View source for Medicine:Congenital adrenal hyperplasia due to 21-hydroxylase deficiency

{{Further|Medicine:Congenital adrenal hyperplasia}}
{{Infobox medical condition (new)
| name            = Congenital adrenal hyperplasia due to 21-hydroxylase deficiency
| synonyms        = '''21-OH CAH'''
| image           = CT scan shows enlarged adrenals with masses consistent with congenital adrenal hyperplasia due to 21-hydroxylase deficiency.png
| caption         = CT scan shows enlarged adrenals with masses consistent with congenital adrenal hyperplasia due to 21-hydroxylase deficiency (image credit: NICHD/A. Mallappa, D. Merke)
| pronounce       =
| field           =
| symptoms        = Androgen excess and corticosteroid deficiencies
| complications   =
| onset           =
| duration        =
| types           =
| causes          =
| risks           =
| diagnosis       =
| differential    =
| prevention      =
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| prognosis       =
| frequency       = 1:18,000 to 1:14,000 (classical forms);<br />1:1000 to 1:50 (nonclassical forms)
| deaths          =
}}
<!-- Definition -->
'''Congenital adrenal hyperplasia due to 21-hydroxylase deficiency''' (CAH) is a genetic disorder characterized by impaired production of cortisol in the adrenal glands.<ref name="pmid29630216">{{cite book| vauthors = Burdea L, Mendez MD | chapter =  21-Hydroxylase Deficiency | date = July 2023 | title = StatPearls [Internet] | location = Treasure Island (FL) | publisher = StatPearls Publishing | pmid = 29630216 | chapter-url = https://www.ncbi.nlm.nih.gov/books/NBK493164/ }}</ref>

<!-- Classification, Signs and Incidence -->
It is classified as an inherited metabolic disorder. CAH is an autosomal recessive condition since it results from inheriting two copies of the faulty ''CYP21A2'' gene responsible for 21-hydroxylase enzyme deficiency. The most common forms of CAH are: ''classical'' form, usually diagnosed at birth, and ''nonclassical'', [[Medicine:Late onset congenital adrenal hyperplasia|late onset form]], typically diagnosed during childhood or adolescence, although it can also be identified in adulthood when seeking medical help for fertility concerns or other related issues, such as PCOS or menstrual irregularities.<ref name="pmid29630216"/> Carriers for the alleles of the nonclassical forms may have no syptoms, such form of CAH is sometimes called ''cryptic'' form.<ref name="pmid28541281"/><ref name="pmid2992207">{{cite journal |vauthors=Dumić M, Brkljacić L, Mardesić D, Plavsić V, Lukenda M, Kastelan A |title='Cryptic' form of congenital adrenal hyperplasia due to 21-hydroxylase deficiency in the Yugoslav population |journal=Acta Endocrinol (Copenh) |volume=109 |issue=3 |pages=386–92 |date=July 1985 |pmid=2992207 |doi=10.1530/acta.0.1090386 |url=}}</ref> Congenital adrenal hyperplasia due to 21-hydroxylase deficiency in all its forms accounts for over 95% of diagnosed cases of all types of [[Medicine:Congenital adrenal hyperplasia|congenital adrenal hyperplasia]].<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> Unless another specific enzyme is mentioned, CAH in most contexts refers to 21-hydroxylase deficiency, and different mutations related to enzyme impairment have been mapped on protein structures of the enzyme.<ref>{{cite journal | vauthors = Neves Cruz J, da Costa KS, de Carvalho TA, de Alencar NA | title = Measuring the structural impact of mutations on cytochrome P450 21A2, the major steroid 21-hydroxylase related to congenital adrenal hyperplasia | journal = Journal of Biomolecular Structure & Dynamics | volume = 38 | issue = 5 | pages = 1425–1434 | date = March 2020 | pmid = 30982438 | doi = 10.1080/07391102.2019.1607560 | s2cid = 115195169 }}</ref> It 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 = 650–667 | 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 = 181–192 | 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 = 601–609 | date = May 2016 | pmid = 26865584 | pmc = 4874183 | doi = 10.1530/EJE-15-1181 }}</ref>

<!-- Health outcomes -->
Due to loss of 21-hydroxylase function, patients are unable to efficiently synthesize cortisol. As a result, ACTH levels increase, leading to adrenocortical hyperplasia and overproduction of cortisol precursors, which are used in the synthesis of sex steroids, which can lead to signs of androgen excess, including ambiguous genitalia in newborn girls and rapid postnatal growth in both sexes.<ref name="pmid29630216" />  In severe cases of CAH in females, surgical reconstruction may be considered to create more female-appearing external genitalia. However, there is ongoing debate regarding timing and necessity of surgery. The way CAH affects the organism is complicated, and not everyone who has it will show signs or have symptoms.<ref name="pmid30272171" /> Individuals with CAH may face challenges related to growth impairment during childhood and fertility issues during adulthood. Psychosocial aspects such as gender identity development and mental health should also be taken into consideration when managing individuals with CAH.<ref name="pmid29630216" /> Overall prognosis for individuals with appropriate medical care is good; however, lifelong management under specialized care is required to ensure optimal outcomes.<ref name="pmid29630216" />

<!-- Treatment -->
Treatment for CAH involves hormone replacement therapy to provide adequate levels of glucocorticoids and mineralocorticoids. Regular monitoring is necessary to optimize hormone balance and minimize potential complications associated with long-term glucocorticoid exposure.<ref name="pmid29630216"/>

==Pathophysiology==
[[File:Steroidogenesis.svg|thumb|upright=1.5|Steroidogenesis: Deficiency in 21-hydroxylase (green vertical bar visible near the top center) leads to accumulation of progesterone and 17α-hydroxyprogesterone; excessive accumulation of these steroids leads to their conversion to androgens (lower left), whereas production of mineralcorticoids and glucocorticoids (top left), including cortisol, is reduced.]]
The enzyme P450c21, commonly referred to as 21-hydroxylase (21-OH), is embedded in the smooth endoplasmic reticulum of the cells of the adrenal cortex. It catalyzes [[Biology:Hydroxylation|hydroxylation]] of 17α-hydroxyprogesterone (17OHP) to 11-deoxycortisol in the [[Chemistry:Glucocorticoid|glucocorticoid]] pathway, which starts from [[Chemistry:Pregnenolone|pregnenolone]] and finishes with [[Chemistry:Cortisol|cortisol]]. It also catalyzes hydroxylation of [[Chemistry:Progesterone|progesterone]] to 11-deoxycorticosterone (DOC) in the [[Chemistry:Mineralocorticoid|mineralocorticoid]] pathway on its way from pregnenolone to [[Chemistry:Aldosterone|aldosterone]].<ref>{{Cite web |title=CYP21A2 gene: MedlinePlus Genetics |url=https://medlineplus.gov/genetics/gene/cyp21a2/ |access-date=2023-11-15 |website=medlineplus.gov |language=en}}</ref>

Deficient activity of this enzyme reduces the efficiency of cortisol synthesis, with consequent hyperplasia of the adrenal cortex and elevation of ACTH levels. ACTH stimulates uptake of [[Chemistry:Cholesterol|cholesterol]] and synthesis of pregnenolone. Steroid precursors up to and including progesterone, 17α-hydroxypregnenolone, and especially 17OHP accumulate in the adrenal cortex and in circulating blood. Blood levels of 17OHP can reach 10-1000 times the normal concentration.<ref name="pmid37902057">{{cite journal | vauthors = Castro SM, Wiest P, Spritzer PM, Kopacek C | title = The impact of neonatal 17-hydroxyprogesterone cutoff determination in a public newborn screening program for congenital adrenal hyperplasia in Southern Brazil: 3 years' experience | journal = Endocrine Connections | volume = 12 | issue = 12 | date = December 2023 | pmid = 37902057 | doi = 10.1530/EC-23-0162 | pmc = 10620452 | s2cid = 263150618 }}</ref>

Since 21-hydroxylase activity is not involved in synthesis of [[Biology:Androgen|androgen]]s, a substantial fraction of the large amounts of 17α-hydroxypregnenolone is diverted to synthesis of DHEA, [[Chemistry:Androstenedione|androstenedione]], and other androgens of adrenal origin beginning in the third month of fetal life in both sexes.<ref name="pmid36734395">{{cite journal | vauthors = S L, Krishna Prasad H, Ramjee B, Venugopalan L, Ganapathy N, Paramasamy B | title = Audit of management of children and adolescents with congenital adrenal hyperplasia as per recent Endocrine Society guidelines | journal = Pediatric Endocrinology, Diabetes, and Metabolism | volume = 29 | issue = 1 | pages = 10–15 | date = 2023 | pmid = 36734395 | pmc = 10226460 | doi = 10.5114/pedm.2022.122547 }}</ref>

Synthesis of aldosterone is also dependent on 21-hydroxylase activity. Although fetal production is impaired, it causes no prenatal effects, as the [[Biology:Placenta|placenta]]l connection allows maternal blood to "[[Engineering:Kidney dialysis|dialyze]]" the fetus and maintain both [[Physics:Electrolyte|electrolyte]] balance and blood volume.<ref name="pmid10088875">{{cite journal |vauthors=Deaton MA, Glorioso JE, McLean DB |title=Congenital adrenal hyperplasia: not really a zebra |journal=Am Fam Physician |volume=59 |issue=5 |pages=1190–6, 1172 |date=March 1999 |pmid=10088875 |doi= |url=}}</ref>

==Presentation==
CAH can occur in various forms. The clinical presentation of each form is different and depends to a large extent on the kind of the underlying 21-hydroxylase enzyme defect.<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 classical CAH can be further subdivided into two forms: salt-wasting and simple-virilizing, depending on whether mineralocorticoid deficiency presents or absents, respectively.<ref name="pmid29630216"/><ref name=pmid35799332>{{cite journal | vauthors = Nordenström A, Lajic S, Falhammar H | title = Long-Term Outcomes of Congenital Adrenal Hyperplasia | language = English | journal = Endocrinology and Metabolism | volume = 37 | issue = 4 | pages = 587–598 | date = August 2022 | pmid = 35799332 | pmc = 9449109 | doi = 10.3803/EnM.2022.1528 }}</ref><ref name = "pmid20558634">{{cite journal | vauthors = Dauber A, Kellogg M, Majzoub JA | title = Monitoring of therapy in congenital adrenal hyperplasia | journal = Clinical Chemistry | volume = 56 | issue = 8 | pages = 1245–1251 | date = August 2010 | pmid = 20558634 | doi = 10.1373/clinchem.2010.146035 | name-list-style = vanc | doi-access = free }}</ref> This subtyping is often not clinically meaningful, because all patients with classical form 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>

===Severe, early onset 21-hydroxylase deficient CAH===
The two most serious neonatal consequences of 21-hydroxylase deficiency are the following: life-threatening salt-wasting crises in the first month of life (for male and female infants alike) and severe virilization of female infants which can cause genital ambiguity.<ref>{{cite journal | vauthors = Trapp CM, Speiser PW, Oberfield SE | title = Congenital adrenal hyperplasia: an update in children | language = en-US | journal = Current Opinion in Endocrinology, Diabetes, and Obesity | volume = 18 | issue = 3 | pages = 166–170 | date = June 2011 | pmid = 21494138 | pmc = 3638875 | doi = 10.1097/MED.0b013e328346938c }}</ref><ref>{{cite journal | vauthors = White PC, Speiser PW | title = Congenital adrenal hyperplasia due to 21-hydroxylase deficiency | journal = Endocrine Reviews | volume = 21 | issue = 3 | pages = 245–291 | date = June 2000 | pmid = 10857554 | doi = 10.1210/edrv.21.3.0398 | doi-access = free }}</ref> The subdivision of the early onset CAH into salt-wasting and simple-virilizing forms, which is based on the capacity of the adrenal to produce small amounts of aldosterone in the simple-virilizing form, is often not clinically meaningful, because clinical presentations overlap and all patients lose salt to some degree.<ref name="pmid32966723"/>

====Salt-wasting crises in infancy====
Excessive levels of androgens of adrenal origin<ref name="pmid22837923">{{cite journal | vauthors = Kulshreshtha B, Eunice M, Ammini AC | title = Pubertal development among girls with classical congenital adrenal hyperplasia initiated on treatment at different ages | journal = Indian Journal of Endocrinology and Metabolism | volume = 16 | issue = 4 | pages = 599–603 | date = July 2012 | pmid = 22837923 | pmc = 3401763 | doi = 10.4103/2230-8210.98018 | doi-access = free }}</ref><ref name="pmid18675711">{{cite journal | vauthors = Mueller SC, Temple V, Oh E, VanRyzin C, Williams A, Cornwell B, Grillon C, Pine DS, Ernst M, Merke DP | display-authors = 6 | title = Early androgen exposure modulates spatial cognition in congenital adrenal hyperplasia (CAH) | journal = Psychoneuroendocrinology | volume = 33 | issue = 7 | pages = 973–980 | date = August 2008 | pmid = 18675711 | pmc = 2566857 | doi = 10.1016/j.psyneuen.2008.04.005 }}</ref><ref name="pmid27460188">{{cite journal | vauthors = Kung KT, Spencer D, Pasterski V, Neufeld S, Glover V, O'Connor TG, Hindmarsh PC, Hughes IA, Acerini CL, Hines M | display-authors = 6 | title = No relationship between prenatal androgen exposure and autistic traits: convergent evidence from studies of children with congenital adrenal hyperplasia and of amniotic testosterone concentrations in typically developing children | journal = Journal of Child Psychology and Psychiatry, and Allied Disciplines | volume = 57 | issue = 12 | pages = 1455–1462 | date = December 2016 | pmid = 27460188 | pmc = 6100761 | doi = 10.1111/jcpp.12602 }}</ref><ref name="pmid19570920">{{cite journal | vauthors = Antal Z, Zhou P | title = Congenital adrenal hyperplasia: diagnosis, evaluation, and management | journal = Pediatrics in Review | volume = 30 | issue = 7 | pages = e49–e57 | date = July 2009 | pmid = 19570920 | doi = 10.1542/pir.30-7-e49 | s2cid = 30104550 }}</ref> have little effect on the genitals of male infants with classical CAH.<ref name="pmid22837923"/> If a male infant with CAH goes undetected during newborn screening, he will exhibit normal health and physical appearance upon examination, leading to his timely discharge from the hospital.<ref name="DSChild"/><ref name="pmid17032723">{{cite journal | vauthors = Nimkarn S, Lin-Su K, Berglind N, Wilson RC, New MI | title = Aldosterone-to-renin ratio as a marker for disease severity in 21-hydroxylase deficiency congenital adrenal hyperplasia | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 92 | issue = 1 | pages = 137–142 | date = January 2007 | pmid = 17032723 | doi = 10.1210/jc.2006-0964 | doi-access = free }}</ref><ref name="pmid16227036">{{cite journal | vauthors = Varness TS, Allen DB, Hoffman GL | title = Newborn screening for congenital adrenal hyperplasia has reduced sensitivity in girls | journal = The Journal of Pediatrics | volume = 147 | issue = 4 | pages = 493–498 | date = October 2005 | pmid = 16227036 | doi = 10.1016/j.jpeds.2005.04.035 }}</ref><ref name="pmid23414665">{{cite journal | vauthors = Chan CL, McFann K, Taylor L, Wright D, Zeitler PS, Barker JM | title = Congenital adrenal hyperplasia and the second newborn screen | journal = The Journal of Pediatrics | volume = 163 | issue = 1 | pages = 109–13.e1 | date = July 2013 | pmid = 23414665 | doi = 10.1016/j.jpeds.2013.01.002 }}</ref>

Aldosterone insufficiency in salt-wasting CAH results in significant loss of sodium in the urine. Urinary sodium concentrations may exceed 50 mEq/L. Due to the loss of salt at that rate, the infant is unable to maintain proper blood volume and begins to suffer from [[Medicine:Dehydration|dehydration]] due to [[Medicine:Hyponatremia|hyponatremia]] by the end of the first week of life. [[Chemistry:Potassium|Potassium]] and [[Chemistry:Acid|acid]] excretion are also impaired when [[Chemistry:Mineralocorticoid|mineralocorticoid]] activity is deficient, and [[Medicine:Hyperkalemia|hyperkalemia]] and metabolic acidosis gradually develop. When there's not enough cortisol in the body due to the classical CAH, it becomes harder to have proper blood circulation. Inadequate circulation can cause problems like spitting and difficulty gaining weight in babies. Furthermore, infants with salt-wasting CAH may experience even worse symptoms like vomiting, extreme dehydration, and their circulation can suddenly fail (which is called [[Medicine:Shock (circulatory)|circulatory shock]]) within two or three weeks after birth.<ref name="DSChild">{{cite journal|url=https://www.researchgate.net/publication/345957058|title=Congenital Adrenal Hyperplasia (Salt Wasting)|journal=DS (Child) H J|year=2015|vauthors=Fahmida Z, Quamrul H, Nurun N}}</ref>

Upon admission to a medical facility, the infant between the ages of 1 and 3 weeks will exhibit signs of both underweight and dehydration.<ref name="DSChild"/> The blood pressure may be abnormally low.
Basic laboratory analyses will indicate low levels of sodium ([[Medicine:Hyponatremia|hyponatremia]]), typically falling between 105 and 125 mEq/L Na<sup>+</sup> in serum samples. These infants may also experience severe [[Medicine:Hyperkalemia|hyperkalemia]] with potassium (K<sup>+</sup>) levels exceeding 10 mEq/L, along with significant metabolic acidosis. [[Medicine:Hypoglycemia|Hypoglycemia]] (low blood sugar) might also be observed. This collection of manifestations is referred to as a "salt-wasting crisis" which poses an imminent risk of fatal consequences if left untreated.<ref name="pmid17199092">{{cite journal | vauthors = Grosse SD, Van Vliet G | title = How many deaths can be prevented by newborn screening for congenital adrenal hyperplasia? | journal = Hormone Research | volume = 67 | issue = 6 | pages = 284–291 | date = 2007 | pmid = 17199092 | doi = 10.1159/000098400 | s2cid = 21497680 | doi-access = free }}</ref>

