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'{{good article}} {{Infobox medical condition |name = Late onset congenital adrenal hyperplasia |synonym = Nonclassic onset congenital adrenal hyperplasia |image = |image_size = |image_thumbtime = |alt = |caption = |pronounce = |specialty = <!--from Wikidata; can be overwritten--> |symptoms = |complications = |onset = |duration = |types = |causes = |risks = |diagnosis = |differential = |prevention = |treatment = <!-- or |management = --> |medication = |prognosis = |frequency = 0.1%–2% |deaths = }}'''Late onset congenital adrenal hyperplasia''' (LOCAH), also known as nonclassic congenital adrenal hyperplasia (NCCAH or NCAH), is a milder form of [[congenital adrenal hyperplasia]] (CAH), a group of [[Genetic disorder#Autosomal recessive|autosomal recessive disorders]] characterized by impaired [[cortisol]] synthesis<ref name="pmid28576284">{{cite journal |vauthors=Adriaansen B, Schröder M, Span PN, Sweep F, van Herwaarden AE, Claahsen-van der Grinten HL |date=December 2022 |title=Challenges in treatment of patients with non-classic congenital adrenal hyperplasia |url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9791115/pdf/fendo-13-1064024.pdf |journal=Frontiers Paediatric Endocrinology |volume=13 |issue= |pages=1064024 |doi=10.3389/fendo.2022.1064024 |pmid=36578966 |s2cid=}}</ref>that leads to variable degrees of [[Postpartum period|postnatal]] [[androgen]] excess.<ref name="pmid30272171">{{cite journal | vauthors = Speiser PW, Arlt W, Auchus RJ, Baskin LS, Conway GS, Merke DP, Meyer-Bahlburg HF, Miller WL, Murad MH, Oberfield SE, White PC | display-authors = 6 | 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 | date = November 2018 | pmid = 30272171 | pmc = 6456929 | doi = 10.1210/jc.2018-01865 }}</ref><ref name="pmid7951484">{{cite journal | vauthors = Hattori N, Ishihara T, Moridera K, Hino M, Ikekubo K, Kurahachi H | title = A case of late-onset congenital adrenal hyperplasia due to partial 3 beta-hydroxysteroid dehydrogenase deficiency | journal = Endocrine Journal | volume = 40 | issue = 1 | pages = 107–9 | date = February 1993 | pmid = 7951484 | doi = 10.1507/endocrj.40.107 | url = https://www.jstage.jst.go.jp/article/endocrj1993/40/1/40_1_107/_article | doi-access = free }}</ref><ref name="omim202010">{{Cite web|url=https://www.omim.org/entry/202010|title=OMIM Entry - # 202010 - ADRENAL HYPERPLASIA, CONGENITAL, DUE TO STEROID 11-BETA-HYDROXYLASE DEFICIENCY|website=www.omim.org}}</ref> The causes of LOCAH are the same as of [[Congenital adrenal hyperplasia#Classic|classic CAH]], and in the majority of the cases are the [[mutation]]s in the ''[[CYP21A2]]'' gene resulting in corresponding activity changes in the associated [[21-Hydroxylase|P450c21 (21-hydroxylase)]] [[enzyme]] which ultimately leads to excessive [[androgen]] production. Other causes, albeit less frequent, are mutations in genes affecting other enzymes involved in [[steroid]] [[metabolism]], like [[Steroid 11β-hydroxylase|11β-hydroxylase]] or [[3β-hydroxysteroid dehydrogenase]]. It has a prevalence between 0.1% and 2% depending on population,<ref name="pmid30272171"/> and is one of the most common autosomal recessive genetic diseases 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 | display-authors = 6 | 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> The pathophysiology is complex and not all individuals are symptomatic.<ref name="pmid30272171"/> ==Presentation== Patients with LOCAH usually present with signs of [[hyperandrogenism]], rather than of glucocorticoid deficiency, a condition characterized by inadequate cortisol production.<ref name="pmid20671993"/><ref name="pmid32145273">{{cite journal | vauthors = Dineen R, Martin-Grace J, Thompson CJ, Sherlock M | title = The management of glucocorticoid deficiency: Current and future perspectives | journal = Clinica Chimica Acta; International Journal of Clinical Chemistry | volume = 505 | pages = 148–159 | date = June 2020 | pmid = 32145273 | doi = 10.1016/j.cca.2020.03.006 | s2cid = 212629520 }}</ref> Cortisol synthesis impairment is mild but clinically silent.<ref name="pmid32966723"/> LOCAH patients usually have the same baseline but lower peak cortisol levels comparing to healthy controls.<ref name="pmid27849625">{{cite journal | vauthors = Karachaliou FH, Kafetzi M, Dracopoulou M, Vlachopapadopoulou E, Leka S, Fotinou A, Michalacos S | title = Cortisol response to adrenocorticotropin testing in non-classical congenital adrenal hyperplasia (NCCAH) | journal = Journal of Pediatric Endocrinology & Metabolism | volume = 29 | issue = 12 | pages = 1365–1371 | date = December 2016 | pmid = 27849625 | doi = 10.1515/jpem-2016-0216 | s2cid = 43390012 | url = }}</ref><ref name="pmid21320597">{{cite journal | vauthors = Chung S, Son GH, Kim K | title = Circadian rhythm of adrenal glucocorticoid: its regulation and clinical implications | journal = Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease | volume = 1812 | issue = 5 | pages = 581–91 | date = May 2011 | pmid = 21320597 | doi = 10.1016/j.bbadis.2011.02.003 | url = | doi-access = free }}</ref> Flatter diurnal cortisol slopes contribute to stress-related dysregulation of central and peripheral circadian mechanisms with negative health outcomes.