=en |volume=97 |issue=1 |pages=36–42 |doi=10.1111/cen.14690 |issn=0300-0664 |pmc=9542109 |pmid=35150157}}</ref> Treatment can be monitored by measuring androstenedione and 17α-hydroxyprogesterone levels in blood or saliva<ref name=":0" />.{{See also|Congenital adrenal hyperplasia due to 21-hydroxylase deficiency#Treatment}} ==Epidemiology== The incidence varies [[ethnically]]. In the United States, congenital adrenal hyperplasia in its classic form is particularly common in Native Americans and [[Yupik peoples|Yupik]] Inuit (incidence {{Frac|1|280}}). Among American Caucasians, the incidence of the classic form is about {{Frac|1|15,000}}).<ref name="DeMais" /> Continued treatment and wellness are enhanced by education and follow up.<ref>{{Cite journal|last1=Kruse|first1=B.|last2=Riepe|first2=F. G.|last3=Krone|first3=N.|last4=Bosinski|first4=H. a. G.|last5=Kloehn|first5=S.|last6=Partsch|first6=C. J.|last7=Sippell|first7=W. G.|last8=Mönig|first8=H.|date=July 2004|title=Congenital adrenal hyperplasia - how to improve the transition from adolescence to adult life|journal=Experimental and Clinical Endocrinology & Diabetes |volume=112|issue=7|pages=343–355|doi=10.1055/s-2004-821013|issn=0947-7349|pmid=15239019|s2cid=260138410 }}</ref> ==History== ===Before 20th century=== An Italian anatomist, [[Luigi De Crecchio]] (1832-1894) provided the earliest known description of a case of probable CAH. {{blockquote|I propose in this narrative that it is sometimes extremely difficult and even impossible to determine sex during life. In one of the [[anatomy|anatomical]] theaters of the hospital..., there arrived toward the end of January a cadaver which in life was the body of a certain Joseph Marzo... The general physiognomy was decidedly male in all respects. There were no feminine curves to the body. There was a heavy beard. There was some delicacy of structure with muscles that were not very well developed... The distribution of [[pubic hair]] was typical of the male. Perhaps the lower extremities were somewhat delicate, resembling the female, and were covered with hair... The [[human penis|penis]] was curved posteriorly and measured 6&nbsp;cm, or with stretching, 10&nbsp;cm. The [[glans penis|corona]] was 3&nbsp;cm long and 8&nbsp;cm in circumference. There was an ample [[foreskin|prepuce]]. There was a first grade [[hypospadias]]... There were two folds of skin coming from the top of the penis and encircling it on either side. These were somewhat loose and resembled [[labia majora]].}} De Crecchio then described the internal organs, which included a normal [[vagina]], [[uterus]], [[fallopian tube]]s, and [[ovary|ovaries]]. {{blockquote|It was of the greatest importance to determine the habits, tendencies, passions, and general character of this individual... I was determined to get as complete a story as possible, determined to get at the base of the facts and to avoid undue exaggeration which was rampant in the conversation of many of the people present at the time of the dissection.}} He interviewed many people and satisfied himself that Joseph Marzo "conducted himself within the sexual area exclusively as a male", even to the point of contracting the "[[syphilis|French disease]]" on two occasions. The cause of death was another in a series of episodes of vomiting and diarrhea.<ref name="Bongio">{{cite journal | name-list-style=vanc |doi=10.1056/NEJM196306062682308 |pmid=13968788 |title=The Adrenogenital Syndrome |year=1963 |last1=Bongiovanni |first1=Alfred M. |last2=Root |first2=Allen W. |journal=[[The New England Journal of Medicine]] |volume=268 |issue=23 |pages=1283–9 contd}}</ref> This account was translated by Alfred Bongiovanni from De Crecchio ("''Sopra un caso di apparenzi virili in una donna''{{-"}}. ''Morgagni'' 7:154–188, 1865) in 1963 for an article in ''[[The New England Journal of Medicine]]''. ===20th and 21st centuries=== The association of excessive sex steroid effects with diseases of the adrenal cortex have been recognized for over a century. The term "adrenogenital syndrome" was applied to both sex-steroid producing tumors and severe forms of CAH for much of the 20th century, before some of the forms of CAH were understood. Congenital adrenal hyperplasia, which also dates to the first half of the century, has become the preferred term to reduce ambiguity and to emphasize the underlying pathophysiology of the disorders. Much modern understanding and treatment of CAH comes from research conducted at [[Johns Hopkins Medical School]] in Baltimore in the middle of the 20th century. [[Lawson Wilkins]], "founder" of [[pediatric endocrinology]], worked out the apparently paradoxical pathophysiology: that hyperplasia and overproduction of adrenal androgens resulted from impaired capacity for making cortisol. He reported use of adrenal cortical extracts to treat children with CAH in 1950. Genital reconstructive