Despite the severity of this condition, affected infants respond swiftly to treatment involving hydrocortisone administration along with intravenous infusion of saline solution and dextrose supplementation. Consequently, normal blood volume is promptly restored alongside stabilization of blood pressure and restoration of appropriate body sodium levels, leading to reversal of hyperkalemia. With prompt and apt management measures in place, most infants are no longer at risk within a span of approximately 24 hours.<ref name="pmid19500763">{{cite journal | vauthors = Hindmarsh PC | title = Management of the child with congenital adrenal hyperplasia | journal = Best Practice & Research. Clinical Endocrinology & Metabolism | volume = 23 | issue = 2 | pages = 193–208 | date = April 2009 | pmid = 19500763 | doi = 10.1016/j.beem.2008.10.010 }}</ref><ref name="pmid28771930">{{cite journal | vauthors = Fleming L, Knafl K, Knafl G, Van Riper M | title = Parental management of adrenal crisis in children with congenital adrenal hyperplasia | journal = Journal for Specialists in Pediatric Nursing | volume = 22 | issue = 4 | date = October 2017 | pmid = 28771930 | pmc = 5884098 | doi = 10.1111/jspn.12190 }}</ref><ref name="pmid18411135">{{cite journal | vauthors = Pang S, Clark A | title = Newborn screening, prenatal diagnosis, and prenatal treatment of congenital adrenal hyperplasia due to 21-hydroxylase deficiency | journal = Trends in Endocrinology and Metabolism | volume = 1 | issue = 6 | pages = 300–307 | date = 1990 | pmid = 18411135 | doi = 10.1016/1043-2760(90)90068-e | s2cid = 21880131 }}</ref>

====Virilization of female infants====
<!-- The image and the description for the androgen backdoor pathway is copied from [[Biology:Androgen backdoor pathway|Androgen backdoor pathway]]; see the page's history for attributions -->[[Image:Androgen backdoor pathway.svg|thumb|right|upright=2|The androgen backdoor pathway (red arrows) roundabout testosterone embedded in within conventional androgen synthesis that lead to 5α-dihydrotestosterone through testosterone<ref name=wj/><ref name="pmid30763313">{{cite journal | vauthors = O'Shaughnessy PJ, Antignac JP, Le Bizec B, Morvan ML, Svechnikov K, Söder O, Savchuk I, Monteiro A, Soffientini U, Johnston ZC, Bellingham M, Hough D, Walker N, Filis P, Fowler PA | display-authors = 6 | title = Alternative (backdoor) androgen production and masculinization in the human fetus | journal = PLOS Biology | volume = 17 | issue = 2 | pages = e3000002 | date = February 2019 | pmid = 30763313 | pmc = 6375548 | doi = 10.1371/journal.pbio.3000002 | veditors = Rawlins E | doi-access = free }}</ref><ref name="pmid28774496">{{cite journal | vauthors = Barnard L, Gent R, van Rooyen D, Swart AC | title = Adrenal C11-oxy C<sub>21</sub> steroids contribute to the C11-oxy C<sub>19</sub> steroid pool via the backdoor pathway in the biosynthesis and metabolism of 21-deoxycortisol and 21-deoxycortisone | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 174 | issue =  | pages = 86–95 | date = November 2017 | pmid = 28774496 | doi = 10.1016/j.jsbmb.2017.07.034 | s2cid = 24071400 }}</ref>]]CAH is a genetic disorder characterized by impaired production of cortisol in the adrenal glands.<ref name="pmid29630216"/><ref name="pmid30272171"/>

Production of cortisol begins at week 8 of fetal life.<ref>{{cite book|title=Robbins and Cotran pathologic basis of disease | vauthors = Kumar V, Abbas AK, Aster JC, Cotran RS, Robbins SL |year=2014 |isbn=978-1-4557-2613-4 |edition=Ninth |location=Philadelphia, PA | publisher = Elsevier/Saunders |page=1128 |oclc=879416939 }}</ref><ref name="pmid34171490">{{cite journal |vauthors=du Toit T, Swart AC |title=Turning the spotlight on the C11-oxy androgens in human fetal development |journal=J Steroid Biochem Mol Biol |volume=212 |issue= |pages=105946 |date=September 2021 |pmid=34171490 |doi=10.1016/j.jsbmb.2021.105946 |s2cid=235603586 |url=}}</ref><ref name="pmid7191459">{{cite journal |vauthors=Murphy BE, Sebenick M, Patchell ME |title=Cortisol production and metabolism in the human fetus and its reflection in the maternal urine |journal=J Steroid Biochem |volume=12 |issue= |pages=37–45 |date=January 1980 |pmid=7191459 |doi=10.1016/0022-4731(80)90248-4 |url=}}</ref>

The 21-hydroxylase enzyme is essential in conversion of [[Chemistry:Progesterone|progesterone]] and [[Chemistry:17α-Hydroxyprogesterone|17OHP]] into 11-deoxycorticosterone and 11-deoxycortisol, respectively.<ref name="pmid30272171"/><ref name="pmid17666484">{{cite journal | vauthors = Araújo RS, Mendonca BB, Barbosa AS, Lin CJ, Marcondes JA, Billerbeck AE, Bachega TA | title = Microconversion between CYP21A2 and CYP21A1P promoter regions causes the nonclassical form of 21-hydroxylase deficiency | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 92 | issue = 10 | pages = 4028–4034 | date = October 2007 | pmid = 17666484 | doi = 10.1210/jc.2006-2163 | doi-access = free }}</ref> This process is done through hydroxylation at C-21 position.<ref name="pmid28065637">{{cite journal | vauthors = Neunzig J, Milhim M, Schiffer L, Khatri Y, Zapp J, Sánchez-Guijo A, Hartmann MF, Wudy SA, Bernhardt R | display-authors = 6 | title = The steroid metabolite 16(β)-OH-androstenedione generated by CYP21A2 serves as a substrate for CYP19A1 | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 167 | pages = 182–191 | date = March 2017 | pmid = 28065637 | doi = 10.1016/j.jsbmb.2017.01.002 | s2cid = 36860068 }}</ref>
It was described in at least 1953 that impaired steroid hydroxylation at C-21 position happens in congenital adrenal hyperplasia and is accompanied by excessive amounts of 17OHP that leads to virilism.<ref>{{cite journal | vauthors = Jailer JW | title = Virilism | journal = Bulletin of the New York Academy of Medicine | volume = 29 | issue = 5 | pages = 377–394 | date = May 1953 | pmid = 13032691 | pmc = 1877295 }}</ref>

In the insufficiency of 21-hydroxylase to participate in the biosynthesis of cortisol, the 21-hydroxylation in the zona fasciculata of the adrenal cortex is impaired, so 17OHP and progesterone will not be properly converted into 11-deoxycortisol and 11-deoxycorticosterone, respectively − the precursors for cortisol and aldosterone. As the plasma concentration of cortisol and aldosterone decreases, ACTH levels increase, leading to excessive production and accumulation of cortisol precursors (especially 17OHP), which are eventually transferred to androsterone that is a feedstock for other androgens.<ref name="pmid32616876"/> Other [[Biology:Androgen|androgen]]s may be additionally produced from 17OHP, due to its elevated levels, that leads, inter alia, to its [[Biology:5α-Reductase|5α-reduction]].<ref name="pmid23073980">{{cite journal | vauthors = Fukami M, Homma K, Hasegawa T, Ogata T | title = Backdoor pathway for dihydrotestosterone biosynthesis: implications for normal and abnormal human sex development | journal = Developmental Dynamics | volume = 242 | issue = 4 | pages = 320–329 | date = April 2013 | pmid = 23073980 | doi = 10.1002/dvdy.23892 | s2cid = 44702659 | doi-access = free }}</ref> These additional androgens are produced via the so-called "[[Biology:Androgen backdoor pathway|backdoor pathway]]" (see red arrows on the diagram).<ref name="pmid29264476"/><ref name="pmid20613954">{{cite journal | vauthors = Auchus RJ | title = Management of the adult with congenital adrenal hyperplasia | journal = International Journal of Pediatric Endocrinology | volume = 2010 | page = 614107 | date = 2010 | pmid = 20613954 | pmc = 2896848 | doi = 10.1155/2010/614107 | doi-access = free }}</ref> For example, in this "backdoor" pathway, 5α-dihydrotestosterone is produced with roundabout of testosterone as an intermediate product.<ref name="pmid23073980"/><ref name="pmid29277707">{{cite journal | vauthors = van Rooyen D, Gent R, Barnard L, Swart AC | title = The in vitro metabolism of 11β-hydroxyprogesterone and 11-ketoprogesterone to 11-ketodihydrotestosterone in the backdoor pathway | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 178 | pages = 203–212 | date = April 2018 | pmid = 29277707 | doi = 10.1016/j.jsbmb.2017.12.014 | s2cid = 3700135 }}</ref><ref>{{cite journal | vauthors = Gueux B, Fiet J, Galons H, Boneté R, Villette JM, Vexiau P, Pham-Huu-Trung MT, Raux-Eurin MC, Gourmelen M, Brérault JL | display-authors = 6 | title = The measurement of 11 beta-hydroxy-4-pregnene-3,20-dione (21-deoxycorticosterone) by radioimmunoassay in human plasma | journal = Journal of Steroid Biochemistry | volume = 26 | issue = 1 | pages = 145–150 | date = January 1987 | pmid = 3546944 | doi = 10.1016/0022-4731(87)90043-4 | department = primary }}</ref> Some of the androgens produced by the backdoor pathway are those that cannot be converted to estrogens by [[Biology:Aromatase|aromatase]], causing [[Biology:Virilization|prenatal virilization]],<ref name="pmid32862221">{{cite journal | vauthors = Nagasaki K, Takase K, Numakura C, Homma K, Hasegawa T, Fukami M | title = Foetal virilisation caused by overproduction of non-aromatisable 11-oxygenated C19 steroids in maternal adrenal tumour | journal = Human Reproduction | volume = 35 | issue = 11 | pages = 2609–2612 | date = November 2020 | pmid = 32862221 | doi = 10.1093/humrep/deaa221 }}</ref> and making them the dominant androgens in classic 21-hydroxylase deficiency.<ref name="pmid26865584"/><ref name=wj>{{cite journal|doi=10.15347/WJM/2023.003  |doi-access=free |title=Alternative androgen pathways |year=2023 | vauthors = Masiutin M, Yadav M |journal=WikiJournal of Medicine |volume=10 |pages=X |s2cid=257943362}}</ref>{{See also|Androgen backdoor pathway}}

Virilization of genetically female (XX) infants usually produces obvious genital ambiguity. Inside the pelvis, the [[Biology:Ovary|ovaries]] are normal and since they have not been exposed to testicular [[Biology:Anti-Müllerian hormone|anti-Müllerian hormone]] (AMH), the [[Biology:Uterus|uterus]], [[Medicine:Fallopian tube|fallopian tube]]s, upper [[Biology:Vagina|vagina]], and other Müllerian structures are normally formed as well. However, the high levels of testosterone<ref name="pmid16569417">{{cite journal | vauthors = Rauh M, Gröschl M, Rascher W, Dörr HG | title = Automated, fast and sensitive quantification of 17 alpha-hydroxy-progesterone, androstenedione and testosterone by tandem mass spectrometry with on-line extraction | journal = Steroids | volume = 71 | issue = 6 | pages = 450–458 | date = June 2006 | pmid = 16569417 | doi = 10.1016/j.steroids.2006.01.015 | s2cid = 11605597 }}</ref> in the blood can enlarge the phallus, partially or completely close the vaginal opening, enclose the urethral groove so that it opens at the base of the phallus, on the shaft or even at the tip like a boy. Testosterone can cause the labial skin to become as thin and rugate as a scrotum,<ref name="pmid21967243">{{cite journal | vauthors = Glaser RL, Dimitrakakis C, Messenger AG | title = Improvement in scalp hair growth in androgen-deficient women treated with testosterone: a questionnaire study | journal = The British Journal of Dermatology | volume = 166 | issue = 2 | pages = 274–278 | date = February 2012 | pmid = 21967243 | pmc = 3380548 | doi = 10.1111/j.1365-2133.2011.10655.x }}</ref><ref name="pmid33519525">{{cite journal | vauthors = Gharahdaghi N, Phillips BE, Szewczyk NJ, Smith K, Wilkinson DJ, Atherton PJ | title = Links Between Testosterone, Oestrogen, and the Growth Hormone/Insulin-Like Growth Factor Axis and Resistance Exercise Muscle Adaptations | journal = Frontiers in Physiology | volume = 11 | issue =  | page = 621226 | date = 2020 | pmid = 33519525 | pmc = 7844366 | doi = 10.3389/fphys.2020.621226 | doi-access = free }}</ref> but cannot produce palpable gonads (i.e., testes) in the folds.<ref name="pmid15102623">{{cite journal | vauthors = Ogilvy-Stuart AL, Brain CE | title = Early assessment of ambiguous genitalia | journal = Archives of Disease in Childhood | volume = 89 | issue = 5 | pages = 401–407 | date = May 2004 | pmid = 15102623 | pmc = 1719899 | doi = 10.1136/adc.2002.011312 }}</ref><ref name="pmid8857201">{{cite journal | vauthors = Anhalt H, Neely EK, Hintz RL | title = Ambiguous genitalia | journal = Pediatrics in Review | volume = 17 | issue = 6 | pages = 213–220 | date = June 1996 | pmid = 8857201 | doi = 10.1542/pir.17-6-213 | s2cid = 261302604 }}</ref><ref name="pmid35999483">{{cite journal | vauthors = Corona G, Maggi M | title = The role of testosterone in male sexual function | journal = Reviews in Endocrine & Metabolic Disorders | volume = 23 | issue = 6 | pages = 1159–1172 | date = December 2022 | pmid = 35999483 | pmc = 9789013 | doi = 10.1007/s11154-022-09748-3 }}</ref><ref name="pmid32090527">{{cite journal | vauthors = Kim HW, Yoo SY, Oh S, Jeon TY, Kim JH | title = Ultrasonography of Pediatric Superficial Soft Tissue Tumors and Tumor-Like Lesions | journal = Korean Journal of Radiology | volume = 21 | issue = 3 | pages = 341–355 | date = March 2020 | pmid = 32090527 | pmc = 7039727 | doi = 10.3348/kjr.2019.0343 }}</ref><ref name="pmid12428198">{{cite journal | vauthors = Sultan C, Paris F, Jeandel C, Lumbroso S, Galifer RB | title = Ambiguous genitalia in the newborn | journal = Seminars in Reproductive Medicine | volume = 20 | issue = 3 | pages = 181–188 | date = August 2002 | pmid = 12428198 | doi = 10.1055/s-2002-35382 | s2cid = 21484378 }}</ref><ref name="pmid23517636">{{cite journal | vauthors = Cabrera SM, Rogol AD | title = Testosterone exposure in childhood: discerning pathology from physiology | journal = Expert Opinion on Drug Safety | volume = 12 | issue = 3 | pages = 375–388 | date = May 2013 | pmid = 23517636 | doi = 10.1517/14740338.2013.782000 | s2cid = 24307618 }}</ref>

Thus, depending on the severity of hyperandrogenism, a female infant can be mildly affected, obviously ambiguous, or so severely virilized as to appear to be a male. Andrea Prader devised the following Prader scale as a way of describing the degree of virilization.<ref>{{Cite web |title=Andrea Prader {{!}} RCP Museum |url=https://history.rcplondon.ac.uk/inspiring-physicians/andrea-prader |access-date=2023-08-01 |website=history.rcplondon.ac.uk}}</ref>
* An infant at stage 1 has a mildly large clitoris and slightly reduced vaginal opening size. This degree may go unnoticed or may be simply assumed to be within normal variation.
* Stages 2 and 3 represent progressively more severe degrees of virilization. The genitalia are obviously abnormal to the eye, with a phallus intermediate in size and a small vaginal opening.
* Stage 4 looks more male than female, with an empty scrotum and a phallus the size of a normal penis, but not quite free enough of the perineum to be pulled onto the abdomen toward the umbilicus (i.e., what is termed a chordee in a male). The single small urethral/vaginal opening at the base or on the shaft of the phallus would be considered a [[Medicine:Hypospadias|hypospadias]] in a male. X-rays taken after dye injection into this opening reveal the internal connection with the upper vagina and uterus. This common opening can predispose to urinary obstruction and [[Medicine:Urinary tract infection|infection]].
* Stage 5 denotes complete male virilization, with a normally formed penis with the urethral opening at or near the tip. The scrotum is normally formed but empty. The internal pelvic organs include normal ovaries and uterus, and the vagina connects internally with the urethra as in Stage 4. These infants are not visibly ambiguous, and are usually assumed to be ordinary boys with undescended testes. In most cases, the diagnosis of CAH is not suspected until signs of salt-wasting develop a week later.<ref name="pmid27242977">{{cite journal | vauthors = González R, Ludwikowski BM | title = Should CAH in Females Be Classified as DSD? | journal = Frontiers in Pediatrics | volume = 4 | issue =  | page = 48 | date = 2016 | pmid = 27242977 | pmc = 4865481 | doi = 10.3389/fped.2016.00048 | doi-access = free }}</ref><ref name="pmid30905417">{{cite journal | vauthors = de Jesus LE, Costa EC, Dekermacher S | title = Gender dysphoria and XX congenital adrenal hyperplasia: how frequent is it? Is male-sex rearing a good idea? | journal = Journal of Pediatric Surgery | volume = 54 | issue = 11 | pages = 2421–2427 | date = November 2019 | pmid = 30905417 | doi = 10.1016/j.jpedsurg.2019.01.062 | s2cid = 85501467 }}</ref><ref name="pmid32485822">{{cite journal | vauthors = Kudela G, Gawlik A, Koszutski T | title = Early Feminizing Genitoplasty in Girls with Congenital Adrenal Hyperplasia (CAH)-Analysis of Unified Surgical Management | journal = International Journal of Environmental Research and Public Health | volume = 17 | issue = 11 | page = 3852 | date = May 2020 | pmid = 32485822 | pmc = 7312042 | doi = 10.3390/ijerph17113852 | doi-access = free }}</ref><ref name="pmid35639647">{{cite journal | vauthors = Jones CL, Houk CP, Barroso JU, Lee PA | title = Fully Masculinized 46,XX Individuals with Congenital Adrenal Hyperplasia: Perspective Regarding Sex of Rearing and Surgery | journal = International Journal of Fertility & Sterility | volume = 16 | issue = 2 | pages = 128–131 | date = April 2022 | pmid = 35639647 | pmc = 9108292 | doi = 10.22074/IJFS.2021.532602.1144 }}</ref>