<ref name="pmid18971218">{{cite journal | vauthors = Dickmeis T | title = Glucocorticoids and the circadian clock | journal = The Journal of Endocrinology | volume = 200 | issue = 1 | pages = 3–22 | date = January 2009 | pmid = 18971218 | doi = 10.1677/JOE-08-0415 | url = | doi-access = free }}</ref><ref name="pmid28229109">{{cite journal | vauthors = Koch CE, Leinweber B, Drengberg BC, Blaum C, Oster H | title = Interaction between circadian rhythms and stress | journal = Neurobiology of Stress | volume = 6 | issue = | pages = 57–67 | date = February 2017 | pmid = 28229109 | pmc = 5314421 | doi = 10.1016/j.ynstr.2016.09.001 | url = }}</ref><ref name="pmid28503165">{{cite journal | vauthors = Nicolaides NC, Charmandari E, Kino T, Chrousos GP | title = Stress-Related and Circadian Secretion and Target Tissue Actions of Glucocorticoids: Impact on Health | journal = Frontiers in Endocrinology | volume = 8 | issue = | pages = 70 | date = 2017 | pmid = 28503165 | pmc = 5408025 | doi = 10.3389/fendo.2017.00070 | url = | doi-access = free }}</ref> Due to hyperandrogenism, females may present with symptoms like [[hirsutism]], [[oligomenorrhea]], [[acne]], infertility,<ref name="pmid30566904">{{cite journal | vauthors = Miller WL, Auchus RJ | title = The "backdoor pathway" of androgen synthesis in human male sexual development | journal = PLOS Biology | volume = 17 | issue = 4 | pages = e3000198 | date = April 2019 | pmid = 30943210 | pmc = 6464227 | doi = 10.1371/journal.pbio.3000198 | s2cid = 92999312 }}</ref> and male-pattern baldness.<ref name="pmid24002412">{{cite journal | vauthors = Pignatelli D | title = Non-classic adrenal hyperplasia due to the deficiency of 21-hydroxylase and its relation to polycystic ovarian syndrome | journal = Frontiers of Hormone Research | volume = 40 | pages = 158–70 | date = 2013 | pmid = 24002412 | doi = 10.1159/000342179 | isbn = 978-3-318-02238-4 }}</ref><ref name="pmid31244776">{{cite journal | vauthors = Livadas S, Bothou C | title = Management of the Female With Non-classical Congenital Adrenal Hyperplasia (NCCAH): A Patient-Oriented Approach | journal = Frontiers in Endocrinology | volume = 10 | pages = 366 | date = 2019 | pmid = 31244776 | pmc = 6563652 | doi = 10.3389/fendo.2019.00366 | s2cid = 174798615 | doi-access = free }}</ref><ref name="pmid28713602">{{cite journal | vauthors = Powell D, Inoue T, Bahtiyar G, Fenteany G, Sacerdote A | title = Treatment of Nonclassic 11-Hydroxylase Deficiency with Ashwagandha Root | journal = Case Reports in Endocrinology | volume = 2017 | pages = 1869560 | date = 2017 | pmid = 28713602 | pmc = 5496100 | doi = 10.1155/2017/1869560 | doi-access = free }}</ref> Males are generally asymptomatic,<ref name="pmid28582566"/><ref name="pmid20671993"/> but may present with [[acne]],<ref name="pmid12828760">{{cite journal | vauthors = Degitz K, Placzek M, Arnold B, Schmidt H, Plewig G | title = Congenital adrenal hyperplasia and acne in male patients | journal = The British Journal of Dermatology | volume = 148 | issue = 6 | pages = 1263–6 | date = June 2003 | pmid = 12828760 | doi = 10.1046/j.1365-2133.2003.05369.x | s2cid = 42921625 }}</ref><ref name="pmid19936418">{{cite journal | vauthors = Sharquie KE, Noaimi AA, Saleh BO, Anbar ZN | title = The frequency of 21-alpha hydroxylase enzyme deficiency and related sex hormones in Iraqi healthy male subjects versus patients with acne vulgaris | journal = Saudi Medical Journal | volume = 30 | issue = 12 | pages = 1547–50 | date = December 2009 | pmid = 19936418 }}</ref><ref name="pmid26082286">{{cite journal | vauthors = Falhammar H, Nordenström A | title = Nonclassic congenital adrenal hyperplasia due to 21-hydroxylase deficiency: clinical presentation, diagnosis, treatment, and outcome | journal = Endocrine | volume = 50 | issue = 1 | pages = 32–50 | date = September 2015 | pmid = 26082286 | doi = 10.1007/s12020-015-0656-0 | s2cid = 23469344 }}</ref> early balding,<ref name="newmi2006">{{cite journal | vauthors = New MI | title = Extensive clinical experience: nonclassical 21-hydroxylase deficiency | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 91 | issue = 11 | pages = 4205–14 | date = November 2006 | pmid = 16912124 | doi = 10.1210/jc.2006-1645 | quote = Loss of scalp hair in females and males is embarrassing, requiring treatment with 5α-reductase inhibitors | doi-access = free }}</ref><ref name="pmid17145028">{{cite journal | vauthors = Bernal González C, Fernández Salas C, Martínez S, Ezquieta Zubicaray B | title = [Premature androgenetic alopecia in adult male with