surgery was also pioneered at Hopkins. After application of [[karyotype|karyotyping]] to CAH and other [[intersex]] disorders in the 1950s, [[John Money]], JL Hampson, and JG Hampson persuaded both the scientific community and the public {{Citation needed|date=April 2019}} that sex assignment should not be based on any single biological criterion, and gender identity was largely learned and has no simple relationship with chromosomes or hormones. See [[Intersex]] for a fuller history, including recent controversies over reconstructive surgery. [[Hydrocortisone]], [[fludrocortisone]], and [[prednisone]] were available by the late 1950s. By 1980, all of the relevant steroids could be measured in blood by reference laboratories for patient care. By 1990, nearly all specific genes and enzymes had been identified. The last decade, though, has seen a number of new developments, discussed more extensively in [[congenital adrenal hyperplasia due to 21-hydroxylase deficiency]]: # Debate over the value of [[intersex medical interventions|genital reconstructive surgery]] and changing standards # Debate over [[sex assignment]] of severely virilized XX infants # New treatments to improve height outcomes # [[Newborn screening]] programs to detect CAH at birth # Increasing attempts to treat CAH before birth ==Society and culture== ===People with CAH=== Notable people with CAH include: * [[Jeff Cagandahan]] is a Filipino who successfully appealed for a change of name and gender on his birth certificate.<ref>{{Cite web| last = International Commission of Jurists | author-link = International Commission of Jurists | date = 2017 | title = Republic of the Philippines v. Jennifer Cagandahan, Supreme Court of the Philippines, Second Division (12 September 2008) | work =International Commission of Jurists | accessdate = March 19, 2021 | url = https://www.icj.org/sogicasebook/republic-of-the-philippines-v-jennifer-cagandahan-supreme-court-of-the-philippines-second-division-12-september-2008/}}</ref> * [[Lisa Lee Dark]]<ref>{{cite web | url = http://www.bbc.co.uk/radio4/hometruths/lisaleedark.shtml |title = BBC Radio 4 – Changing Sex |access-date=6 August 2008}}</ref> * [[Betsy Driver]]<ref name="yahoonowthis">{{cite news |title=Mayor Betsy Driver is Promoting Intersex Visibility Through Activism and Politics |url=https://www.yahoo.com/lifestyle/mayor-betsy-driver-promoting-intersex-033405813.html |work=Yahoo |date=23 August 2019 |access-date=September 10, 2019}}</ref> * [[Casimir Pulaski]], hypothesized based on examination of remains<ref>{{Cite web|title='It's a woman. It's not Pulaski.': New documentary argues Revolutionary War hero was intersex|url=https://www.chicagotribune.com/lifestyles/ct-life-casimir-pulaski-intersex-040319-story.html|last=Schoenberg|first=Nara|website=chicagotribune.com|date=3 April 2019 |access-date=May 28, 2020|archive-url=https://web.archive.org/web/20191102160348/https://www.chicagotribune.com/lifestyles/ct-life-casimir-pulaski-intersex-040319-story.html|archive-date=November 2, 2019|url-status=live}}</ref> ==See also== <!--already cited * [[Congenital adrenal hyperplasia due to 21-hydroxylase deficiency]] * [[Congenital adrenal hyperplasia due to 3β-hydroxysteroid dehydrogenase deficiency]] * [[Congenital adrenal hyperplasia due to 11β-hydroxylase deficiency]] * [[Congenital adrenal hyperplasia due to 17α-hydroxylase deficiency]] --> * [[Disorders of sex development]] * [[Inborn errors of steroid metabolism]] * [[Intersex]] * [[List of vaginal anomalies]] * [[5α-Reductase 2 deficiency]] * [[Androgen insensitivity syndrome]] ==References== {{Reflist}} ==Further reading== * {{cite journal|last=Han|first=Thang S.|author2=Walker, Brian R. |author3=Arlt, Wiebke |author4= Ross, Richard J. |title=Treatment and health outcomes in adults with congenital adrenal hyperplasia|journal=Nature Reviews Endocrinology|date=17 December 2013|volume=10|issue=2|pages=115–124|doi=10.1038/nrendo.2013.239|pmid=24342885|s2cid=6090764|postscript=Figure 2: The adrenal steroidogenesis pathway.}} ==External links== {{Commons category}} * {{Curlie|Health/Conditions_and_Diseases/Sex-Development_Disorders/Intersex/Congenital_Adrenal_Hyperplasia/}} {{Medical resources | ICD11 = 5A71.01 | ICD10 = E25.0 | ICD10CM = <!--{{ICD10CM|Xxx.xxxx}}--> | ICD9 = <!--{{ICD9|xxx}}--> | ICDO = | OMIM = | DiseasesDB = | Curlie = | MedlinePlus = | eMedicineSubj = | eMedicineTopic = | PatientUK = | MeshID = D000312 | GeneReviewsNBK = | GeneReviewsName = | NORD = | GARDNum = | GARDName = | Orphanet = | AO = | RP = | WO = | OrthoInfo = | NCI = | Scholia = | SNOMED CT = }} {{Adrenal gland disorder}} {{Defects of cholesterol and steroid metabolism}} {{Authority control}} [[Category:Autosomal recessive disorders]] [[Category:Congenital disorders of endocrine system]] [[Category:Endocrine-related cutaneous conditions]] [[Category:Intersex variations]]'