When the genitalia are determined to be ambiguous at birth, CAH is one of the leading diagnostic possibilities. Evaluation reveals the presence of a uterus, extreme elevation of 17OHP,<ref name="pmid33272921"/> levels of testosterone<ref name="pmid16569417" /> approaching or exceeding the male range<ref name="pmid34000839">{{cite journal | vauthors = Li JR, Goodman X, Cho J, Holditch-Davis D | title = The Variability and Determinants of Testosterone Measurements in Children: A Critical Review | journal = Biological Research for Nursing | volume = 23 | issue = 4 | pages = 646–657 | date = October 2021 | pmid = 34000839 | pmc = 8726425 | doi = 10.1177/10998004211017323 }}</ref> but low [[Biology:Anti-Müllerian hormone|AMH]] levels. The karyotype is that of an ordinary female: 46,XX. With this information, the diagnosis of CAH is readily made and female sex confirmed.<ref name="pmid27242977"/><ref name="pmid37473408">{{cite journal | vauthors = Zwayne N, Chawla R, van Leeuwen K | title = Caring for Patients With Congenital Adrenal Hyperplasia Throughout the Lifespan | journal = Obstetrics and Gynecology | volume = 142 | issue = 2 | pages = 257–268 | date = August 2023 | pmid = 37473408 | doi = 10.1097/AOG.0000000000005263 | s2cid = 259996994 }}</ref><ref name="pmid36218438">{{cite journal | vauthors = Amais DS, da Silva TE, Barros BA, de Andrade JG, de Lemos-Marini SH, de Mello MP, Marques-de-Faria AP, Mazzola TN, Guaragna MS, Fabbri-Scallet H, Vieira TA, Viguetti-Campos NL, Morcillo AM, Hiort O, Maciel-Guerra AT, Guerra-Junior G | display-authors = 6 | title = Sex dimorphism of weight and length at birth: evidence based on disorders of sex development | journal = Annals of Human Biology | volume = 49 | issue = 7–8 | pages = 274–279 | date = December 2022 | pmid = 36218438 | doi = 10.1080/03014460.2022.2134452 | s2cid = 252816435 }}</ref><ref name="pmid36242011">{{cite journal | vauthors = Dehneh N, Jarjour R, Idelbi S, Alibrahem A, Al Fahoum S | title = Syrian females with congenital adrenal hyperplasia: a case series | journal = Journal of Medical Case Reports | volume = 16 | issue = 1 | page = 371 | date = October 2022 | pmid = 36242011 | pmc = 9569117 | doi = 10.1186/s13256-022-03609-y | doi-access = free }}</ref><ref name="pmid27125449">{{cite journal | vauthors = Khattab A, Yau M, Qamar A, Gangishetti P, Barhen A, Al-Malki S, Mistry H, Anthony W, Toralles MB, New MI | display-authors = 6 | title = Long term outcomes in 46, XX adult patients with congenital adrenal hyperplasia reared as males | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 165 | issue = Pt A | pages = 12–17 | date = January 2017 | pmid = 27125449 | doi = 10.1016/j.jsbmb.2016.03.033 | s2cid = 21521508 }}</ref>
Evaluation of ambiguous genitalia is described in detail elsewhere. In most cases it is possible to confirm and [[Biology:Sex assignment|assign]] female sex within 12–36 hours of birth. The exception are the rare, completely virilized genetic females (Prader stage 5), who present the most challenging assignment and surgery dilemmas.<ref name="pmid16010462">{{cite journal | vauthors = Dessens AB, Slijper FM, Drop SL | title = Gender dysphoria and gender change in chromosomal females with congenital adrenal hyperplasia | journal = Archives of Sexual Behavior | volume = 34 | issue = 4 | pages = 389–397 | date = August 2005 | pmid = 16010462 | doi = 10.1007/s10508-005-4338-5 | s2cid = 11328239 }}</ref><ref name="pmid30620712">{{cite journal | vauthors = Riedl S, Röhl FW, Bonfig W, Brämswig J, Richter-Unruh A, Fricke-Otto S, Bettendorf M, Riepe F, Kriegshäuser G, Schönau E, Even G, Hauffa B, Dörr HG, Holl RW, Mohnike K | display-authors = 6 | title = Genotype/phenotype correlations in 538 congenital adrenal hyperplasia patients from Germany and Austria: discordances in milder genotypes and in screened versus prescreening patients | journal = Endocrine Connections | volume = 8 | issue = 2 | pages = 86–94 | date = February 2019 | pmid = 30620712 | pmc = 6365666 | doi = 10.1530/EC-18-0281 }}</ref>

When the degree of ambiguity is obvious, corrective surgery is usually offered and performed, but reconstructive surgery on infant genitalia has controversies.<ref name="pmid29330019">{{cite journal | vauthors = Szymanski KM, Whittam B, Kaefer M, Frady H, Casey JT, Tran VT, Cain MP, Rink RC | display-authors = 6 | title = Parental decisional regret and views about optimal timing of female genital restoration surgery in congenital adrenal hyperplasia | journal = Journal of Pediatric Urology | volume = 14 | issue = 2 | pages = 156.e1–156.e7 | date = April 2018 | pmid = 29330019 | doi = 10.1016/j.jpurol.2017.11.012 }}</ref><ref name="pmid36720126">{{cite journal | vauthors = Liao L, Sun M, Wang F, Pan S, Wu X, Huang X | title = Clinical characteristics of female patients diagnosed with congenital adrenal hyperplasia and plastic-esthetic related thoughts: a retrospective study | journal = Neuro Endocrinology Letters | volume = 43 | issue = 7–8 | pages = 378–384 | date = December 2022 | pmid = 36720126 | doi =  }}</ref><ref name="pmid33848081">{{cite journal | vauthors = Fernandez N, Chavarriaga J, Pérez J | title = Complete corporeal preservation clitoroplasty: new insights into feminizing genitoplasty | journal = International Braz J Urol | volume = 47 | issue = 4 | pages = 861–867 | date = 2021 | pmid = 33848081 | pmc = 8321476 | doi = 10.1590/S1677-5538.IBJU.2020.0839 }}</ref>{{See also|#Sex assignment issues and controversies}}

==== Reduced fertility ====

===== Testicular adrenal rest tumors =====
Infertility observed in adult males with classica CAH has been associated with testicular adrenal rest tumors (TART) that may originate during childhood.<ref name="pmid37845103">{{cite journal |vauthors=Eyer de Jesus L, Paz de Oliveira AP, Porto LC, Dekermacher S |title=Testicular adrenal rest tumors - Epidemiology, diagnosis and treatment |journal=J Pediatr Urol |volume= |issue= |pages= |date=October 2023 |pmid=37845103 |doi=10.1016/j.jpurol.2023.10.005 |s2cid=263817094 |url=}}</ref> Delayed diagnosis of CAH was associated with a higher risk of developing TART, which may be attributable to poor disease control early in life,<ref name="pmid37837609">{{cite journal |vauthors=Schröder MA, Neacşu M, Adriaansen BP, Sweep FC, Ahmed SF, Ali SR, Bachega TA, Baronio F, Birkebæk NH, de Bruin C, Bonfig W, Bryce J, Clemente M, Cools M, Elsedfy H, Globa E, Guran T, Güven A, Amr NH, Janus D, Taube NL, Markosyan R, Miranda M, Poyrazoğlu Ş, Rees A, Salerno M, Stancampiano MR, Vieites A, de Vries L, Yavas Abali Z, Span PN, Claahsen-van der Grinten HL |title=Hormonal control during infancy and testicular adrenal rest tumor development in males with congenital adrenal hyperplasia: a retrospective multicenter cohort study |journal=Eur J Endocrinol |volume=189 |issue=4 |pages=460–468 |date=October 2023 |pmid=37837609 |doi=10.1093/ejendo/lvad143 |url=|doi-access=free }}</ref> emphasizing the need of early detection and management of CAH, and, once CAH is detected, detection and management of TART.<ref name="pmid37789918">{{cite journal |vauthors=Tuladhar S, Katwal S, Joshi HO, Yadav B, Bhusal A, Bhandari S |title=Testicular adrenal rest tumors (TART) secondary to congenital adrenal hyperplasia: A case report emphasizing early detection and management |journal=Radiology Case Reports |volume=18 |issue=12 |pages=4351–4356 |date=December 2023 |pmid=37789918 |pmc=10542771 |doi=10.1016/j.radcr.2023.09.006}}</ref> TART in prepubertal males with classical CAH could be found during childhood (20%). Martinez-Aguayo et al. reported differences in markers of gonadal function in a subgroup of patients, especially in those with inadequate control.<ref>{{cite journal | vauthors = Martinez-Aguayo A, Rocha A, Rojas N, García C, Parra R, Lagos M, Valdivia L, Poggi H, Cattani A | display-authors = 6 | title = Testicular adrenal rest tumors and Leydig and Sertoli cell function in boys with classical congenital adrenal hyperplasia | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 92 | issue = 12 | pages = 4583–4589 | date = December 2007 | pmid = 17895312 | doi = 10.1210/jc.2007-0383 | collaboration = Chilean Collaborative Testicular Adrenal Rest Tumor Study Group | doi-access = free }}</ref> Early glucocorticoid therapy may be beneficial to the reduction of TART.<ref name="pmid34979773">{{cite journal | vauthors = Zhang Q, Zang L, Zhang CY, Gu WJ, Li B, Jia XF, Chen K, Pei Y, Du J, Guo QH, Ba JM, Lyu ZH, Dou JT, Mu YM | display-authors = 6 | title = [Diagnosis and treatment of 21-hydroxylase deficiency with testicular adrenal rest tumors:a report of three cases and literature review] | language = Chinese | journal = Zhonghua Nei Ke Za Zhi | volume = 61 | issue = 1 | pages = 72–76 | date = January 2022 | pmid = 34979773 | doi = 10.3760/cma.j.cn112138-20210718-00488 }}</ref> Early detection and management of TART in CAH patients is important for preserving testicular function and preventing long-term complications that may impact fertility,<ref name="pmid37789918" /> To avoid long-term complications in male patients with CAH, regular ultrasound examination of the scrotum is recommended,<ref name="pmid37789918"/> especially in patients presenting with the most profound phenotypes of CAH and suboptimal endocrine regulation of the condition.<ref name="pmid37761418">{{cite journal |vauthors=Ortolano R, Cassio A, Alqaisi RS, Candela E, Di Natale V, Assirelli V, Bernardini L, Bortolamedi E, Cantarelli E, Corcioni B, Renzulli M, Balsamo A, Baronio F |title=Testicular Adrenal Rest Tumors in Congenital Adrenal Hyperplasia: Study of a Cohort of Patients from a Single Italian Center |journal= Children|volume=10 |issue=9 |date=August 2023 |page=1457 |pmid=37761418 |pmc=10528159 |doi=10.3390/children10091457 |url= |doi-access=free }}</ref> Subsequently, male subjects with nonclassic CAH rarely present with TARTs, and even though these tumors do not affect fertility and do not require regular ultrasound examination of the scrotum.<ref name="pmid36578966">{{cite journal |vauthors=((Adriaansen BPH)), ((Schröder MAM)), Span PN, ((Sweep FCGJ)), van Herwaarden AE, Claahsen-van der Grinten HL |title=Challenges in treatment of patients with non-classic congenital adrenal hyperplasia |journal= Frontiers in Endocrinology|volume=13 |issue= |pages=1064024 |date=2022 |pmid=36578966 |pmc=9791115 |doi=10.3389/fendo.2022.1064024 |url= |doi-access=free }}</ref>

===== Female fertility =====
Women with classical CAH have statistically reduced fertility, especially those with the salt-losing form.<ref name="pmid33135723">{{cite journal | vauthors = Hirschberg AL, Gidlöf S, Falhammar H, Frisén L, Almqvist C, Nordenskjöld A, Nordenström A | title = Reproductive and Perinatal Outcomes in Women with Congenital Adrenal Hyperplasia: A Population-based Cohort Study | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 106 | issue = 2 | pages = e957–e965 | date = January 2021 | pmid = 33135723 | doi = 10.1210/clinem/dgaa801 | doi-access = free }}</ref> Live birth rate is 33–50% in simple virilized form of CAH, and 0–10% in most severe salt-wasting form. In the [[Medicine:Late onset congenital adrenal hyperplasia|nonclassical]] form of CAH the live birth is 63–90%, similar to the age-matched control groups.<ref name="pmid33158283">{{cite journal | vauthors = Acién P, Acién M | title = Disorders of Sex Development: Classification, Review, and Impact on Fertility | journal = Journal of Clinical Medicine | volume = 9 | issue = 11 | page = 3555 | date = November 2020 | pmid = 33158283 | pmc = 7694247 | doi = 10.3390/jcm9113555 | doi-access = free }}</ref>

====Sex assignment issues and controversies====
Classical CAH leads to female [[Medicine:Pseudohermaphroditism|pseudohermaphroditism]] at birth, and is the most common case of sex ambiguity, the second one is mixed gonadal dysgenesis. Most commonly, at birth, the phallus enlarges, so it is larger than normal female but smaller than normal male. Instead of separate urethral and vaginal openings, there is an urogenital sinus that is often covered by tissue resulting from the posterior fusion of the labioscrotal ridges. Therefore, different degrees of external genital abnormalities can be found, ranging from normal perineum to penile urethra.<ref name="pmid33158283"/>

There are no difficulties [[Biology:Sex assignment|assigning]] appropriate sex for most infants with CAH. Genetic males have normal male genitalia and gonads and simply need hormone replacement. Most virilized females are assigned and raised as girls even if their genitalia are ambiguous or look more male than female. They have normal ovaries and uterus and potential fertility with hormone replacement and surgery. The complex issues encountered in appropriate [[Biology:Sex assignment|sex assignment]] for severely virilized XX infants have contributed to a deeper understanding of [[Philosophy:Gender identity|gender identity]] and [[Social:Sexual orientation|sexual orientation]]. Consequently, this matter remains an ongoing subject of debate within medical discourse.<ref name="pmid37319358"/><ref name="pmid36162947">{{cite journal | vauthors = Hamori CA | title = Female Aesthetic Genital Procedures | journal = Clinics in Plastic Surgery | volume = 49 | issue = 4 | page = ix | date = October 2022 | pmid = 36162947 | doi = 10.1016/j.cps.2022.07.003 | s2cid = 252527170 }}</ref><ref name="pmid36162938">{{cite journal | vauthors = Hamori CA | title = The Aesthetic Genital Consultation: Inquiry to Scheduling | journal = Clinics in Plastic Surgery | volume = 49 | issue = 4 | pages = 435–445 | date = October 2022 | pmid = 36162938 | doi = 10.1016/j.cps.2022.06.006 | s2cid = 252526513 }}</ref>

Until the 1950s, some virilized XX infants were assigned and raised as girls, and some as boys. Most developed gender identities congruent with their sex of rearing. In a few cases of male rearing, a [[Biology:Sex assignment#Reassignment of sex or gender|sex reassignment]] was attempted in mid-childhood when newly discovered karyotyping revealed "female" chromosomes. These reassignments were rarely successful, leading New Zealand American psychologist John Money and other influential psychologists and physicians to conclude that gender identity was (1) unrelated to chromosomes, (2) primarily a result of social learning, and (3) could not be easily changed after infancy.<ref name="pmid37319358"/><ref name="pmid36162947"/>

By the 1960s, CAH was well understood, [[Biology:Karyotype|karyotyping]] was routine, and standard management was to assign and raise all children with CAH according to their gonads and karyotypes, no matter how virilized. Markedly virilized girls were usually referred to a pediatric surgeon, often a [[Medicine:Pediatric urology|pediatric urologist]] for a reconstructive vaginoplasty and clitoral reduction or recession—surgery to create or enlarge a vaginal opening and reduce the size or protrusion of the clitoris. This approach was designed to preserve fertility for both sexes and remains the standard management, but two aspects of this management have been challenged: assignment of completely virilized genetic females and the value and age of corrective surgery.<ref name="pmid12199338"/><ref name="pmid37319358">{{cite journal | vauthors = Orozco-Poore C, Keuroghlian AS | title = Neurological Considerations for "Nerve-Sparing" Cosmetic Genital Surgeries Performed on Children with XX Chromosomes Diagnosed with 21-Hydroxylase Congenital Adrenal Hyperplasia and Clitoromegaly | journal = LGBT Health | volume =  10| issue =  8| date = June 2023 | pages = 567–575 | pmid = 37319358 | doi = 10.1089/lgbt.2022.0160 | s2cid = 259173363 }}</ref>

The first questions about assignment were raised in the early 1980s when Money and others reported an unexpectedly high rate of failure to achieve normal adult sexual relationships (i.e., heterosexual orientation, marriage, and children) in grown women with CAH (though all had female gender identities). However, the sample was small, and results seemed interpretable in many ways: selection bias, early hormone effects on orientation, or sexual dysfunction created by residual body abnormalities or by the genital surgery itself. From a perspective two decades later, the report was one of the first pieces of evidence that the standard management paradigm was not always producing hoped-for outcomes.<ref name="pmid12199338">{{cite journal | vauthors = Money J | title = Amative orientation: the hormonal hypothesis examined | journal = Journal of Pediatric Endocrinology & Metabolism | volume = 15 | issue = 7 | pages = 951–957 | date = 2002 | pmid = 12199338 | doi = 10.1515/jpem.2002.15.7.951 | s2cid = 43116615 }}</ref><ref name="doi978-1-4612-1230-0_1">{{cite book|doi=10.1007/978-1-4612-1230-0_1|chapter=Outcome Research in Pediatric Psychoendocrinology and Sexology |title=Therapeutic Outcome of Endocrine Disorders |date=2000 | vauthors = Money J |pages=1–6 |isbn=978-1-4612-7052-2|publisher=Springer New York, NY}}</ref>