nonclassic 21-OH deficiency. A novel nonsense CYP21A2 mutation (Y336X) in 2 affected siblings] | language = es-es | journal = Medicina Clinica | volume = 127 | issue = 16 | pages = 617–21 | date = October 2006 | pmid = 17145028 | doi = 10.1016/s0025-7753(06)72688-4 }}</ref><ref name="pmid25905311">{{cite book | vauthors = Feingold KR, Anawalt B, Boyce A, Chrousos G, de Herder WW, Dungan K, Grossman A, Hershman JM, Hofland J, Kaltsas G, Koch C, Kopp P, Korbonits M, McLachlan R, Morley JE, New M, Purnell J, Singer F, Stratakis CA, Trence DL, Wilson DP, Yau M, Gujral J, New MI | title = Congenital Adrenal Hyperplasia: Diagnosis and Emergency Treatment | date = April 2019 | publisher = MDText.com | pmid = 25905311 | url = https://www.ncbi.nlm.nih.gov/books/NBK279085/}}</ref> chronic prostatitis, chronic pelvic pain syndrome,<ref name="pmid18308097">{{cite journal | vauthors = Dimitrakov J, Joffe HV, Soldin SJ, Bolus R, Buffington CA, Nickel JC | title = Adrenocortical hormone abnormalities in men with chronic prostatitis/chronic pelvic pain syndrome | journal = Urology | volume = 71 | issue = 2 | pages = 261–6 | date = February 2008 | pmid = 18308097 | pmc = 2390769 | doi = 10.1016/j.urology.2007.09.025 | url = }}</ref><ref name="pmid35987379">{{Cite journal|year=2022|title=Letter to the editor regarding the article "Adrenocortical hormone abnormalities in men with chronic prostatitis/chronic pelvic pain syndrome"|url=https://www.goldjournal.net/article/S0090-4295(22)00690-2/abstract|vauthors=Masiutin MG, Yadav MK |journal=Urology|volume=169 |page=273 |language=English|doi=10.1016/j.urology.2022.07.051|issn=0090-4295|pmid=35987379|s2cid=251657694}}</ref><ref name="pmid35985522">{{Cite journal|vauthors=Dimitrakoff J, Nickel JC |year=2022|title=AUTHOR REPLY|url=https://www.goldjournal.net/article/S0090-4295(22)00691-4/abstract|journal=Urology|volume=169 |pages=273–274 |language=English|doi=10.1016/j.urology.2022.07.049|pmid=35985522 |s2cid=251658492 |issn=0090-4295}}</ref> and very rarely, testicular adrenal rest tumors.<ref name="pmid33718059">{{cite journal | vauthors = Corcioni B, Renzulli M, Marasco G, Baronio F, Gambineri A, Ricciardi D, Ortolano R, Farina D, Gaudiano C, Cassio A, Pagotto U, Golfieri R | title = Prevalence and ultrasound patterns of testicular adrenal rest tumors in adults with congenital adrenal hyperplasia | journal = Translational Andrology and Urology | volume = 10 | issue = 2 | pages = 562–573 | date = February 2021 | pmid = 33718059 | pmc = 7947447 | doi = 10.21037/tau-20-998 | url = }}</ref><ref name="pmid30566904"/><ref name="newmi2006"/> While symptoms are usually diagnosed after puberty, children may present with premature [[adrenarche]].<ref name="pmid20671993">{{cite journal | vauthors = Witchel SF, Azziz R | title = Nonclassic congenital adrenal hyperplasia | journal = International Journal of Pediatric Endocrinology | volume = 2010 | pages = 625105 | date = 2010 | pmid = 20671993 | pmc = 2910408 | doi = 10.1155/2010/625105 | doi-access = free }}</ref> The degree of hormonal disorder in patients with LOCAH is relatively mild. However, alterations in the hypothalamic–pituitary–adrenal axis are present even in this mild form of the disease and might contribute to psychiatric vulnerability.<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> ==Molecular genetics== LOCAH is most commonly attributed to mutations in the ''[[CYP21A2]]'' gene, which encodes the [[21-hydroxylase]] enzyme. Cases of LOCAH due to deficiencies in other enzymes that are known causes of CAH ([[3β-hydroxysteroid dehydrogenase]], [[steroid 11β-hydroxylase]], etc.) are rare and have no established prevalence estimates.<ref name=pmid18690539>{{cite journal | vauthors = Speiser PW | title = Nonclassic adrenal hyperplasia | journal = Reviews in Endocrine & Metabolic Disorders | volume = 10 | issue = 1 | pages = 77–82 | date = March 2009 | pmid = 18690539 | doi = 10.1007/s11154-008-9097-x | s2cid = 30469525 }}</ref> Several severe mutations have been associated with LOCAH: the deletion of the ''CYP21A2'' gene, small [[gene conversion]]s, the p.&nbsp;I172N (rs6475, c.518T>A, CYP21A2*11) mutation, the c.293-13A/C>G (rs6467, CYP21A2*9) mutation, and the p.Gln318Stop (p.Q318X, rs7755898, c.952C>T, CYP21A2*17) mutation.<ref name="pmid32647925"/> Besides that, LOCAH due to 21-hydroxylase deficiency can be caused by duplications of ''CYP21A1P'' pseudogene and ''C4B'' gene. Due to the high degree of homology between the CYP21A2 gene and the CYP21A1P pseudogene, and the complexity of the locus, research on the sequencing level can be difficult.