Despite these concerns, no significant opposition to standard management arose until the mid-1990s, when a confluence of evidence and opinion from several sources led to a re-examination of outcomes. Several [[Biology:Intersex|intersex]] support and advocacy groups (e.g., the Intersex Society of North America) began to publicly criticize infant genital surgery based on unsatisfactory outcomes of some adults who had been operated on as infants. Their complaints were that they had reduced ability to enjoy sexual relations or that they resented not having had the choice of gender assignment or surgical reconstruction left until they were old enough to participate.<ref name="pmid33121480">{{cite journal |vauthors=Behrens KG |title=A principled ethical approach to intersex paediatric surgeries |journal=BMC Med Ethics |volume=21 |issue=1 |pages=108 |date=October 2020 |pmid=33121480 |pmc=7597036 |doi=10.1186/s12910-020-00550-x |url= |doi-access=free }}</ref><ref>{{cite web | url=https://abc7chicago.com/what-it-means-to-be-intersex-and-why-controversial-surgeries-are-st/13518968/ | title=What it means to be intersex and why controversial surgeries are still allowed | date=18 July 2023 }}</ref> {{see also|History of intersex surgery}}

In 1997, influential articles by Reiner, Diamond, and Sigmundson advocated ''consideration'' of (1) male sex assignment in the unambiguously male XX infants (most of whom are considered male until the CAH is recognized at 1–2 weeks of age), and (2) delaying reconstructive surgery until the patient is old enough to participate in the decision.<ref name="pmid16010462"/>

Although the standard management approach remains "standard", more time and consideration are being given in many cases to explaining alternatives to parents and a small number of XX children with unambiguously male external genitalia are again being raised as boys.<ref name="doi978-1-59259-336-1_24">{{cite book|doi=10.1007/978-1-59259-336-1 |chapter=Management of Infants Born with Ambiguous Genitalia |title=Pediatric Endocrinology |series=Contemporary Endocrinology |date=2003 |pages=429–449 |publisher=Humana Press |isbn=978-1-61737-268-1 |editor-last1=Radovick |editor-last2=MacGillivray |editor-first1=Sally |editor-first2=Margaret H. |chapter-url=https://link.springer.com/chapter/10.1007/978-1-59259-336-1_24 }}</ref><ref name="pmid10654885">{{cite journal | vauthors = Lerman SE, McAleer IM, Kaplan GW | title = Sex assignment in cases of ambiguous genitalia and its outcome | journal = Urology | volume = 55 | issue = 1 | pages = 8–12 | date = January 2000 | pmid = 10654885 | doi = 10.1016/s0090-4295(99)00398-2 | doi-access = free }}</ref><ref name="pmid28535943">{{cite journal | vauthors = Bangalore Krishna K, Houk CP, Lee PA | title = Pragmatic approach to intersex, including genital ambiguity, in the newborn | journal = Seminars in Perinatology | volume = 41 | issue = 4 | pages = 244–251 | date = June 2017 | pmid = 28535943 | doi = 10.1053/j.semperi.2017.03.013 }}</ref><ref name="pmid16877870">{{cite journal | vauthors = Thyen U, Lanz K, Holterhus PM, Hiort O | title = Epidemiology and initial management of ambiguous genitalia at birth in Germany | journal = Hormone Research | volume = 66 | issue = 4 | pages = 195–203 | date = 2006 | pmid = 16877870 | doi = 10.1159/000094782 | s2cid = 24768524 }}</ref><ref name="pmid20541148">{{cite journal | vauthors = Ahmed SF, Rodie M | title = Investigation and initial management of ambiguous genitalia | journal = Best Practice & Research. Clinical Endocrinology & Metabolism | volume = 24 | issue = 2 | pages = 197–218 | date = April 2010 | pmid = 20541148 | doi = 10.1016/j.beem.2009.12.001 | s2cid = 205973113 }}</ref>

===Late onset (nonclassical) CAH===

Appearance of pubic hair in mid-childhood is the most common feature that leads to evaluation and diagnosis of the [[Medicine:Late onset congenital adrenal hyperplasia|late onset]] (nonclassical) CAH. Other accompanying features are likely to be tall stature and accelerated [[Medicine:Bone age|bone age]] (often 3–5 years ahead). Often present are increased muscle mass, acne, and adult [[Biology:Body odor|body odor]]. In boys the [[Medicine:Human penis|penis]] will be enlarged. Mild clitoral enlargement may occur in girls, and sometimes a degree of prenatal virilization is recognized that may have gone unnoticed in infancy.<ref name="pmid31013157"/><ref name="pmid15134301">{{cite journal | vauthors = Labarta JI, Bello E, Ruiz-Echarri M, Rueda C, Martul P, Mayayo E, Ferrández Longás A | title = Childhood-onset congenital adrenal hyperplasia: long-term outcome and optimization of therapy | journal = Journal of Pediatric Endocrinology & Metabolism | volume = 17 | issue = Suppl 3 | pages = 411–422 | date = March 2004 | pmid = 15134301 | doi =  }}</ref>

The principal goals of treatment of nonclassical CAH are to preserve as much growth as possible and to prevent central [[Medicine:Precocious puberty|precocious puberty]] if it has not already been triggered. These are more difficult challenges than in CAH detected in infancy because moderate levels of [[Biology:Androgen|androgen]]s will have had several years to advance bone maturation and to trigger central puberty before the disease is detected.<ref name="pmid15615479">{{cite journal | vauthors = Jesić M, Jesić M, Sajić S, Maglajlić S, Necić S, Bojić V | title = [Nonclassic congenital adrenal hyperplasia resulting from 21-hydroxylase deficiency] | journal = Srpski Arhiv Za Celokupno Lekarstvo | volume = 132 | issue = Suppl 1 | pages = 106–108 | date = October 2004 | pmid = 15615479 | doi = 10.2298/sarh04s1106j | doi-access = free }}</ref><ref name="pmid31013157"/>

A diagnosis of nonclassical CAH is usually confirmed by discovering extreme elevations of 17OHP along with moderately high testosterone levels. A cosyntropin stimulation test may be needed in mild cases, but usually the random levels of 17OHP are high enough to confirm the diagnosis.<ref name="pmid36704043">{{cite journal | vauthors = Nakhleh A, Saiegh L, Shehadeh N, Weintrob N, Sheikh-Ahmad M, Supino-Rosin L, Alboim S, Gendelman R, Zloczower M | display-authors = 6 | title = Screening for non-classic congenital adrenal hyperplasia in women: New insights using different immunoassays | journal = Frontiers in Endocrinology | volume = 13 | issue =  | page = 1048663 | date = 2022 | pmid = 36704043 | pmc = 9871807 | doi = 10.3389/fendo.2022.1048663 | doi-access = free }}</ref><ref name="pmid36427016">{{cite journal | vauthors = Bachelot G, Bachelot A, Bonnier M, Salem JE, Farabos D, Trabado S, Dupont C, Kamenicky P, Houang M, Fiet J, Le Bouc Y, Young J, Lamazière A | display-authors = 6 | title = Combining metabolomics and machine learning models as a tool to distinguish non-classic 21-hydroxylase deficiency from polycystic ovary syndrome without adrenocorticotropic hormone testing | journal = Human Reproduction | volume = 38 | issue = 2 | pages = 266–276 | date = February 2023 | pmid = 36427016 | doi = 10.1093/humrep/deac254 }}</ref><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 | issue =  | page = 526287 | date = 2020 | pmid = 33117272 | pmc = 7551200 | doi = 10.3389/fendo.2020.526287 | doi-access = free }}</ref>

Elevated 17OHP may activate androgen "backdoor" pathway, that leads to excess of 5α-dihydrotestosterone and other potent androgens.<ref name="pmid2537337">{{cite journal | vauthors = Fiet J, Gueux B, Raux-DeMay MC, Kuttenn F, Vexiau P, Brerault JL, Couillin P, Galons H, Villette JM, Julien R | display-authors = 6 | title = Increased plasma 21-deoxycorticosterone (21-DB) levels in late-onset adrenal 21-hydroxylase deficiency suggest a mild defect of the mineralocorticoid pathway | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 68 | issue = 3 | pages = 542–547 | date = March 1989 | pmid = 2537337 | doi = 10.1210/jcem-68-3-542 | department = primary }}</ref><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 | page = 4622 | date = June 2020 | pmid = 32610579 | pmc = 7369945 | doi = 10.3390/ijms21134622 | doi-access = free }}</ref>{{see also|Androgen backdoor pathway}}

The mainstay of treatment of symptomos of hyperandrogenism is suppression of androgens of adrenal origin by a [[Chemistry:Glucocorticoid|glucocorticoid]] such as [[Chemistry:Hydrocortisone|hydrocortisone]]. Mineralocorticoid is only added in cases where the plasma [[Biology:Renin|renin]] activity is high.<ref name="pmid37410094">{{cite journal | vauthors = Pofi R, Bonaventura I, Duffy J, Maunsell Z, Shine B, Isidori AM, Tomlinson JW | title = Assessing treatment adherence is crucial to determine adequacy of mineralocorticoid therapy | journal = Endocrine Connections | volume = 12 | issue = 9 | date = August 2023 | pmid = 37410094 | pmc = 10448575 | doi = 10.1530/EC-23-0059 }}</ref><ref name="pmid32165891">{{cite journal | vauthors = Foster C, Diaz-Thomas A, Lahoti A | title = Low prevalence of organic pathology in a predominantly black population with premature adrenarche: need to stratify definitions and screening protocols | journal = International Journal of Pediatric Endocrinology | volume = 2020 | issue =  | page = 5 | date = 2020 | pmid = 32165891 | pmc = 7061481 | doi = 10.1186/s13633-020-0075-8 | doi-access = free }}</ref><ref name="pmid37878953"/> Most patients that have the nonclassic form do not require any [[Chemistry:Glucocorticoid|glucocorticoid]] replacement therapy,<ref name="pmid30272171"/> as cortisol synthesis impairment is mild but clinically silent.<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><ref name="pmid32966723"/> 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 }}</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 = 581–591 | date = May 2011 | pmid = 21320597 | doi = 10.1016/j.bbadis.2011.02.003 | doi-access = free }}</ref> The exact degree of cortisol synthesis impairment depends on genotype.<ref name="pmid37715965"/>

An important aspect of management of nonclassic CAH is suppression of central precocious puberty if it has begun. The usual clues to central puberty in boys are that the testes are pubertal in size, or that androgens of adrenal origin remain elevated even when the 17OHP has been reduced toward normal. In girls central puberty is less often a problem, but breast development would be the main clue. Central precocious puberty is suppressed when appropriate by leuprolide.<ref name="pmid29750651">{{cite journal | vauthors = Klein KO, Dragnic S, Soliman AM, Bacher P | title = Predictors of bone maturation, growth rate and adult height in children with central precocious puberty treated with depot leuprolide acetate | journal = Journal of Pediatric Endocrinology & Metabolism | volume = 31 | issue = 6 | pages = 655–663 | date = June 2018 | pmid = 29750651 | doi = 10.1515/jpem-2017-0523 | s2cid = 21666126 }}</ref><ref name="pmid1403402">{{cite journal | vauthors = Neely EK, Hintz RL, Parker B, Bachrach LK, Cohen P, Olney R, Wilson DM | title = Two-year results of treatment with depot leuprolide acetate for central precocious puberty | journal = The Journal of Pediatrics | volume = 121 | issue = 4 | pages = 634–640 | date = October 1992 | pmid = 1403402 | doi = 10.1016/s0022-3476(05)81162-x | doi-access = free }}</ref><ref name="pmid9160816">{{cite journal | vauthors = Soliman AT, AlLamki M, AlSalmi I, Asfour M | title = Congenital adrenal hyperplasia complicated by central precocious puberty: linear growth during infancy and treatment with gonadotropin-releasing hormone analog | journal = Metabolism | volume = 46 | issue = 5 | pages = 513–517 | date = May 1997 | pmid = 9160816 | doi = 10.1016/s0026-0495(97)90186-4 }}</ref>

As outlined above, recent additions to treatment to preserve growth include [[Biology:Aromatase|aromatase]] inhibition to slow bone maturation by reducing the amount of testosterone converted to [[Chemistry:Estradiol|estradiol]], and use of blockers of estrogen for the same purpose.<ref name="pmid31390647">{{cite journal | vauthors = Goedegebuure WJ, Hokken-Koelega AC | title = Aromatase Inhibitor as Treatment for Severely Advanced Bone Age in Congenital Adrenal Hyperplasia: A Case Report | journal = Hormone Research in Paediatrics | volume = 92 | issue = 3 | pages = 209–213 | date = 2019 | pmid = 31390647 | pmc = 7050682 | doi = 10.1159/000501746 }}</ref><ref name="pmid31070802">{{cite journal | vauthors = Halper A, Sanchez B, Hodges JS, Dengel DR, Petryk A, Sarafoglou K | title = Use of an aromatase inhibitor in children with congenital adrenal hyperplasia: Impact of anastrozole on bone mineral density and visceral adipose tissue | journal = Clinical Endocrinology | volume = 91 | issue = 1 | pages = 124–130 | date = July 2019 | pmid = 31070802 | doi = 10.1111/cen.14009 | s2cid = 148569761 }}</ref><ref name="pmid36936152">{{cite journal | vauthors = Liu SC, Suresh M, Jaber M, Mercado Munoz Y, Sarafoglou K | title = Case Report: Anastrozole as a monotherapy for pre-pubertal children with non-classic congenital adrenal hyperplasia | journal = Frontiers in Endocrinology | volume = 14 | issue =  | page = 1101843 | date = 2023 | pmid = 36936152 | pmc = 10018749 | doi = 10.3389/fendo.2023.1101843 | doi-access = free }}</ref><ref name="doi10.7759_cureus.47485">{{cite journal|doi=10.7759/cureus.47485 |title=Precocious Puberty: Types, Pathogenesis and Updated Management |date=2023 | vauthors = Alghamdi A |journal=Cureus |volume=15 |issue=10 |pages=e47485 |doi-access=free |pmid=38021712 |pmc=10663169 }}</ref>

Once adrenal suppression has been achieved, the patient needs stress steroid coverage as described above for significant illness or injury.<ref name="pmid29584889">{{cite journal | vauthors = El-Maouche D, Hargreaves CJ, Sinaii N, Mallappa A, Veeraraghavan P, Merke DP | title = Longitudinal Assessment of Illnesses, Stress Dosing, and Illness Sequelae in Patients With Congenital Adrenal Hyperplasia | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 103 | issue = 6 | pages = 2336–2345 | date = June 2018 | pmid = 29584889 | pmc = 6276663 | doi = 10.1210/jc.2018-00208 }}</ref>

Various variants of the ''CYP21A2'' gene result various degrees of hyperandrogenism, some of which may be such a mild that they may not even cause problems in males and may not be recognized until adolescence or later in females.<ref name="pmid37964596">{{cite journal |vauthors=Balagamage C, Arshad A, Elhassan YS, Ben Said W, Krone RE, Gleeson H, Idkowiak J |title=Management aspects of congenital adrenal hyperplasia during adolescence and transition to adult care |journal=Clin Endocrinol (Oxf) |volume= |issue= |pages= |date=November 2023 |pmid=37964596 |doi=10.1111/cen.14992 |url=|doi-access=free }}</ref> Mild androgen effects in young women may include hirsutism, acne, or [[Medicine:Anovulation|anovulation]] (which in turn can cause [[Medicine:Infertility|infertility]]). Testosterone levels in these women may be mildly elevated, or simply above average. Despite the prevailing notion that [[Chemistry:Testosterone|testosterone]] and 5α-dihydrotestosterone (DHT) are the primary human androgens, this notion only applies to healthy men.<ref name="pmid28234803">{{cite journal | vauthors = Turcu AF, Auchus RJ | title = Clinical significance of 11-oxygenated androgens | journal = Current Opinion in Endocrinology, Diabetes, and Obesity | volume = 24 | issue = 3 | pages = 252–259 | date = June 2017 | pmid = 28234803 | pmc = 5819755 | doi = 10.1097/MED.0000000000000334 }}</ref> Although testosterone has been traditionally used as a biomarker of hyperandrogenism,<ref name="pmid32912651">{{cite journal | vauthors = Yang Y, Ouyang N, Ye Y, Hu Q, Du T, Di N, Xu W, Azziz R, Yang D, Zhao X | display-authors = 6 | title = The predictive value of total testosterone alone for clinical hyperandrogenism in polycystic ovary syndrome | journal = Reproductive Biomedicine Online | volume = 41 | issue = 4 | pages = 734–742 | date = October 2020 | pmid = 32912651 | doi = 10.1016/j.rbmo.2020.07.013 | s2cid = 221625488 }}</ref> it correlates poorly with clinical measurements of androgen excess.<ref name=wj/><ref name="pmid28234803" /> While testosterone levels can appear normal, ignoring the alternative androgen pathways may lead to diagnostic errors since hyperandrogenism may be caused by potent androgens such as DHT produced by a backdoor pathway and 11-oxygenated androgens.<ref name=wj/><ref name="pmid33415088">{{cite journal | vauthors = Balsamo A, Baronio F, Ortolano R, Menabo S, Baldazzi L, Di Natale V, Vissani S, Cassio A | display-authors = 6 | title = Congenital Adrenal Hyperplasias Presenting in the Newborn and Young Infant | journal = Frontiers in Pediatrics | volume = 8 | page = 593315 | year = 2020 | pmid = 33415088 | pmc = 7783414 | doi = 10.3389/fped.2020.593315 | publisher = Frontiers Media SA | doi-access = free }}</ref><ref name="pmid29277706">{{cite journal | vauthors = Kamrath C, Wettstaedt L, Boettcher C, Hartmann MF, Wudy SA | title = Androgen excess is due to elevated 11-oxygenated androgens in treated children with congenital adrenal hyperplasia | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 178 | pages = 221–228 | date = April 2018 | pmid = 29277706 | doi = 10.1016/j.jsbmb.2017.12.016 | publisher = Elsevier BV | s2cid = 3709499 }}</ref>
It may be that 11-ketotestosterone is the main androgen in women since it circulates at similar level to testosterone and may<ref name="pmid31390028">{{cite journal | vauthors = Skiba MA, Bell RJ, Islam RM, Handelsman DJ, Desai R, Davis SR | title = Androgens During the Reproductive Years: What Is Normal for Women? | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 104 | issue = 11 | pages = 5382–5392 | date = November 2019 | pmid = 31390028 | doi = 10.1210/jc.2019-01357 | s2cid = 199467054 | doi-access = free }}</ref> or may not<ref name="pmid30753518">{{cite journal | vauthors = Nanba AT, Rege J, Ren J, Auchus RJ, Rainey WE, Turcu AF | title = 11-Oxygenated C19 Steroids Do Not Decline With Age in Women | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 104 | issue = 7 | pages = 2615–2622 | date = July 2019 | pmid = 30753518 | pmc = 6525564 | doi = 10.1210/jc.2018-02527 }}</ref><ref name="pmid32498089">{{cite journal | vauthors = Davio A, Woolcock H, Nanba AT, Rege J, O'Day P, Ren J, Zhao L, Ebina H, Auchus R, Rainey WE, Turcu AF | display-authors = 6 | title = Sex Differences in 11-Oxygenated Androgen Patterns Across Adulthood | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 105 | issue = 8 | pages = e2921–e2929 | date = August 2020 | pmid = 32498089 | pmc = 7340191 | doi = 10.1210/clinem/dgaa343 }}</ref> decline with age as testosterone does. While 11-ketodihydrotestosterone (11KDHT) is equipotent to DHT, circulating levels of 11KDHT are lower than DHT.<ref name=wj/> Unlike testosterone and androstenedione, 11-oxygenated androgens are not known to be aromatized to estrogens in the human body.<ref name=wj/><ref name="pmid32862221"/><ref name="pmid33340399">{{cite journal | vauthors = Barnard L, Schiffer L, Louw du-Toit R, Tamblyn JA, Chen S, Africander D, Arlt W, Foster PA, Storbeck KH | display-authors = 6 | title = 11-Oxygenated Estrogens Are a Novel Class of Human Estrogens but Do not Contribute to the Circulating Estrogen Pool | journal = Endocrinology | volume = 162 | issue = 3 | date = March 2021 | pmid = 33340399 | pmc = 7814299 | doi = 10.1210/endocr/bqaa231 }}</ref>

These clinical features are those of [[Medicine:Polycystic ovary syndrome|polycystic ovary syndrome]] (PCOS), and a small percentage of women with PCOS are found to have late onset CAH when investigated. Late onset CAH is often misdiagnosed as 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 = 143–148 | date = February 1982 | pmid = 6977282 | doi = 10.7326/0003-4819-96-2-143 }}</ref>

Late onset CAH is often diagnosed in the context of infertility assessment in women. Diagnosis of late onset CAH may be suspected from a high 17OHP level, but some cases are so mild that the elevation is only demonstrable after [[Medicine:ACTH stimulation test|cosyntropin stimulation]]. Treatment may involve a combination of very low dose glucocorticoid to reduce adrenal androgen production and any of various agents to block the androgen effects and/or induce ovulation. During the follicular phase of the menstrual cycle, [[Chemistry:Progesterone|progesterone]] accumulates along with [[Chemistry:17α-Hydroxyprogesterone|17OHP]] which can thin the endometrium and change cervical mucus in a manner similar to the effect of [[Chemistry:Progestogen (medication)|progestogen]] contraceptives, interferes with the normal menstrual cycle, which can lead to oligomenorrhea or [[Medicine:Amenorrhea|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 = 275–296 | 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 book |publisher=S.Karger AG|vauthors = Pignatelli D, Pereira SS, Pasquali R | title = Hyperandrogenism in Women | chapter = Androgens in Congenital Adrenal Hyperplasia | series = Frontiers of Hormone Research | volume = 53 | 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 late onset CAH will become pregnant within a year with or without treatment, but they have an increased risk of miscarriage.<ref name="pmid37842302">{{cite journal |vauthors=Guo X, Zhang Y, Yu Y, Zhang L, Ullah K, Ji M, Jin B, Shu J |title=Corrigendum: Getting pregnant with congenital adrenal hyperplasia: assisted reproduction and pregnancy complications. A systematic review and meta-analysis |journal=Front Endocrinol (Lausanne) |volume=14 |page=1269711 |date=2023 |pmid=37842302 |pmc=10575760 |doi=10.3389/fendo.2023.1269711 |doi-access=free}}</ref><ref name="pmid32966723"/>

Late onset CAH was 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 = 416–422 | date = May 1957 | pmid = 13470408 | trans-title = Clinically late virilism with excretion of pregnanetriol and insufficiency of cortisol production }}</ref> but the association with mild 21-hydroxylase deficiency called nonclassical 21-hydroxylase deficiency, which is characterized by diverse hyperandrogenic symptoms appearing postnatally in males and females, was first described in 1979 by Maria New.<ref>{{cite journal | vauthors = New MI, Lorenzen F, Pang S, Gunczler P, Dupont B, Levine LS | title = "Acquired" adrenal hyperplasia with 21-hydroxylase deficiency is not the same genetic disorders as congenital adrenal hyperplasia | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 48 | issue = 2 | pages = 356–359 | date = February 1979 | pmid = 218988 | doi = 10.1210/jcem-48-2-356 }}</ref> New since then have studied ways to reduce androgen excess and found out that treatment with [[Biology:Dexamethasone|dexamethasone]] 0.25&nbsp;mg orally every evening reversed acne and irregular menstruation in 3 months, but hirsutism required up to 30 months.<ref name="pmid16912124"/><ref name="pmid22186144">{{cite journal | vauthors = Trapp CM, Oberfield SE | title = Recommendations for treatment of nonclassic congenital adrenal hyperplasia (NCCAH): an update | journal = Steroids | volume = 77 | issue = 4 | pages = 342–346 | date = March 2012 | pmid = 22186144 | pmc = 3638754 | doi = 10.1016/j.steroids.2011.12.009 }}</ref> Dexamethasone has glucocorticoid activity, and potent ACTH-suppression properties within the [[Medicine:Hypothalamic–pituitary–adrenal axis|hypothalamic–pituitary–adrenal axis]].<ref>{{cite book |url=https://www.ncbi.nlm.nih.gov/books/NBK279156/ |title=Glucocorticoid Therapy and Adrenal Suppression|year=2000|publisher=MDText.com|pmid=25905379 | vauthors = Feingold KR, Anawalt B, Blackman MR, Boyce A, Chrousos G, Corpas E, De Herder WW, Dhatariya K, Hofland J, Dungan K, Hofland J, Kalra S, Kaltsas G, Kapoor N, Koch C, Kopp P, Korbonits M, Kovacs CS, Kuohung W, Laferrère B, Levy M, McGee EA, McLachlan R, New M, Purnell J, Sahay R, Singer F, Sperling MA, Stratakis CA, Trence DL | display-authors = 6 }}</ref><ref name="pmid4881892">{{cite journal | vauthors = Rabhan NB | title = Pituitary-adrenal suppression and Cushing's syndrome after intermittent dexamethasone therapy | journal = Annals of Internal Medicine | volume = 69 | issue = 6 | pages = 1141–1148 | date = December 1968 | pmid = 4881892 | doi = 10.7326/0003-4819-69-6-1141 }}</ref> Lower ACTH leads to reduced production of all the steroids, including androgens. According to 2018 Clinical Practice Guideline, glucocorticoid treatment is not recommended in asymptomatic individuals, however, if the symptoms of androgen excess are sufficient, dexamethasone treatment may be prescribed.<ref name="pmid30272171"/> Another treatment option is oral contraceptive pills.<ref name="pmid23039910">{{cite journal | vauthors = Matthews D, Cheetham T | title = What is the best approach to the teenage patient presenting with nonclassical congenital adrenal hyperplasia: should we always treat with glucocorticoids? | journal = Clinical Endocrinology | volume = 78 | issue = 3 | pages = 338–341 | date = March 2013 | pmid = 23039910 | doi = 10.1111/cen.12065 | s2cid = 24131309 | doi-access = free }}</ref><ref name="pmid20671993">{{cite journal | vauthors = Witchel SF, Azziz R | title = Nonclassic congenital adrenal hyperplasia | journal = International Journal of Pediatric Endocrinology | volume = 2010 | issue =  | page = 625105 | date = 2010 | pmid = 20671993 | pmc = 2910408 | doi = 10.1155/2010/625105 | doi-access = free }}</ref>

==Genetics==
[[File:autorecessive.svg|thumb|right|21-hydroxylase CAH is inherited in an autosomal recessive fashion]]{{Main article|21-Hydroxylase}}The ''CYP21A2'' gene for the P450c21 enzyme (also known as 21-hydroxylase) is at 6p21.3,<ref name="pmid19228439">{{cite journal | vauthors = Trakakis E, Loghis C, Kassanos D | title = Congenital adrenal hyperplasia because of 21-hydroxylase deficiency. A genetic disorder of interest to obstetricians and gynecologists | journal = Obstetrical & Gynecological Survey | volume = 64 | issue = 3 | pages = 177–189 | date = March 2009 | pmid = 19228439 | doi = 10.1097/OGX.0b013e318193301b | s2cid = 37242194 }}</ref> amid genes ''HLA B'' and ''HLA DR'' coding for the major human histocompatibility loci (HLA). The protein-coding ''CYP21A2'' gene may be accompanied with one or several copies of the nonfunctional pseudogene ''CYP21A1P''.<ref name="ncbi-refseq">{{NCBI RefSeq|title=CYP21A2 cytochrome P450 family 21 subfamily A member 2 [ Homo sapiens (human) ]|url=https://www.ncbi.nlm.nih.gov/gene/1589}}</ref><ref name="pmid32616876"/> Scores of abnormal alleles of ''CYP21A2'' have been documented, most arising from recombinations of homologous regions of ''CYP21A2'' and ''CYP21A1P''.<ref name="pmid32616876"/> The 21-hydroxylase deficiency may be caused by macrodeletions of about 30 Kb, which includes not only most of the 5′ region of the ''CYP21A2'' gene, but also all of the ''C4B'' gene and 3′ regions of the ''CYP21A1P'' pseudogene. Duplications of ''CYP21A1P'' pseudogene and ''C4B'' gene are often associated with [[Medicine:Late onset congenital adrenal hyperplasia|nonclassic]] 21-hydroxylase deficiency.<ref name="pmid17666484"/>

Due to the high degree of homology between the ''CYP21A2'' gene and the ''CYP21A1P'' pseudogene, and the complexity of the locus, research on the molecular level is 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 | page = 165 | date = November 2020 | pmid = 33168061 | pmc = 7653887 | doi = 10.1186/s12902-020-00643-z | doi-access = free }}</ref>

Differences in residual enzyme activity of the various alleles account for the various degrees of severity of the disease.<ref name="pmid34978615"/><ref name="pmid36992809">{{cite journal | vauthors = Tang P, Zhang J, Peng S, Wang Y, Li H, Wang Z, Zhang Y, Huang Y, Xu J, Zhang D, Liu Q, Wang L, Lan W, Jiang J | display-authors = 6 | title = Genotype-phenotype correlation in patients with 21-hydroxylase deficiency | journal = Frontiers in Endocrinology | volume = 14 | issue =  | page = 1095719 | date = 2023 | pmid = 36992809 | pmc = 10042299 | doi = 10.3389/fendo.2023.1095719 | doi-access = free }}</ref><ref name="pmid37401054">{{cite journal | vauthors = Kim JH, Kim GH, Yoo HW, Choi JH | title = Molecular basis and genetic testing strategies for diagnosing 21-hydroxylase deficiency, including CAH-X syndrome | journal = Annals of Pediatric Endocrinology & Metabolism | volume = 28 | issue = 2 | pages = 77–86 | date = June 2023 | pmid = 37401054 | pmc = 10329939 | doi = 10.6065/apem.2346108.054 }}</ref> Inheritance of all forms of 21-hydroxylase CAH is autosomal recessive,<ref name="pmid30272171"/> except some mild disease-causing variants such as p.<!--AWB, this is not a page-->V281L that seem to exert dominant negative effects on enzymatic activity.<ref name="pmid28541281"/>

Persons affected by any forms of the disease have two abnormal alleles, and both parents are usually heterozygotes (or [[Biology:Genetic carrier|carriers]]).  When both parents carry an abnormal allele, each child has a 25% chance of having the disease, a 50% chance of being a carrier like the parents, and a 25% chance of having two normal genes.<ref name="pmid30272171"/>

It is possible to test for heterozygosity by measuring 17OHP elevation after ACTH stimulation.<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 = Journal of Clinical Research in Pediatric Endocrinology | volume = 14 | issue = 1 | pages = 56–68 | date = March 2022 | pmid = 34743977 | pmc = 8900072 | doi = 10.4274/jcrpe.galenos.2021.2021.0184 }}</ref>

More than 200 disease-causing variants within the ''CYP21A2'' gene have been identified so far that lead to 21-hydroxylase deficiency.<ref name="pmid31317337">{{cite journal | vauthors = Concolino P | title = Issues with the Detection of Large Genomic Rearrangements in Molecular Diagnosis of 21-Hydroxylase Deficiency | journal = Molecular Diagnosis & Therapy | volume = 23 | issue = 5 | pages = 563–567 | date = October 2019 | pmid = 31317337 | doi = 10.1007/s40291-019-00415-z | s2cid = 197543506 }}</ref> Most patients have at least two of these variants present as [[Biology:Compound heterozygosity|compound heterozygous]].<ref name="pmid35255871">{{cite journal | vauthors = Cheng T, Liu J, Sun W, Song G, Ma H | title = Congenital adrenal hyperplasia with homozygous and heterozygous mutations: a rare family case report | journal = BMC Endocrine Disorders | volume = 22 | issue = 1 | page = 57 | date = March 2022 | pmid = 35255871 | pmc = 8900299 | doi = 10.1186/s12902-022-00969-w | doi-access = free }}</ref><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 | page = 8 | date = July 2020 | pmid = 32647925 | pmc = 7347723 | doi = 10.1186/s40348-020-00100-w | doi-access = free }}</ref><ref name="pmid31333583">{{cite journal | vauthors = Pignatelli D, Carvalho BL, Palmeiro A, Barros A, Guerreiro SG, Macut D | title = The Complexities in Genotyping of Congenital Adrenal Hyperplasia: 21-Hydroxylase Deficiency | journal = Frontiers in Endocrinology | volume = 10 | issue =  | page = 432 | date = 2019 | pmid = 31333583 | pmc = 6620563 | doi = 10.3389/fendo.2019.00432 | doi-access = free }}</ref>

There are some mild disease-causing variants that seem to exert dominant negative effects on enzymatic activity, even if present as single heterozygous. One example is a point mutation in exon 7 of ''CYP21A2'', (p.<!--AWB, this is not a page-->V281L), which 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"/> 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 = 20916–20922 | date = December 1990 | pmid = 2249999 | doi = 10.1016/S0021-9258(17)45304-X | doi-access = free }}</ref><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> but are at higher risk of symptoms of androgen excess than carriers of the severe mutations,<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 = 40–47 | date = September 2012 | pmid = 23045419 }}</ref> and had higher [[Medicine:ACTH stimulation test|adrenocorticotropic hormone (ACTH) stimulated]] 17OHP,<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 = 645–651 | date = June 2006 | pmid = 16712666 | doi = 10.1111/j.1365-2265.2006.02521.x | s2cid = 37571628 }}</ref> suggesting that the mutant protein V281L enzyme co-expressed with the wild-type (healthy) enzyme resulted in an apparent dominant negative effect on the enzymatic activity.<ref name="pmid14513879">{{cite journal | vauthors = Félix-López X, Riba L, Ordóñez-Sánchez ML, Ramírez-Jiménez S, Ventura-Gallegos JL, Zentella-Dehesa A, Tusié-Luna MT | title = Steroid 21-hydroxylase (P450c21) naturally occurring mutants I172N, V281L and I236n/V237E/M239K exert a dominant negative effect on enzymatic activity when co-expressed with the wild-type protein | journal = Journal of Pediatric Endocrinology & Metabolism | volume = 16 | issue = 7 | pages = 1017–1024 | date = September 2003 | pmid = 14513879 | doi = 10.1515/jpem.2003.16.7.1017 | s2cid = 40680772 }}</ref>

There is a good correlation between the genotype and phenotype. As a result, the ''CYP21A2'' genotyping has high diagnostic value. However, the genotyping of the ''CYP21A2'' gene is prone to errors, especially due to the closely located and highly homologous pseudogene ''CYP21A1P'' and the complex duplications, deletions and rearrangements within the chromosome 6p21.3. That's why ''CYP21A2'' genotyping, interpretation of the results, and adequate genetic counseling for patients and their families requires deep understanding of ''CYP21A2'' genetics.<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 | doi-access = free }}</ref>