<ref name="pmid33168061">{{cite journal | vauthors = Espinosa Reyes TM, Collazo Mesa T, Lantigua Cruz PA, Agramonte Machado A, Domínguez Alonso E, Falhammar H | title = Molecular diagnosis of patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency | journal = BMC Endocrine Disorders | volume = 20 | issue = 1 | pages = 165 | date = November 2020 | pmid = 33168061 | pmc = 7653887 | doi = 10.1186/s12902-020-00643-z }}</ref> A 2021 study showed that mild genotypes associated with LOCAH have a low concordance rate with those phenotypes, probably due to the complex characteristics of 21-hydroxylase genotyping and the limitation of using [[massive parallel sequencing]] alone without combining with other comprehensive methods.<ref name="pmid33677812">{{cite journal | vauthors = Karaoğlan M, Nacarkahya G, Aytaç EH, Keskin M | title = Challenges of CYP21A2 genotyping in children with 21-hydroxylase deficiency: determination of genotype-phenotype correlation using next generation sequencing in Southeastern Anatolia | journal = Journal of Endocrinological Investigation | volume = 44| issue = 11| pages = 2395–2405| date = March 2021 | pmid = 33677812 | doi = 10.1007/s40618-021-01546-z | s2cid = 232133292 }}</ref> The following three mutations to the ''CYP21A2'' gene have been found to result in a moderate reduction in enzyme activity associated with that allele (20–60% residual activity),<ref name="pmid32647925"/> and are associated with LOCAH:<ref name="pmid28541281"/> * p.<!--AWB, this is not a page-->V281L (rs6471, c.844G>C, CYP21A2*15); * p.P453S (rs6445, c.1360C>T, CYP21A2*19); * p.P30L (rs9378251, c.92C>T, CYP21A2*8). A point mutation in exon 7 of ''CYP21A2'', (p.<!--AWB, this is not a page-->V281L), is commonly found in LOCAH-associated alleles.<ref name="pmid28541281">{{cite journal | vauthors = Hannah-Shmouni F, Morissette R, Sinaii N, Elman M, Prezant TR, Chen W, Pulver A, Merke DP | display-authors = 6 | title = Revisiting the prevalence of nonclassic congenital adrenal hyperplasia in US Ashkenazi Jews and Caucasians | journal = Genetics in Medicine | volume = 19 | issue = 11 | pages = 1276–1279 | date = November 2017 | pmid = 28541281 | pmc = 5675788 | doi = 10.1038/gim.2017.46 }}</ref><ref name="pmid33168061"/><ref name="pmid32647925">{{cite journal | vauthors = Dörr HG, Schulze N, Bettendorf M, Binder G, Bonfig W, Denzer C, Dunstheimer D, Salzgeber K, Schmidt H, Schwab KO, Voss E, Wabitsch M, Wölfle J | display-authors = 6 | title = Genotype-phenotype correlations in children and adolescents with nonclassical congenital adrenal hyperplasia due to 21-hydroxylase deficiency | journal = Molecular and Cellular Pediatrics | volume = 7 | issue = 1 | pages = 8 | date = July 2020 | pmid = 32647925 | pmc = 7347723 | doi = 10.1186/s40348-020-00100-w }}</ref> Carriers for this mutation retain 20%–50% of 21-hydroxylase activity,<ref name="pmid2249999">{{cite journal | vauthors = Tusie-Luna MT, Traktman P, White PC | title = Determination of functional effects of mutations in the steroid 21-hydroxylase gene (CYP21) using recombinant vaccinia virus | journal = The Journal of Biological Chemistry | volume = 265 | issue = 34 | pages = 20916–22 | date = December 1990 | doi = 10.1016/S0021-9258(17)45304-X | pmid = 2249999 | doi-access = free }}</ref><ref name="pmid28582566"/> but are at higher risk of symptoms of androgen excess than carriers of the severe mutations and had higher [[ACTH stimulation test|adrenocorticotropic hormone (ACTH) stimulated]] [[17α-hydroxyprogesterone]],<ref name="pmid16712666">{{cite journal | vauthors = Admoni O, Israel S, Lavi I, Gur M, Tenenbaum-Rakover Y | title = Hyperandrogenism in carriers of CYP21 mutations: the role of genotype | journal = Clinical Endocrinology | volume = 64 | issue = 6 | pages = 645–51 | date = June 2006 | pmid = 16712666 | doi = 10.1111/j.1365-2265.2006.02521.x | s2cid = 37571628 }}</ref> suggesting heterozygous mutations on CYP21A2 play an important role in disease.<ref>{{cite journal | vauthors = Neocleous V, Shammas C, Phedonos AP, Karaoli E, Kyriakou A, Toumba M, Phylactou LA, Skordis N | display-authors = 6 | title = Genetic defects in the cyp21a2 gene in heterozygous girls with premature adrenarche and adolescent females with hyperandrogenemia | journal = Georgian Medical News | issue = 210 | pages = 40–7 | date = September 2012 | pmid = 23045419 }}</ref> The particularly mild clinical symptoms of LOCAH such as [[hyperandrogenism]], [[hirsutism]] and [[acne]] or [[infertility]] overlap with other diseases such as [[polycystic ovary syndrome]]. Biochemical parameters like [[17α-hydroxyprogesterone]] may not be elevated in very mild cases of LOCAH, and may vary between labs that makes interpretation difficult. It may not be possible to perform [[ACTH stimulation test]]s in all institutions, depending on the availability of the injectable [[adrenocorticotropic hormone]] medication. This is why a comprehensive ''CYP21A2'' genotyping (rather than variant-specific assays alone) is a good way to exclude/confirm 21-hydroxylase deficiency and heterozygosity (carrier) status.