<!-- The following two paragraphs are copied from [[Biology:21-Hydroxylase|21-Hydroxylase]], see that page's history at https://en.wikipedia.org/w/index.php?title=21-Hydroxylase&action=history for attribution; for the attribution, the relevant section at the history page related to the following two paragraphs may be at https://en.wikipedia.org/w/index.php?title=21-Hydroxylase&diff=991471704&oldid=967052757 and earlier edit -->
The ''CYP21A1P'' [[Biology:Pseudogene|pseudogene]] retains 98% [[Biology:Exon|exon]]ic sequence identity with the functional gene ''CYP21A2'',<ref name="pmid3486422">{{cite journal | vauthors = Higashi Y, Yoshioka H, Yamane M, Gotoh O, Fujii-Kuriyama Y | title = Complete nucleotide sequence of two steroid 21-hydroxylase genes tandemly arranged in human chromosome: a pseudogene and a genuine gene | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 83 | issue = 9 | pages = 2841–2845 | date = May 1986 | pmid = 3486422 | pmc = 323402 | doi = 10.1073/pnas.83.9.2841 | doi-access = free | bibcode = 1986PNAS...83.2841H }}</ref><ref name="pmid28521877">{{cite journal | vauthors = Concolino P, Rizza R, Costella A, Carrozza C, Zuppi C, Capoluongo E | title = CYP21A2 intronic variants causing 21-hydroxylase deficiency | journal = Metabolism | volume = 71 | pages = 46–51 | date = June 2017 | pmid = 28521877 | doi = 10.1016/j.metabol.2017.03.003 }}</ref> and the high degree of sequence similarity between them indicates that these two genes are evolving in tandem through intergenic exchange of DNA.<ref name="pmid29734195">{{cite journal | vauthors = Miller WL, Merke DP | title = Tenascin-X, Congenital Adrenal Hyperplasia, and the CAH-X Syndrome | journal = Hormone Research in Paediatrics | volume = 89 | issue = 5 | pages = 352–361 | date = 2018 | pmid = 29734195 | pmc = 6057477 | doi = 10.1159/000481911 }}</ref> Both genes are located on chromosome 6, in the [[Biology:Major histocompatibility complex|major histocompatibility complex]] [[Biology:MHC class III|III]] (MHC class III)<ref name="pmid10072631">{{cite journal | vauthors = Yu CY | title = Molecular genetics of the human MHC complement gene cluster | journal = Experimental and Clinical Immunogenetics | volume = 15 | issue = 4 | pages = 213–230 | year = 1999 | pmid = 10072631 | doi = 10.1159/000019075 | s2cid = 25061446 }}</ref> close to the [[Medicine:Complement component 4|Complement component 4]] genes ''[[Medicine:C4A|C4A]]'' and ''C4B'', the Tenascin X gene ''TNXB'' and ''[[Biology:STK19|STK19]]''.<ref>{{cite journal | vauthors = White PC, Grossberger D, Onufer BJ, Chaplin DD, New MI, Dupont B, Strominger JL | title = Two genes encoding steroid 21-hydroxylase are located near the genes encoding the fourth component of complement in man | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 82 | issue = 4 | pages = 1089–1093 | date = February 1985 | pmid = 2983330 | pmc = 397199 | doi = 10.1073/pnas.82.4.1089 | doi-access = free | bibcode = 1985PNAS...82.1089W }}</ref> MHC class III is the most gene-dense region of the human genome, containing many genes that yet have unknown function or structure.<ref name="pmid14656967">{{cite journal | vauthors = Xie T, Rowen L, Aguado B, Ahearn ME, Madan A, Qin S, Campbell RD, Hood L | display-authors = 6 | title = Analysis of the gene-dense major histocompatibility complex class III region and its comparison to mouse | journal = Genome Research | volume = 13 | issue = 12 | pages = 2621–2636 | date = December 2003 | pmid = 14656967 | pmc = 403804 | doi = 10.1101/gr.1736803 }}</ref><ref name="pmid10072631"/>

The ''CYP21A2'' gene is located within the [[Biology:RCCX|RCCX]] cluster (an abbreviation composed of the names of the genes ''RP'' (a former name for ''[[Biology:STK19|STK19]]'' serine/threonine kinase 19),<ref name="pmid22785613">{{cite journal | vauthors = Bánlaki Z, Doleschall M, Rajczy K, Fust G, Szilágyi A | title = Fine-tuned characterization of RCCX copy number variants and their relationship with extended MHC haplotypes | journal = Genes and Immunity | volume = 13 | issue = 7 | pages = 530–535 | date = October 2012 | pmid = 22785613 | doi = 10.1038/gene.2012.29 | s2cid = 36582994 | doi-access = free }}</ref><ref name="pmid34394006">{{cite journal | vauthors = Carrozza C, Foca L, De Paolis E, Concolino P | title = Genes and Pseudogenes: Complexity of the RCCX Locus and Disease | journal = Frontiers in Endocrinology | volume = 12 | issue =  | page = 709758 | date = 2021 | pmid = 34394006 | pmc = 8362596 | doi = 10.3389/fendo.2021.709758 | doi-access = free }}</ref> ''[[Medicine:Complement component 4|C4]]'', ''CYP21'' and ''TNX''),<ref name="pmid18179706">{{cite journal | vauthors = Sweeten TL, Odell DW, Odell JD, Torres AR | title = C4B null alleles are not associated with genetic polymorphisms in the adjacent gene CYP21A2 in autism | journal = BMC Medical Genetics | volume = 9 | page = 1 | date = January 2008 | pmid = 18179706 | pmc = 2265260 | doi = 10.1186/1471-2350-9-1 | doi-access = free }}</ref> which is the most complex gene cluster in the human genome.<ref name="pmid11487476">{{cite journal | vauthors = Milner CM, Campbell RD | title = Genetic organization of the human MHC class III region | journal = Frontiers in Bioscience | volume = 6 | pages = D914–D926 | date = August 2001 | pmid = 11487476 | doi = 10.2741/milner | doi-access = free }}</ref> <!-- Attribution: copied text from [[Biology:RCCX|RCCX]], see the pages' history for more information on attribution --> The number of RCCX segments varies between one and four in a [[Biology:Chromosome|chromosome]],<ref name="pmid22785613"/> with the prevalence of approximately 15% for monomodular, 75% for bimodular (''STK19-C4A-CYP21A1P-TNXA-STK19B-C4B-CYP21A2-TNXB''),<ref name="pmid34394006"/><ref name="pmid37401054"/> and 10% for trimodular in Europeans.<ref name="pmid23241443">{{cite journal |vauthors=Bánlaki Z, Szabó JA, Szilágyi Á, Patócs A, Prohászka Z, Füst G, Doleschall M |title=Intraspecific evolution of human RCCX copy number variation traced by haplotypes of the CYP21A2 gene |journal=Genome Biol Evol |volume=5 |issue=1 |pages=98–112 |date=2013 |pmid=23241443 |pmc=3595039 |doi=10.1093/gbe/evs121}}</ref> The quadrimodular structure of the RCCX unit is very rare.<ref name="pmid22771554">{{cite journal |vauthors=Tsai LP, Lee HH |title=Analysis of CYP21A1P and the duplicated CYP21A2 genes |journal=Gene |volume=506 |issue=1 |pages=261–262 |date=September 2012 |pmid=22771554 |doi=10.1016/j.gene.2012.06.045}}</ref><ref name="pmid22785613"/><ref name="pmid23241443"/> In a monomodular structure, all of the genes are functional i.e. protein-coding, but if a module count is two or more, there is only one copy of each functional gene rest being non-coding [[Biology:Pseudogene|pseudogene]]s with the exception of the ''C4'' gene which always has active copies.<ref name="pmid22785613"/><ref name="pmid23241443"/>

Due to the high degree of homology between the ''CYP21A2'' gene and the ''CYP21P1'' pseudogene and the complexity of the locus, it is difficult to study the ''CYP21A2'' gene at the molecular level, giving sometimes inaccurate or inconclusive results.<ref name="pmid33168061"/> Targeted long-read sequencing method aims to improve the accuracy of the findings,<ref name="pmid37842302" /> however, the clinical use of this method is limited.<ref name="pmid37804107">{{cite journal |vauthors=Adachi E, Nakagawa R, Tsuji-Hosokawa A, Gau M, Kirino S, Yogi A, Nakatani H, Takasawa K, Yamaguchi T, Kosho T, Murakami M, Tajima T, Hasegawa T, Yamada T, Morio T, Ohara O, Kashimada K |title=A MinION-Based Long-Read Sequencing Application with One-Step PCR for the Genetic Diagnosis of 21-Hydroxylase Deficiency |journal=J Clin Endocrinol Metab |volume= |issue= |pages= |date=October 2023 |pmid=37804107 |doi=10.1210/clinem/dgad577 |s2cid=263742489 |url=|doi-access=free }}</ref>

The ''cryptic'' form of (CAH) refers to a condition in which an individual is genetically determined to have the nonclassic variant of CAH but does not display any obvious symptoms. The term "cryptic" is used due to the lack of symptomatology in these individuals. Most males and some females with nonclassic CAH do not exhibit clinical signs or symptoms. However, the exact prevalence of asymptomatic individuals among those genetically identified with nonclassic CAH is currently unknown. Therefore, it is also uncertain what proportion of this population represents the cryptic form of CAH.<ref name="pmid28541281"/>

==Diagnosis==
Since CAH is an autosomal recessive disease, most children with CAH are born to parents unaware of the risk and with no family history. Each child will have a 25% chance of being born with the disease.<ref name="pmid30272171"/>

===Classification===
The condition can be classified into "salt-wasting", "simple virilizing", and "nonclassical" forms.<ref name="pmid30272171"/>

{| class="wikitable"
|-
! Type
! [[Biology:Sex steroid|Sex steroid]] effects
! Other effects
|-
| Severe 21-hydroxylase deficiency causes '''''salt-wasting CAH'''''
| The most common cause of ambiguous genitalia due to prenatal [[Biology:Virilization|virilization]] of genetically female (XX) infants.
| Life-threatening vomiting and [[Medicine:Dehydration|dehydration]] occurring within the first few weeks of life. Aldosterone and cortisol levels are both reduced.
|-
| Moderate 21-hydroxylase deficiency is referred to as '''''simple virilizing CAH'''''
| Typically is recognized as causing virilization of prepubertal children.
| Cortisol is reduced, but aldosterone is not.
|-
| Still milder forms of 21-hydroxylase deficiency are referred to as '''''nonclassical CAH'''''
| Can cause [[Biology:Androgen|androgen]] effects and [[Medicine:Infertility|infertility]] in adolescent and adult women.
| Cortisol is mildly reduced depending on genotype,<ref name="pmid37715965">{{cite journal |vauthors=Koren I, Weintrob N, Kebesch R, Majdoub H, Stein N, Naor S, Segev-Becker A |title=Genotype-Specific Cortisol Reserve in a Cohort of Subjects with Non-Classic Congenital Adrenal Hyperplasia (NCCAH) |journal=J Clin Endocrinol Metab |volume= |issue= |pages= |date=September 2023 |pmid=37715965 |doi=10.1210/clinem/dgad546 |url=|doi-access=free }}</ref> but aldosterone is not.
|-
| Patients who are genetically found to have nonclassical CAH but are asymptomatic
| No symptoms of androgen excess, levels of androgens are within the normal range.
| Neither aldosterone nor cortisol are reduced.
|}

The salt-wasting and simple virilizing types are sometimes grouped together as "classical".<ref name="pmid15988383">{{cite journal | vauthors = Forest MG, Tardy V, Nicolino M, David M, Morel Y | title = 21-Hydroxylase deficiency: an exemplary model of the contribution of molecular biology in the understanding and management of the disease | journal = Annales d'Endocrinologie | volume = 66 | issue = 3 | pages = 225–232 | date = June 2005 | pmid = 15988383 | doi = 10.1016/s0003-4266(05)81754-8 }}</ref>

===Newborn screening===
Conditions justifying [[Medicine:Newborn screening|newborn screening]] for any disorder include (1) a simple test with an acceptable sensitivity and specificity, (2) a dire consequence if not diagnosed early, (3) an effective treatment if diagnosed, and (4) a frequency in the population high enough to justify the expense. In the last decade more states and countries are adopting newborn screening for salt-wasting CAH due to 21-hydroxylase deficiency, which leads to death in the first month of life if not recognized.<ref name="pmid33272921">{{cite journal | vauthors = Prentice P | title = Guideline review: congenital adrenal hyperplasia clinical practice guideline 2018 | journal = Archives of Disease in Childhood. Education and Practice Edition | volume = 106 | issue = 6 | pages = 354–357 | date = December 2021 | pmid = 33272921 | doi = 10.1136/archdischild-2019-317573 | s2cid = 227258191 }}</ref><ref name="pmid17199092"/>

The salt-wasting form of CAH has an incidence of 1 in 15,000 births and is potentially fatal within a month if untreated. Steroid replacement is a simple, effective treatment. However, the screening test itself is less than perfect, because of low specificity and high levels of false positives, meaning that the tests sometimes give incorrect results, saying the baby has CAH when they actually do not. This can make the family worried and spend money unnecessarily on hospital visits and extra tests that are not needed.<ref name="pmid36854385">{{cite journal | vauthors = Yoon YA, Woo S, Kim MS, Kim B, Choi YJ | title = Establishing 17-Hydroxyprogesterone Cutoff Values for Congenital Adrenal Hyperplasia in Preterm, Low Birth Weight, and Sick Newborns | journal = Experimental and Clinical Endocrinology & Diabetes | volume = 131 | issue = 4 | pages = 216–221 | date = April 2023 | pmid = 36854385 | doi = 10.1055/a-2022-8399 | s2cid = 257255642 }}</ref> For the newborn screening, levels of 17α-hydroxyprogesterone (17OHP) are typically measured against predetermined cutoff, which depends on the measurement method.<ref name="pmid37902057"/><ref name="pmid33272921"/> While the 17OHP level is easy to measure and sensitive (rarely missing real cases), the test has a poorer specificity, giving high rates of false positives.<ref name="pmid36854385"/> Screening programs in the United States have reported that 99% of positive screens turn out to be false positives upon investigation of the infant.<ref name="pmid10891024">{{cite journal | vauthors = Kwon C, Farrell PM | title = The magnitude and challenge of false-positive newborn screening test results | journal = Archives of Pediatrics & Adolescent Medicine | volume = 154 | issue = 7 | pages = 714–718 | date = July 2000 | pmid = 10891024 | doi = 10.1001/archpedi.154.7.714 }}</ref><ref name="pmid11344933">{{cite journal | vauthors = Therrell BL | title = Newborn screening for congenital adrenal hyperplasia | journal = Endocrinology and Metabolism Clinics of North America | volume = 30 | issue = 1 | pages = 15–30 | date = March 2001 | pmid = 11344933 | doi = 10.1016/s0889-8529(08)70017-3 }}</ref><ref name="doi10.21037_pm-21-104}">{{cite journal|doi=10.21037/pm-21-104 |doi-access=free |title=Pitfalls of prenatal and newborn screening in congenital adrenal hyperplasia: A narrative review |date=2022 |journal=Pediatric Medicine | vauthors = Kotwal N, Lekarev O |volume=6 |page=34 }}</ref> This is a higher rate of false positives than the screening tests for many other congenital metabolic diseases.<ref name="pmid37902057"/><ref name="pmid33272921"/>

Measurement 17OHP by [[Physics:Liquid chromatography–mass spectrometry|LC-MS/MS]] reduces false positive rate in newborn screening in comparison to measurement by immunoassays. 17OHP steroid precursors and their sulphated conjugates which are present in the first two days after birth in healthy infants and longer in pre-term neonates, cross-react in immunoassays with 17OHP, giving falsely high 17OHP levels.<ref name="pmid33073005">{{cite journal | vauthors = de Hora MR, Heather NL, Patel T, Bresnahan LG, Webster D, Hofman PL | title = Measurement of 17-Hydroxyprogesterone by LCMSMS Improves Newborn Screening for CAH Due to 21-Hydroxylase Deficiency in New Zealand | journal = International Journal of Neonatal Screening | volume = 6 | issue = 1 | page = 6 | date = March 2020 | pmid = 33073005 | pmc = 7422986 | doi = 10.3390/ijns6010006 | doi-access = free }}</ref><ref name="pmid33072992">{{cite journal | vauthors = Bialk ER, Lasarev MR, Held PK | title = Wisconsin's Screening Algorithm for the Identification of Newborns with Congenital Adrenal Hyperplasia | journal = International Journal of Neonatal Screening | volume = 5 | issue = 3 | page = 33 | date = September 2019 | pmid = 33072992 | pmc = 7510207 | doi = 10.3390/ijns5030033 | doi-access = free }}</ref>

When a positive result is detected, the infant must be referred to a pediatric endocrinologist to confirm or disprove the diagnosis. Since most infants with salt-wasting CAH become critically ill by 2 weeks of age, the evaluation must be done rapidly despite the high false positive rate.<ref name="pmid33001476">{{cite journal | vauthors = Gau M, Konishi K, Takasawa K, Nakagawa R, Tsuji-Hosokawa A, Hashimoto A, Sutani A, Tajima T, Hasegawa T, Morio T, Kashimada K | display-authors = 6 | title = The progression of salt-wasting and the body weight change during the first 2 weeks of life in classical 21-hydroxylase deficiency patients | journal = Clinical Endocrinology | volume = 94 | issue = 2 | pages = 229–236 | date = February 2021 | pmid = 33001476 | doi = 10.1111/cen.14347 | s2cid = 222165169 }}</ref>

Levels of [[Chemistry:17α-Hydroxyprogesterone|17OHP]], [[Chemistry:Androstenedione|androstenedione]], and [[Chemistry:Cortisol|cortisol]] may play a role in screening.<ref name="pmid19390483">{{cite journal | vauthors = Schwarz E, Liu A, Randall H, Haslip C, Keune F, Murray M, Longo N, Pasquali M | display-authors = 6 | title = Use of steroid profiling by UPLC-MS/MS as a second tier test in newborn screening for congenital adrenal hyperplasia: the Utah experience | journal = Pediatric Research | volume = 66 | issue = 2 | pages = 230–235 | date = August 2009 | pmid = 19390483 | doi = 10.1203/PDR.0b013e3181aa3777 | doi-access = free }}</ref>