<ref name="pmid32616876">{{cite journal | vauthors = Baumgartner-Parzer S, Witsch-Baumgartner M, Hoeppner W | title = EMQN best practice guidelines for molecular genetic testing and reporting of 21-hydroxylase deficiency | journal = European Journal of Human Genetics | volume = 28 | issue = 10 | pages = 1341–1367 | date = October 2020 | pmid = 32616876 | pmc = 7609334 | doi = 10.1038/s41431-020-0653-5 | s2cid = 220295067 }}</ref> Genetic testing can be used to exclude false positive diagnosis based on biochemical parameters alone, even with ACTH stimulation, since elevated 17-OHP levels may be also caused by [[Ovarian tumor|ovarian]] or [[adrenal tumor]]s, rather than by the variants in the ''CYP21A2'' gene.<ref name="pmid33117272">{{cite journal | vauthors = Tsai WH, Wong CH, Dai SH, Tsai CH, Zeng YH | title = Adrenal Tumor Mimicking Non-Classic Congenital Adrenal Hyperplasia | journal = Frontiers in Endocrinology | volume = 11 | pages = 526287 | date = 2020 | pmid = 33117272 | pmc = 7551200 | doi = 10.3389/fendo.2020.526287 | s2cid = 221979120 | doi-access = free }}</ref> ==Diagnosis== Originally characterized in 1957 by French biochemist Jacques Decourt,<ref>{{cite journal | vauthors = Decourt J, Jayle MF, Baulieu E | title = [Clinically late virilism with excretion of pregnanetriol and insufficiency of cortisol production] | language = fr | journal = Annales d'Endocrinologie | volume = 18 | issue = 3 | pages = 416–22 | date = May 1957 | pmid = 13470408 | trans-title = Clinically late virilism with excretion of pregnanetriol and insufficiency of cortisol production }}</ref> LOCAH differs from [[Congenital adrenal hyperplasia#Classic|classic CAH]] in that it does not cause atypical neonatal genital morphology, is not life-threatening and presents after birth. Unlike classic CAH, LOCAH generally cannot be reliably detected with neonatal screening.<ref name=pmid27354284>{{cite journal | vauthors = Kurtoğlu S, Hatipoğlu N | title = Non-Classical Congenital Adrenal Hyperplasia in Childhood | journal = Journal of Clinical Research in Pediatric Endocrinology | volume = 9 | issue = 1 | pages = 1–7 | date = March 2017 | pmid = 27354284 | pmc = 5363159 | doi = 10.4274/jcrpe.3378 }}</ref> Many individuals (both male and female) present no symptoms during childhood and adolescence and only become aware of the possibility of LOCAH due to the diagnosis of another family member. It is thought that 90% of women with LOCAH never receive a diagnosis.<ref name="pmid32966723"/> In young females, premature pubarche is generally the first symptom to present.<ref name="pmid31244776"/> The earliest known diagnosis was in a 6 month old female who developed pubic hair.<ref>{{cite journal | vauthors = Kohn B, Levine LS, Pollack MS, Pang S, Lorenzen F, Levy D, Lerner AJ, Rondanini GF, Dupont B, New MI | display-authors = 6 | title = Late-onset steroid 21-hydroxylase deficiency: a variant of classical congenital adrenal hyperplasia | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 55 | issue = 5 | pages = 817–27 | date = November 1982 | pmid = 6288753 | doi = 10.1210/jcem-55-5-817 }}</ref> Additional symptoms include acne, menstrual irregularities and hirsutism in females as well as [[alopecia]] in males. LOCAH is often misdiagnosed as [[polycystic ovarian disease]] (PCOS).<ref>{{cite journal | vauthors = Chrousos GP, Loriaux DL, Mann DL, Cutler GB | title = Late-onset 21-hydroxylase deficiency mimicking idiopathic hirsutism or polycystic ovarian disease | journal = Annals of Internal Medicine | volume = 96 | issue = 2 | pages = 143–8 | date = February 1982 | pmid = 6977282 | doi = 10.7326/0003-4819-96-2-143 }}</ref> LOCAH is often diagnosed in the context of infertility assessment in women. During the follicular phase of the menstrual cycle, [[progesterone]] accumulates along with [[17α-Hydroxyprogesterone|17α-hydroxyprogesterone]] which can thin the endometrium and change cervical mucus in a manner similar to the effect of [[Progestogen (medication)|progestogen]] contraceptives, interferes with the normal menstrual cycle, which can lead to oligomenorrhea or [[amenorrhea]]<ref name="pmid32966723"/> and impairs sperm penetration.<ref name="pmid26038201">{{cite journal | vauthors = Turcu AF, Auchus RJ | title = Adrenal steroidogenesis and congenital adrenal hyperplasia | journal = Endocrinology and Metabolism Clinics of North America | volume = 44 | issue = 2 | pages = 275–96 | date = June 2015 | pmid = 26038201 | pmc = 4506691 | doi = 10.1016/j.ecl.2015.02.002}}</ref> Abnormal endometrial development leads to decreased uterine receptivity, which also contributes to infertility.<ref name="pmid31499506">{{cite journal | vauthors = Pignatelli D, Pereira SS, Pasquali R | title = Androgens in Congenital Adrenal Hyperplasia | journal = Frontiers of Hormone Research | volume = 53 | issue = | pages = 65–76 | date = 2019 | pmid = 31499506 | doi = 10.1159/000494903| isbn = 978-3-318-06470-4 | s2cid = 202412336 }}</ref> Once attempting to conceive, most women with LOCAH will become pregnant within a year with or without treatment, but women with LOCAH have an increased risk of miscarriage.