===Additional markers===
While 17OHP with or without ACTH stimulation is the main marker for 21-hydroxylase deficiency, other markers have been proposed, with various degrees of acceptance:<ref name="pmid36950738">{{cite journal |vauthors=Sarafoglou K, Merke DP, Reisch N, Claahsen-van der Grinten H, Falhammar H, Auchus RJ |title=Interpretation of Steroid Biomarkers in 21-Hydroxylase Deficiency and Their Use in Disease Management |journal=J Clin Endocrinol Metab |volume=108 |issue=9 |pages=2154–2175 |date=August 2023 |pmid=36950738 |pmc=10438890 |doi=10.1210/clinem/dgad134 |url=}}</ref><ref name="pmid37608608"/>
* [[Chemistry:21-Deoxycortisol|21-Deoxycortisol]] is elevated in 21-hydroxylase deficiency.<ref name="pmid37873849">{{cite journal | vauthors = Greaves RF, Kumar M, Mawad N, Francescon A, Le C, O'Connell M, Chi J, Pitt J | display-authors = 6 | title = Best Practice for Identification of Classical 21-Hydroxylase Deficiency Should Include 21 Deoxycortisol Analysis with Appropriate Isomeric Steroid Separation | journal = International Journal of Neonatal Screening | volume = 9 | issue = 4 | page = 58 | date = October 2023 | pmid = 37873849 | pmc = 10594498 | doi = 10.3390/ijns9040058 | doi-access = free }}</ref> However, it is not elevated in preterm infants or in other forms of congenital adrenal hyperplasia. Unlike 17OHP, 21-deoxycortisol is not produced in the gonads and is uniquely adrenal-derived.<ref name="pmid32966723"/> Consequently, 21-deoxycortisol it is a more specific marker of the 21-hydroxylase deficiency than 17OHP. Even so, 21-deoxycortisol measurement has not been commonly performed by laboratories until 2019.<ref name="pmid14689562">{{cite journal | vauthors = Cristoni S, Cuccato D, Sciannamblo M, Bernardi LR, Biunno I, Gerthoux P, Russo G, Weber G, Mora S | display-authors = 6 | title = Analysis of 21-deoxycortisol, a marker of congenital adrenal hyperplasia, in blood by atmospheric pressure chemical ionization and electrospray ionization using multiple reaction monitoring | journal = Rapid Communications in Mass Spectrometry | volume = 18 | issue = 1 | pages = 77–82 | year = 2004 | pmid = 14689562 | doi = 10.1002/rcm.1284 | bibcode = 2004RCMS...18...77C }}</ref><ref name="pmid31450227">{{cite journal | vauthors = Miller WL | title = Congenital Adrenal Hyperplasia: Time to Replace 17OHP with 21-Deoxycortisol | journal = Hormone Research in Paediatrics | volume = 91 | issue = 6 | pages = 416–420 | year = 2019 | pmid = 31450227 | doi = 10.1159/000501396 | s2cid = 201733086 | doi-access = free }}</ref> Still, 21-deoxycortisol can be a key screening marker for 21-hydroxylase deficiency in newborn screening.<ref name="pmid37873849"/><ref name="pmid34780778">{{cite journal | vauthors = Held PK, Bialk ER, Lasarev MR, Allen DB | title = 21-Deoxycortisol is a Key Screening Marker for 21-Hydroxylase Deficiency | journal = The Journal of Pediatrics | volume = 242 | issue =  | pages = 213–219.e1 | date = March 2022 | pmid = 34780778 | doi = 10.1016/j.jpeds.2021.10.063 | s2cid = 244106268 }}</ref>
* 21-Deoxycorticosterone, also known as 11β-hydroxyprogesterone (11β-OHP), have been proposed as a marker in 1987.<ref name="pmid3546944">{{cite journal | vauthors = Gueux B, Fiet J, Galons H, Boneté R, Villette JM, Vexiau P, Pham-Huu-Trung MT, Raux-Eurin MC, Gourmelen M, Brérault JL | display-authors = 6 | title = The measurement of 11 beta-hydroxy-4-pregnene-3,20-dione (21-deoxycorticosterone) by radioimmunoassay in human plasma | journal = Journal of Steroid Biochemistry | volume = 26 | issue = 1 | pages = 145–150 | date = January 1987 | pmid = 3546944 | doi = 10.1016/0022-4731(87)90043-4 }}</ref><ref>{{cite journal | vauthors = Fiet J, Gueux B, Raux-DeMay MC, Kuttenn F, Vexiau P, Brerault JL, Couillin P, Galons H, Villette JM, Julien R | display-authors = 6 | title = Increased plasma 21-deoxycorticosterone (21-DB) levels in late-onset adrenal 21-hydroxylase deficiency suggest a mild defect of the mineralocorticoid pathway | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 68 | issue = 3 | pages = 542–547 | date = March 1989 | pmid = 2537337 | doi = 10.1210/jcem-68-3-542 }}</ref> A study in 2017 has shown that in subjects with 21-hydroxylase deficiency, serum 11β-OHP concentrations range from 0.012 to 3.37&nbsp;ng/mL, while in control group it was below detection limit of 0.012&nbsp;ng/mL.<ref name="pmid29264476">{{cite journal | vauthors = Fiet J, Le Bouc Y, Guéchot J, Hélin N, Maubert MA, Farabos D, Lamazière A | title = A Liquid Chromatography/Tandem Mass Spectometry Profile of 16 Serum Steroids, Including 21-Deoxycortisol and 21-Deoxycorticosterone, for Management of Congenital Adrenal Hyperplasia | journal = Journal of the Endocrine Society | volume = 1 | issue = 3 | pages = 186–201 | date = March 2017 | pmid = 29264476 | pmc = 5686660 | doi = 10.1210/js.2016-1048 }}</ref> This marker did not gain acceptance due to the fact that the test for the levels of this steroid is not routinely offered by diagnostic laboratories.<ref>{{cite journal | vauthors = Sarathi V, Atluri S, Pradeep TV, Rallapalli SS, Rakesh CV, Sunanda T, Kumar KD | title = Utility of a Commercially Available Blood Steroid Profile in Endocrine Practice | journal = Indian Journal of Endocrinology and Metabolism | volume = 23 | issue = 1 | pages = 97–101 | year = 2019 | pmid = 31016162 | pmc = 6446682 | doi = 10.4103/ijem.IJEM_531_18 | doi-access = free }}</ref>
* [[Chemistry:Progesterone|Progesterone]] levels are higher in CAH subjects. A study has revealed that serum progesterone concentrations in boys (10 days to 18 years old) with 21-hydroxylase deficiency reached levels up to 10.14&nbsp;ng/mL, i.e. similar to female luteal values, while in the control group of boys average level was 0.07&nbsp;ng/mL (0.22 nmol/L), with values ranging from 0.05 to 0.40&nbsp;ng/mL.<ref name="pmid29264476"/> The authors of the study propose to use progesterone as an additional marker for 21-hydroxylase deficiency. The study shows that the progesterone levels in CAH and non-CAH females are the same as in CAH and non-CAH males respectively – it is the condition that affects progesterone levels, not the sex, but for women between menarch and menopause, progesterone should be measured in days 3–5 of the cycle to have diagnostic value – the same condition also applies for 17OHP. The specificity of progesterone as a marker of 21-hydroxylase deficiency, as opposed to deficiency of other enzymes involved in steroid pathways, is still not well studied.<ref name="pmid18308097">{{cite journal|title=Adrenocortical hormone abnormalities in men with chronic prostatitis/chronic pelvic pain syndrome |journal=Urology |volume=71 |issue=2 |pages=261–6  |pmid=18308097 |pmc=2390769 |doi=10.1016/j.urology.2007.09.025 |last1=Dimitrakov |first1=Jordan |last2=Joffe |first2=Hylton V. |last3=Soldin |first3=Steven J. |last4=Bolus |first4=Roger |last5=Buffington |first5=C.A. Tony |last6=Nickel |first6=J. Curtis |year=2008 }}</ref><ref name="pmid35987379">{{Cite journal|last1=Masiutin|first1=Maxim G.|last2=Yadav|first2=Maneesh K.|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|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|last1=Dimitrakoff|first1=Jordan|last2=Nickel|first2=J. Curtis|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>
* [[Chemistry:Cortisol|Cortisol]] is one of the two main final products of 21-hydroxylase, and the deficiency of this enzyme may lead to a certain degree of cortisol deficiency. Cortisol levels are lower in CAH subjects, on average,<ref name="pmid29264476"/> however, in milder cases cortisol levels can be normal, but, this has not been yet well studied. Cortisol measurement using [[Biology:Immunoassay|immunoassay]]s is prone to cross-reactivity with various substances including 21-deoxycortisol that raises due to 21-hydroxylase deficiency, leading to falsely high cortisol levels when the true cortisol is actually low.<ref name="aacc1">{{cite journal | vauthors = Winter WE, Bazydlo L, Harris NS | title = Cortisol – Clinical Indications and Laboratory Testing | journal = AACC Clinical Laboratory News | year = 2012 | url = https://www.aacc.org/Publications/CLN/Articles/2012/september/Cortisol.aspx }}</ref><ref name="pmid25071417">{{cite journal | vauthors = Krasowski MD, Drees D, Morris CS, Maakestad J, Blau JL, Ekins S | title = Cross-reactivity of steroid hormone immunoassays: clinical significance and two-dimensional molecular similarity prediction | journal = BMC Clinical Pathology | volume = 14 | issue = 33 | page = 33 | year = 2014 | pmid = 25071417 | pmc = 4112981 | doi = 10.1186/1472-6890-14-33 | doi-access = free }}</ref> The selectivity offered by [[Physics:Liquid chromatography–mass spectrometry|liquid chromatography-tandem mass spectrometry]] (LC-MS/MS) has largely overcome these limitations.<ref name="pmid27208627">{{cite journal | vauthors = Hawley JM, Keevil BG | title = Endogenous glucocorticoid analysis by liquid chromatography-tandem mass spectrometry in routine clinical laboratories | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 162 | pages = 27–40 | date = September 2016 | pmid = 27208627 | doi = 10.1016/j.jsbmb.2016.05.014 | s2cid = 206501499 }}</ref><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> As a result, the use of LC-MS/MS instead of immunoassays in cortisol measurement aims to provide greater specificity.<ref name="pmid37873849"/><ref name="pmid29083134">{{cite journal | vauthors = D'aurizio F, Cantù M | title = Clinical endocrinology and hormones quantitation: the increasing role of mass spectrometry | journal = Minerva Endocrinologica | volume = 43 | issue = 3 | pages = 261–284 | date = September 2018 | pmid = 29083134 | doi = 10.23736/S0391-1977.17.02764-X | s2cid = 12984040 }}</ref>
* [[Chemistry:11-Deoxycortisol|11-Deoxycortisol]] is a direct product of 17α-hydroxyprogesterone, with 21-hydroxylase catalyzing the reaction, and an intermediate product towards cortisol pathway. Reduced 21-hydroxylase activity leads to decreased levels of 11-deoxycortisol, but not all laboratories specify minimum reference value it, since it is mostly used as a biomarker for 11β-hydroxylase deficiency, where 11-deoxycortisol levels increase dramatically, so the laboratories may only specify the maximum reference value.<ref name="pmid36950738"/>

==Treatment==
===Prenatal treatment===
Clinical Practice Guideline advise that clinicians continue to regard prenatal therapy as experimental.<ref name="pmid30272171"/>

Because the period during which fetal genitalia may become virilized begins about 6 weeks after conception, prenatal treatment to avoid virilization must be started by 6 to 7 weeks.<ref name="pmid30272171"/>

==== Application of dexamethasone in prenatal treatment ====
Adrenal glands of female fetuses with CAH begin producing excess androgens<ref name="pmid36399318"/> by the 9th week of gestation.<ref name="pmid20392211">{{cite journal | vauthors = Nimkarn S, New MI | title = Congenital adrenal hyperplasia due to 21-hydroxylase deficiency: A paradigm for prenatal diagnosis and treatment | journal = Annals of the New York Academy of Sciences | volume = 1192 | issue =  | pages = 5–11 | date = March 2010 | pmid = 20392211 | doi = 10.1111/j.1749-6632.2009.05225.x | s2cid = 38359933 }}</ref><ref name="pmid26683339">{{cite book |vauthors=Khattab A, Yuen T, Sun L, Yau M, Barhan A, Zaidi M, Lo YM, New MI |title=Advanced Therapies in Pediatric Endocrinology and Diabetology |chapter=Noninvasive Prenatal Diagnosis of Congenital Adrenal Hyperplasia |series=Endocrine Development |volume=30 |pages=37–41 |date=2016 |pmid=26683339 |doi=10.1159/000439326 |isbn=978-3-318-05636-5 |publisher=S.Karger AG}}</ref> The most important aspects of virilization (urogenital closure and phallic urethra) occur between 8 and 12 weeks.<ref name="isbn_978-3-642-22964-0">{{cite book|isbn=978-3-642-22964-0|doi=10.1007/978-3-642-22964-0|title=Disorders of Sex Development |date=2012 | veditors = Hutson JM, Warne GL, Grover SL|publisher=Springer Berlin, Heidelberg}}</ref> Theoretically, if enough [[Chemistry:Glucocorticoid|glucocorticoid]] could be supplied to the fetus to reduce adrenal androgen biosynthesis by the 9th week, virilization could be prevented and the difficult decision about timing of [[Biology:History of intersex surgery|surgery]] avoided.<ref name="pmid20392211"/><ref name="pmid23123167">{{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 = 354–359 | date = May 2013 | pmid = 23123167 | doi = 10.1016/j.ajog.2012.10.885 }}</ref>

The challenge of preventing severe virilization of girls is twofold: detection of CAH at the beginning of the pregnancy, and delivery of an effective amount of glucocorticoid to the fetus without causing harm to the mother.<ref name="pmid26051303">{{cite journal | vauthors = Miller WL | title = Fetal endocrine therapy for congenital adrenal hyperplasia should not be done | journal = Best Practice & Research. Clinical Endocrinology & Metabolism | volume = 29 | issue = 3 | pages = 469–483 | date = June 2015 | pmid = 26051303 | doi = 10.1016/j.beem.2015.01.005 }}</ref><ref name="pmid36294476">{{cite journal | vauthors = Cera G, Locantore P, Novizio R, Maggio E, Ramunno V, Corsello A, Policola C, Concolino P, Paragliola RM, Pontecorvi A | display-authors = 6 | title = Pregnancy and Prenatal Management of Congenital Adrenal Hyperplasia | journal = Journal of Clinical Medicine | volume = 11 | issue = 20 | page = 6156 | date = October 2022 | pmid = 36294476 | pmc = 9605322 | doi = 10.3390/jcm11206156 | doi-access = free }}</ref><ref name="pmid7820212">{{cite journal | vauthors = Levine LS, Pang S | title = Prenatal diagnosis and treatment of congenital adrenal hyperplasia | journal = The Journal of Pediatric Endocrinology | volume = 7 | issue = 3 | pages = 193–200 | date = 1994 | pmid = 7820212 | doi = 10.1515/jpem.1994.7.3.193 | s2cid = 37158917 }}</ref>

The first problem has not yet been entirely solved, but it has been shown that if [[Biology:Dexamethasone|dexamethasone]] is taken by a pregnant woman, enough can cross the placenta to suppress fetal adrenal function.<ref name="pmid26661642">{{cite journal | vauthors = Heland S, Hewitt JK, McGillivray G, Walker SP | title = Preventing female virilisation in congenital adrenal hyperplasia: The controversial role of antenatal dexamethasone | journal = The Australian & New Zealand Journal of Obstetrics & Gynaecology | volume = 56 | issue = 3 | pages = 225–232 | date = June 2016 | pmid = 26661642 | doi = 10.1111/ajo.12423 | s2cid = 25816572 | doi-access = free }}</ref>

At present no program screens for risk in families who have not yet had a child with CAH. For families desiring to avoid virilization of a second child, the current strategy is to start dexamethasone as soon as a pregnancy has been confirmed even though at that point the chance that the pregnancy is a girl with CAH is only 12.5%. Dexamethasone is taken by the mother each day until it can be safely determined whether she is carrying an affected girl.<ref name="pmid36752813">{{cite journal | vauthors = Van't Westeinde A, Karlsson L, Messina V, Wallensteen L, Brösamle M, Dal Maso G, Lazzerini A, Kristensen J, Kwast D, Tschaidse L, Auer MK, Nowotny HF, Persani L, Reisch N, Lajic S | display-authors = 6 | title = An update on the long-term outcomes of prenatal dexamethasone treatment in congenital adrenal hyperplasia | journal = Endocrine Connections | volume = 12 | issue = 4 | date = April 2023 | pmid = 36752813 | pmc = 10083667 | doi = 10.1530/EC-22-0400 }}</ref>

Whether the fetus is an affected girl can be determined by chorionic villus sampling at 9–11 weeks of gestation, or by amniocentesis at 15–18 weeks gestation. In each case the fetal sex can be determined quickly, and if the fetus is a male the dexamethasone can be discontinued. If female, fetal [[Biology:DNA|DNA]] is analyzed to see if she carries one of the known abnormal alleles of the ''CYP21'' gene. If so, dexamethasone is continued for the remainder of the pregnancy at a dose of about 1&nbsp;mg daily.<ref name="pmid36752813"/>

Most mothers who have followed this treatment plan have experienced at least mild [[Medicine:Cushing's syndrome|cushingoid]] effects from the glucocorticoid but have borne daughters whose genitalia are much less virilized.<ref name="pmid36752813"/>

[[Biology:Dexamethasone|Dexamethasone]] is used as an off-label early prenatal treatment for the symptoms of CAH in female fetuses, but it does not treat the underlying congenital disorder. A 2007 Swedish clinical trial found that treatment may cause cognitive and behavioural defects, but the small number of test subjects means the study cannot be considered definitive. A 2012 American study found no negative short-term outcomes, but "lower cognitive processing in CAH girls and women with long-term dexamethasone exposure."<ref>{{cite journal | vauthors = Meyer-Bahlburg HF, Dolezal C, Haggerty R, Silverman M, New MI | title = Cognitive outcome of offspring from dexamethasone-treated pregnancies at risk for congenital adrenal hyperplasia due to 21-hydroxylase deficiency | journal = European Journal of Endocrinology | volume = 167 | issue = 1 | pages = 103–110 | date = July 2012 | pmid = 22549088 | pmc = 3383400 | doi = 10.1530/EJE-11-0789 }}</ref> Administration of pre-natal dexamethasone has been the subject of controversy over issues of [[Philosophy:Informed consent|informed consent]] and because treatment must predate a clinical diagnosis of CAH in the female fetus,<ref>{{cite magazine | vauthors = Elton C | title = A Prenatal Treatment Raises Questions of Medical Ethics | magazine = {{wipe|Time (magazine)}} | date = 2010-06-18 }}</ref> especially because in utero dexamethasone may cause metabolic problems that are not evident until later in life; Swedish clinics ceased recruitment for research in 2010.<ref>{{cite journal | vauthors = Hirvikoski T, Nordenström A, Wedell A, Ritzén M, Lajic S | title = Prenatal dexamethasone treatment of children at risk for congenital adrenal hyperplasia: the Swedish experience and standpoint | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 97 | issue = 6 | pages = 1881–1883 | date = June 2012 | pmid = 22466333 | doi = 10.1210/jc.2012-1222 | doi-access = free }}</ref>