<ref name="pmid32966723"/> The diagnostic procedure varies according to the specific enzyme deficiency causing LOCAH and the precise [[Serum (blood)|serum]] [[androgen]] levels required for diagnosis are the subject to variance from different measurement methods, refinement in specific cases and are under active research. Some protocols are based on measuring [[17α-hydroxyprogesterone]] levels, with or without [[ACTH stimulation test]].<ref name=pmid27354284/><ref name="pmid34743977">{{cite journal |vauthors=Polat S, Arslan YK |title=17-Hydroxyprogesterone Response to Standard Dose Synacthen Stimulation Test in CYP21A2 Heterozygous Carriers and Non-carriers in Symptomatic and Asymptomatic Groups: Meta-analyses |journal=J Clin Res Pediatr Endocrinol |volume=14 |issue=1 |pages=56–68 |date=March 2022 |pmid=34743977 |pmc=8900072 |doi=10.4274/jcrpe.galenos.2021.2021.0184 }}</ref> ===21-Hydroxylase deficiency=== ==== Screening ==== {{Main|Congenital adrenal hyperplasia due to 21-hydroxylase deficiency}}The condition of [[21-hydroxylase]] deficiency is screened by measuring [[Serum (blood)|serum]] levels of [[17α-hydroxyprogesterone]] (17-OHP) in the morning and between day 3 and 5 of the menstrual cycle (for females) to reduce the possibility of false positive results.<ref name="pmid32966723"/> 17-OHP is used as a marker of the [[21-hydroxylase]] enzyme activity since the 1980s.<ref name="pmid2547827">{{cite journal | vauthors = Azziz R, Zacur HA | title = 21-Hydroxylase deficiency in female hyperandrogenism: screening and diagnosis | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 69 | issue = 3 | pages = 577–84 | date = September 1989 | pmid = 2547827 | doi = 10.1210/jcem-69-3-577 }}</ref> The cutoff basal 17-OHP value is matter of debate.<ref name="pmid28582566"/> Most commonly, the value of 2.0&nbsp;ng/mL<ref name="pmid30272171"/><ref name="doi10264422075175320164819">{{cite journal | doi=10.26442/2075-1753_2016.4.8-19 | title=Клинические рекомендации Российской ассоциации эндокринологов по диагностике и лечебно-профилактическим мероприятиям при врожденной дисфункции коры надпочечников у пациентов во взрослом возрасте|journal=Consilium Medicum|year=2016}}</ref> is used, but a value of 1.7&nbsp;ng/mL provides better selectivity.<ref name="pmid28582566"/><ref name=pmid27354284/> Most research on the biochemical diagnosis of LOCAH relied on direct [[immunoassay]]s, such as [[radioimmunoassay]]s or time-resolved fluorescence assay to measure 17-OHP, therefore, cross-reactivity and reliability problems of these methods might have caused differences in the 17-OHP cutoff values recommended, so the use of [[liquid chromatography–mass spectrometry]] aims to improve the accuracy of 17-OHP measurement and increase diagnostic quality of LOCAH.<ref name="pmid28582566"/> Randomly timed measurements of 17-OHP have not been shown to be useful for screening since they are often normal and are known to be very high in the [[luteal phase]] of the female menstrual cycle. After basal levels have been measured, confirmation is done by administering ACTH, and comparing 17-OHP pre and post test. 17-OHP levels over 10&nbsp;ng/mL at the 60th minute post stimulation is considered diagnostic for LOCAH.<ref name=pmid27354284/> ====Androgen backdoor pathway==== {{main|Androgen backdoor pathway}}In [[21-hydroxylase]] deficiency, especially in mild cases (LOCAH), the androgen "backdoor" pathway may be the reason of androgen excess.<ref>{{cite journal | vauthors = White PC | title = Update on diagnosis and management of congenital adrenal hyperplasia due to 21-hydroxylase deficiency | journal = Current Opinion in Endocrinology, Diabetes and Obesity | volume = 25 | issue = 3 | pages = 178–184 | date = June 2018 | pmid = 29718004 | doi = 10.1097/MED.0000000000000402 | s2cid = 26072848 }}</ref> This backdoor pathway is not always considered in the clinical evaluation of patients with [[hyperandrogenism]] conditions such as LOCAH and may be a source of diagnostic pitfalls and confusion.<ref name="pmid32610579"/> One case study demonstrated the importance of considering [[Serum (blood)|serum]] [[5α-dihydrotestosterone]] (DHT) levels and the androgen backdoor pathway in a LOCAH diagnosis that would have not been apparent from testosterone levels alone.<ref name="pmid32610579">{{cite journal | vauthors = Sumińska M, Bogusz-Górna K, Wegner D, Fichna M | title = Non-Classic Disorder of Adrenal Steroidogenesis and Clinical Dilemmas in 21-Hydroxylase Deficiency Combined with Backdoor Androgen Pathway. Mini-Review and Case Report | journal = International Journal of Molecular Sciences | volume = 21 | issue = 13 | pages = 4622 | date = June 2020 | pmid = 32610579 | pmc = 7369945 | doi = 10.3390/ijms21134622 | doi-access = free }}</ref> ===11β-Hydroxylase deficiency=== {{Main|Congenital adrenal hyperplasia due to 11β-hydroxylase deficiency}}The activity of [[Steroid 11β-hydroxylase|11β-hydroxylase]] can be determined by observing the basal [[11-deoxycortisol]] level. A level over 10&nbsp;ng/mL, indicates followup with ACTH stimulation test. The 60th minute post-stimulation [[11-deoxycortisol]] levels higher than 18&nbsp;ng/mL are diagnostic of LOCAH.<ref name=pmid27354284/> === 3β-Hydroxysteroid dehydrogenase deficiency === {{Main|Congenital adrenal hyperplasia due to 3β-hydroxysteroid dehydrogenase deficiency}}The activity of [[3β-hydroxysteroid dehydrogenase]] can be determined by observing the basal [[17α-hydroxypregnenolone]] level. A level above 30&nbsp;ng/mL and [[17α-hydroxypregnenolone]]/[[cortisol]] ratio above 10 SD are diagnostic of LOCAH.<ref name=pmid27354284/> == Management == Management and treatment of LOCAH is case specific<ref name=pmid18690539/><ref name=pmid27354284/><ref>{{cite journal | vauthors = Kelestimur F | title = Non-classic congenital adrenal hyperplasia | journal = Pediatric Endocrinology Reviews | volume = 3 Suppl 3 | pages = 451–4 | date = August 2006 | pmid = 17551465 | quote = NCAH is not characterized by cortisol insufficiency and these patients do not need glucocorticoid replacement before and/or during surgery unless they have been treated chronically with glucocorticoids. }}</ref><ref name="pmid28576284" /> and the application of [[glucocorticoid]] treatment is not standard as it is in [[Congenital adrenal hyperplasia#Classic|classic CAH]]. LOCAH is not a life-threatening medical condition and the risks of treatment given prenatally or to asymptomatic children outweigh potential benefits.<ref>{{cite journal | vauthors = Miller WL, Witchel SF | title = Prenatal treatment of congenital adrenal hyperplasia: risks outweigh benefits | journal = American Journal of Obstetrics and Gynecology | volume = 208 | issue = 5 | pages = 354–9 | date = May 2013 | pmid = 23123167 | doi = 10.1016/j.ajog.2012.10.885 }}</ref><ref>{{cite journal | vauthors = Clayton PE, Miller WL, Oberfield SE, Ritzén EM, Sippell WG, Speiser PW | title = Consensus statement on 21-hydroxylase deficiency from the European Society for Paediatric Endocrinology and the Lawson Wilkins Pediatric Endocrine Society | journal = Hormone Research | volume = 58 | issue = 4 | pages = 188–95 | date = 2002 | pmid = 12324718 | doi = 10.1159/000065490 | s2cid = 41346214 | author7 = ESPE/ LWPES CAH Working Group }}</ref><ref>{{cite journal | title = Consensus statement on 21-hydroxylase deficiency from the Lawson Wilkins Pediatric Endocrine Society and the European Society for Paediatric Endocrinology | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 87 | issue = 9 | pages = 4048–53 | date = September 2002 | pmid = 12213842 | doi = 10.1210/jc.2002-020611 | doi-access = free | author1 = Joint LWPES/ESPE CAH Working Group }}</ref> In appropriate cases, glucocorticoids (usually [[hydrocortisone]] in children) are administered to suppress secretion of [[corticotropin releasing hormone]] (CRH) produced by [[hypothalamus]] and of [[adrenocorticotropic hormone]] (ACTH) produced by [[pituitary gland]]. This suppression will reduce concentration in [[blood]] of sex steroids produced by [[adrenal gland]]s. Some of the main considerations in treatment include the watchful waiting of symptom severity as well as adverse responses to [[glucocorticoid]]s administered as drugs, seen in patient [[bone density|bone mineral density]], height and weight<ref name="pmid28576284" />. For women, an [[oral contraceptive pill]] and [[androgen blockers]] such as [[spironolactone]] or [[cyproterone acetate]] are alternatives to glucocorticoids for managing symptoms of androgen excess<ref name="pmid28576284" />. There is still debate whether miscarriage rates in women with LOCAH are influenced by hydrocortisone treatment <ref name="pmid28576284" />. ==Prevalence== According to [[Haplotype estimation|haplotype association studies]], the prevalence of LOCAH in the general white population is estimated to be 1:500 to 1:1000, but in people with a high rate of marriage between relatives, the prevalence rate is as high as 1:50 to 1:100. A 2017 ''CYP21A2'' genotype analysis predicted that the total frequency of LOCAH in the white population of the [[United States]] is about 1:200 (95% confidence level, from 1:100 to 1:280).<ref name="pmid30272171"/><ref>{{cite journal | vauthors = Hannah-Shmouni F, Morissette R, Sinaii N, Elman M, Prezant TR, Chen W, Pulver A, Merke DP | display-authors = 6 | title = Revisiting the prevalence of nonclassic congenital adrenal hyperplasia in US Ashkenazi Jews and Caucasians | journal = Genetics in Medicine | volume = 19 | issue = 11 | pages = 1276–1279 | date = November 2017 | pmid = 28541281 | doi = 10.1038/gim.2017.46 | pmc = 5675788 | s2cid = 4630175 | doi-access = free }}</ref> According to a 2017 meta-analysis, the prevalence of LOCAH among women with signs and symptoms of androgen excess is 4.2% globally, and between 1% and 10% depending on the ethnicity of the population being studied.<ref name="pmid28582566">{{cite journal | vauthors = Carmina E, Dewailly D, Escobar-Morreale HF, Kelestimur F, Moran C, Oberfield S, Witchel SF, Azziz R | display-authors = 6 | title = Non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency revisited: an update with a special focus on adolescent and adult women | journal = Human Reproduction Update | volume = 23 | issue = 5 | pages = 580–599 | date = September 2017 | pmid = 28582566 | doi = 10.1093/humupd/dmx014 | doi-access = free }}</ref> [[Anne Fausto-Sterling]], an American sexologist, in a 2000 book "Sexing the Body" came up with an estimate that people with [[intersex]] conditions account for 1.7% of the general population.<ref name="sexing-the-body">{{cite book | vauthors = Fausto-Sterling A |title=Sexing the body : gender politics and the construction of sexuality |date=30 November 2000 |location=[New York] |isbn=9780465077137}}</ref> This estimate is cited by a number of prominent intersex advocacy organizations.<ref>{{cite web |title=Intersex babies are perfect just as they are! |url=https://www.unfe.org/intersex-awareness/ |website=UN Free & Equal |quote=up to 1.7 percent of babies are born with sex characteristics that don't fit typical definitions of male and female. That makes being intersex almost as common as being a redhead!}}</ref><ref>{{cite web |title=Its Intersex Awareness Day - here are 5 myths we need to shatter |url=https://www.amnesty.org/en/latest/news/2018/10/its-intersex-awareness-day-here-are-5-myths-we-need-to-shatter/ |website=www.amnesty.org |date=26 October 2018 |language=en |quote=According to experts, around 1.7% of the population is born with intersex traits - comparable to the number of people born with red hair.}}</ref><ref>{{cite web |title=What is Intersex? Frequently Asked Questions |url=https://interactadvocates.org/faq/#howcommon |website=interACT: Advocates for Intersex Youth |quote=About 1.7% of people are born intersex. (Compare that to a ~0.3% chance of having identical twins!) 1 in 2,000 babies (0.05% of humans) are born with genital differences that a doctor might suggest changing with unnecessary surgery.}}</ref><ref>{{cite web |title=Intersex population figures |url=https://ihra.org.au/16601/intersex-numbers/ |website=Intersex Human Rights Australia |language=en |date=28 September 2013 |quote=Given that intersex people only come to the attention of data collectors through chance or an apparent medical reason, the actual numbers of people with intersex variations are likely to be as much as 1.7%. Despite the limitations of the data, 1.7% seems more justifiable as an upper limit figure than alternatives, to date.}}</ref> Of these [[intersex]] individuals, according to Fausto-Sterling, 88% have LOCAH.<ref name="sexing-the-body"/> [[Leonard Sax]], an American psychologist and a family physician, criticized these figures in a review published in 2002 in The [[Journal of Sex Research]], stating that from the clinician's perspective, LOCAH is not an intersex condition.<ref>{{cite journal | vauthors = Sax L | title = How common is intersex? a response to Anne Fausto-Sterling | journal = [[Journal of Sex Research]] | volume = 39 | issue = 3 | pages = 174–8 | date = August 2002 | pmid = 12476264 | doi = 10.1080/00224490209552139 | url = https://www.leonardsax.com/how-common-is-intersex-a-response-to-anne-fausto-sterling/ | s2cid = 33795209 | quote = Reviewing the list of conditions which Fausto-Sterling considers to be intersex, we find that this one condition–late-onset congenital adrenal hyperplasia (LOCAH)–accounts for 88% of all those patients whom Fausto-Sterling classifies as intersex (1.5/1.7 = 88%). From a clinician's perspective, however, LOCAH is not an intersex condition. The genitalia of these babies are normal at birth, and consonant with their chromosomes: XY males have normal male genitalia, and XX females have normal female genitalia. }}</ref> Including LOCAH in intersex prevalence estimates has been cited as an example of misleading statistical practice.<ref>{{cite book | vauthors = Best J |title=Stat-spotting : a field guide to identifying dubious data |date=14 September 2013 |location=Berkeley |isbn=978-0520279988 |pages=12–13 |edition=Updated and expand}}</ref> == See also == * [[Congenital adrenal hyperplasia due to 17α-hydroxylase deficiency]] * [[Lipoid congenital adrenal hyperplasia]] == References == {{reflist}} ==External links== {{Medical resources | ICD11 = 5A71.01 | ICD10 = E25.0 }} [[Category:Adrenal gland disorders]] [[Category:Autosomal recessive disorders]] [[Category:Congenital disorders of endocrine system]] [[Category:Endocrine-related cutaneous conditions]] [[Category:Genetic diseases and disorders]] [[Category:Cholesterol and steroid metabolism disorders]] [[Category:Intersex variations]]'