The treatment has also raised concerns in LGBT and bioethics communities following publication of an essay posted to the forum of the Hastings Center, and research in the Journal of Bioethical Inquiry, which found that pre-natal treatment of female fetuses was suggested to prevent those fetuses from becoming lesbians after birth, may make them more likely to engage in "traditionally" female-identified behaviour and careers, and more interested in bearing and raising children. Citing a known attempt by a man using his knowledge of the fraternal birth order effect to avoid having a homosexual son by using a [[Biology:Surrogacy|surrogate]], the essayists (Professor [[Biography:Alice Dreger|Alice Dreger]] of Northwestern University's Feinberg School of Medicine, Professor Ellen Feder of American University and attorney Anne Tamar-Mattis) suggest that prenatal dexamethasone treatments constitute the first known attempt to use ''[[Biology:Uterus|in utero]]'' protocols to reduce the incidence of homosexuality and bisexuality in humans.<ref>{{cite web | vauthors = Dreger A, Feder EK, Tamar-Mattis A | author-link3= Anne Tamar-Mattis |title = Preventing Homosexuality (and Uppity Women) in the Womb? | publisher = Bioethics Forum, a service of the Hastings Center | date = 2010-06-29 | url = http://www.thehastingscenter.org/Bioethicsforum/Post.aspx?id=4754&blogid=140 | access-date = 2010-07-05}}</ref><ref name="pmid22904609"/> Research on the use of prenatal hormone treatments to prevent homosexuality stretches back to the early 1990s or earlier.<ref>{{Cite journal | vauthors = Meyer-Bahlburg H | title = Will Prenatal Hormone Treatment Prevent Homosexuality?| journal = Journal of Child and Adolescent Psychopharmacology | date = 1990 | volume = 1| issue = 4| pages = 279–283 | doi = 10.1089/cap.1990.1.279 }}</ref>

Since CAH is a recessive gene, both the mother and father must be recessive carriers of CAH for a child to have CAH. Due to advances in modern medicine, those couples with the recessive CAH genes have an option to prevent CAH in their offspring through [[Medicine:Preimplantation genetic diagnosis|preimplantation genetic diagnosis]] (PGD). In PGD, the egg is fertilized outside the woman's body in a Petri dish (IVF). On the 3rd day, when the [[Biology:Embryo|embryo]] has developed from one cell to about 4 to 6 [[Biology:Cell|cells]], one of those cells is removed from the embryo without harming the embryo. The embryo continues to grow until day 5 when it is either frozen or implanted into the mother. Meanwhile, the removed cell is analyzed to determine if the embryo has CAH. If the embryo is determined to have CAH, the parents may make a decision as to whether they wish to have it implanted in the mother or not.<ref name="pmid36399318">{{cite journal | vauthors = Maher JY, Gomez-Lobo V, Merke DP | title = The management of congenital adrenal hyperplasia during preconception, pregnancy, and postpartum | journal = Reviews in Endocrine & Metabolic Disorders | volume = 24 | issue = 1 | pages = 71–83 | date = February 2023 | pmid = 36399318 | pmc = 9884653 | doi = 10.1007/s11154-022-09770-5 }}</ref>

Meta-analysis of the studies supporting the use of dexamethasone on CAH at-risk fetuses found "less than one half of one percent of published 'studies' of this intervention were regarded as being of high enough quality to provide meaningful data for a meta-analysis. Even these four studies were of low quality&nbsp;... in ways so slipshod as to breach professional standards of medical ethics"<ref name="pmid22904609">{{cite journal | vauthors = Dreger A, Feder EK, Tamar-Mattis A | title = Prenatal Dexamethasone for Congenital Adrenal Hyperplasia: An Ethics Canary in the Modern Medical Mine | journal = Journal of Bioethical Inquiry | volume = 9 | issue = 3 | pages = 277–294 | date = September 2012 | pmid = 22904609 | pmc = 3416978 | doi = 10.1007/s11673-012-9384-9 }}</ref> and "there were no data on long-term follow-up of physical and metabolic outcomes in children exposed to dexamethasone".<ref name="pmid20550539">{{cite journal | vauthors = Mercè Fernández-Balsells M, Muthusamy K, Smushkin G, Lampropulos JF, Elamin MB, Abu Elnour NO, Elamin KB, Agrwal N, Gallegos-Orozco JF, Lane MA, Erwin PJ, Montori VM, Murad MH | display-authors = 6 | title = Prenatal dexamethasone use for the prevention of virilization in pregnancies at risk for classical congenital adrenal hyperplasia because of 21-hydroxylase (CYP21A2) deficiency: a systematic review and meta-analyses | journal = Clinical Endocrinology | volume = 73 | issue = 4 | pages = 436–444 | date = October 2010 | pmid = 20550539 | doi = 10.1111/j.1365-2265.2010.03826.x | s2cid = 29694687 | doi-access = free }}</ref>

===Long-term management of CAH===
Management of infants and children with CAH is complex and warrants long-term care in a [[Medicine:Pediatric endocrinology|pediatric endocrine clinic]]. After the diagnosis is confirmed, and any salt-wasting crisis averted or reversed, major management issues include:

# Initiating and monitoring hormone replacement
# Stress coverage, crisis prevention, parental education
# Reconstructive surgery
# Optimizing growth
# Optimizing androgen suppression and fertility in women with CAH

Management of adults with CAH should take into consideration side effects of long-term glucocorticoid exposure, such as cardiovascular morbidities.<ref name="pmid37878953"/>

====Hormone replacement====
The primary goals of hormone replacement are to protect from adrenal insufficiency and to suppress the excessive adrenal [[Biology:Androgen|androgen]] production.<ref name="pmid31187081">{{cite journal |vauthors=Whittle E, Falhammar H |title=Glucocorticoid Regimens in the Treatment of Congenital Adrenal Hyperplasia: A Systematic Review and Meta-Analysis |journal=J Endocr Soc |volume=3 |issue=6 |pages=1227–1245 |date=June 2019 |pmid=31187081 |pmc=6546346 |doi=10.1210/js.2019-00136 |url=}}</ref><ref name="pmid32190901">{{cite journal |vauthors=Ng SM, Stepien KM, Krishan A |title=Glucocorticoid replacement regimens for treating congenital adrenal hyperplasia |journal=Cochrane Database Syst Rev |volume=2020 |issue=3 |pages=CD012517 |date=March 2020 |pmid=32190901 |pmc=7081382 |doi=10.1002/14651858.CD012517.pub2 |url=}}</ref>

[[Chemistry:Glucocorticoid|Glucocorticoid]]s are provided to all children and adults with all but the mildest and latest-onset forms of CAH. The glucocorticoids provide a reliable substitute for [[Chemistry:Cortisol|cortisol]], thereby reducing ACTH levels. Reducing ACTH also reduces the stimulus for continued hyperplasia and overproduction of androgens. In other words, glucocorticoid replacement is the primary method of reducing the excessive adrenal androgen production in both sexes. A number of glucocorticoids are available for therapeutic use. [[Chemistry:Hydrocortisone|Hydrocortisone]] or liquid [[Chemistry:Prednisolone|prednisolone]] is preferred in infancy and childhood, and prednisone or [[Biology:Dexamethasone|dexamethasone]] are often more convenient for adults.<ref name="pmid31187081"/><ref name="pmid37608608">{{cite journal |vauthors=Bacila IA, Lawrence NR, Badrinath SG, Balagamage C, Krone NP |title=Biomarkers in congenital adrenal hyperplasia |journal=Clin Endocrinol (Oxf) |volume= |issue= |pages= |date=August 2023 |pmid=37608608 |doi=10.1111/cen.14960 |url=|doi-access=free }}</ref>

The glucocorticoid dose is typically started at the low end of physiologic replacement (6–12&nbsp;mg/m<sup>2</sup>)<ref name="pmid30272171"/>  but is adjusted throughout childhood to prevent both growth suppression from too much glucocorticoid and androgen escape from too little. Serum levels of [[Chemistry:17α-Hydroxyprogesterone|17OHP]], [[Chemistry:Testosterone|testosterone]], [[Chemistry:Androstenedione|androstenedione]], and other adrenal steroids are followed for additional information, but may not be entirely normalized even with optimal treatment. As regular monitoring is needed, patients can be monitored non-invasively by measuring 17OHP and androstenedione in saliva.<ref>{{cite journal | vauthors = Adriaansen BP, Kamphuis JS, Schröder MA, Olthaar AJ, Bock C, Brandt A, Stikkelbroeck NM, Lentjes EG, Span PN, Sweep FC, Claahsen-van der Grinten HL, van Herwaarden AE | display-authors = 6 | title = Diurnal salivary androstenedione and 17-hydroxyprogesterone levels in healthy volunteers for monitoring treatment efficacy of patients with congenital adrenal hyperplasia | journal = Clinical Endocrinology | volume = 97 | issue = 1 | pages = 36–42 | date = July 2022 | pmid = 35150157 | pmc = 9542109 | doi = 10.1111/cen.14690 }}</ref> (''See [[Chemistry:Glucocorticoid|Glucocorticoid]] for more on this topic.'') However, the currently used glucocorticoid therapy methods may lead to unphysiological doses that, in addition to the problems caused by overexposure of androgens, can harm health. Various clinical results, besides the steroids, require regular monitoring. The negative consequences are primarily the result of non-physiological glucocorticoid replacement.<ref name="pmid33741777">{{cite journal | vauthors = Nordenström A, Lajic S, Falhammar H | title = Clinical outcomes in 21-hydroxylase deficiency | journal = Current Opinion in Endocrinology, Diabetes, and Obesity | volume = 28 | issue = 3 | pages = 318–324 | date = June 2021 | pmid = 33741777 | doi = 10.1097/MED.0000000000000625 | s2cid = 232298877 }}</ref> During illness or physical or mental stress, the demand for cortisol can increase, sometimes leading to adrenal crises. As current glucocorticoid therapy regiments fail to replicate the physiologic circadian rhythm and the glucocorticoids are often administered at a higher dose to treat androgen excess, the long-term consequences of the therapy, such as decreased bone density and an increased cardiometabolic risk profile,<ref name="pmid37878953">{{cite journal | vauthors = Charoensri S, Auchus RJ | title = Predictors of cardiovascular morbidities in adults with 21-hydroxylase deficiency congenital adrenal hyperplasia | journal = The Journal of Clinical Endocrinology and Metabolism | volume =  | issue =  | date = October 2023 | pmid = 37878953 | doi = 10.1210/clinem/dgad628 | doi-access = free }}</ref> should be addressed; other consequences of CAH such as impaired quality of life and affected mental health should be taken into consideration; periodic assessments and monitoring of patients should take place in specialized centers to detect and treat potential complications early.<ref name="pmid34978615">{{cite journal | vauthors = Tschaidse L, Quitter F, Hübner A, Reisch N | title = [Long-term morbidity in congenital adrenal hyperplasia] | language = German | journal = Der Internist | volume = 63 | issue = 1 | pages = 43–50 | date = January 2022 | pmid = 34978615 | doi = 10.1007/s00108-021-01223-6 | s2cid = 245636454 }}</ref> Clinical studies are underway to find ways to better mimic the normal circadian rhythm of cortisol secretion and to reduce the total dose of glucocorticoids.<ref name="pmid35283460">{{cite journal | vauthors = White PC | title = Emerging treatment for congenital adrenal hyperplasia | journal = Current Opinion in Endocrinology, Diabetes, and Obesity | volume = 29 | issue = 3 | pages = 271–276 | date = June 2022 | pmid = 35283460 | pmc = 9302862 | doi = 10.1097/MED.0000000000000723 }}</ref>

[[Chemistry:Mineralocorticoid|Mineralocorticoid]]s are replaced in all infants with salt-wasting and in most patients with elevated [[Biology:Renin|renin]] levels. [[Chemistry:Fludrocortisone|Fludrocortisone]] is the only pharmaceutically available mineralocorticoid and is usually used in doses of 0.05 to 2&nbsp;mg daily.<ref name="pmid30272171"/> [[Physics:Electrolyte|Electrolyte]]s, renin, and [[Physics:Blood pressure|blood pressure]] levels are followed to optimize the dose.<ref name="pmid24818525">{{cite journal |vauthors=Bonfig W, Schwarz HP |title=Blood pressure, fludrocortisone dose and plasma renin activity in children with classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency followed from birth to 4 years of age |journal=Clin Endocrinol (Oxf) |volume=81 |issue=6 |pages=871–5 |date=December 2014 |pmid=24818525 |doi=10.1111/cen.12498 |url=|doi-access=free }}</ref>

=====Stress coverage, crisis prevention, parental education=====
Even after diagnosis and initiation of treatment, a small percentage of children and adults with infancy or childhood onset CAH die of adrenal crisis.<ref name="pmid30272171"/> Deaths from this are entirely avoidable if the child and family understand that the daily glucocorticoids cannot be allowed to be interrupted by an illness. When a person is well, missing a dose, or even several doses, may produce little in the way of immediate symptoms. However, glucocorticoid needs are increased during illness and stress, and missed doses during an illness such as the [[Medicine:Influenza|ifluenza]] or [[Medicine:Viral gastroenteritis|viral gastroenteritis]] can lead within hours to reduced blood pressure, [[Medicine:Shock (circulatory)|shock]], and death.<ref name="pmid25279502">{{cite journal |vauthors=Falhammar H, Frisén L, Norrby C, Hirschberg AL, Almqvist C, Nordenskjöld A, Nordenström A |title=Increased mortality in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency |journal=J Clin Endocrinol Metab |volume=99 |issue=12 |pages=E2715–21 |date=December 2014 |pmid=25279502 |doi=10.1210/jc.2014-2957 |s2cid=3159398 |url=|doi-access=free |hdl=10616/45611 |hdl-access=free }}</ref><ref name="pmid34721304">{{cite journal |vauthors=Worth C, Vyas A, Banerjee I, Lin W, Jones J, Stokes H, Komlosy N, Ball S, Clayton P |title=Acute Illness and Death in Children With Adrenal Insufficiency |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=757566 |date=2021 |pmid=34721304 |pmc=8548653 |doi=10.3389/fendo.2021.757566 |url= |doi-access=free }}</ref>

To prevent this, all persons taking replacement glucocorticoids are taught to increase their doses in the event of illness, surgery, severe injury, or severe exhaustion. More importantly, they are taught that vomiting warrants an injection within hours of [[Chemistry:Hydrocortisone|hydrocortisone]] (e.g., SoluCortef) or other glucocorticoid. This recommendation applies to both children and adults. Because young children are more susceptible to vomiting illnesses than adults, pediatric endocrinologists usually teach parents how to give hydrocortisone injections.<ref name="pmid34721304"/><ref name="pmid31187081"/>

As an additional precaution, persons with adrenal insufficiency are advised to wear a [[Medicine:Medical identification tag|medical identification tag]] or carry a wallet card to alert those who may be providing emergency medical care of the urgent need for glucocorticoids.<ref>{{Cite web |date=2022-08-10 |title=Medical Conditions: Adrenal Insufficiency |url=https://www.medicalert.org/medical-conditions/adrenal-insufficiency/ |access-date=2023-11-15 |website=MedicAlert Foundation |language=en-US}}</ref>

====Reconstructive surgery====
Surgery need never be considered for genetically male (XY) infants because the excess androgens do not produce anatomic abnormality. However, surgery for severely virilized XX infants is often performed and has become a subject of [[Biology:History of intersex surgery|debate]].<ref name="pmid32060243">{{cite journal |vauthors=Dabas A, Vats P, Sharma R, Singh P, Seth A, Jain V, Batra P, Gupta N, Kumar R, Kabra M, Kapoor S, Yadav S |title=Management of Infants with Congenital Adrenal Hyperplasia |journal=Indian Pediatr |volume=57 |issue=2 |pages=159–164 |date=February 2020 |pmid=32060243 |doi= 10.1007/s13312-020-1735-8|s2cid=211122771 |url=}}</ref>

Surgical reconstruction of abnormal genitalia has been offered to parents of severely virilized girls with CAH since the first half of the 20th century. The purposes of surgery have generally been a combination of the following:<ref name="pmid30272250">{{cite journal |vauthors=Almasri J, Zaiem F, Rodriguez-Gutierrez R, Tamhane SU, Iqbal AM, Prokop LJ, Speiser PW, Baskin LS, Bancos I, Murad MH |title=Genital Reconstructive Surgery in Females With Congenital Adrenal Hyperplasia: A Systematic Review and Meta-Analysis |journal=J Clin Endocrinol Metab |volume=103 |issue=11 |pages=4089–4096 |date=November 2018 |pmid=30272250 |doi=10.1210/jc.2018-01863 |s2cid=52890676 |url=|doi-access=free }}</ref>

# To make the external genitalia look more female than male;
# To make it possible for these girls to participate in normal [[Biology:Sexual intercourse|sexual intercourse]] when they grow up;
# To improve their chances of fertility;
# To reduce the frequency of urinary infections.<ref name="pmid30272250"/>

In the 1950s and 1960s, surgery often involved clitorectomy (removal of most of the clitoris), an operation that also reduced genital sensation. In the 1970s, new operative methods were developed to preserve innervation and clitoral function. However, a number of retrospective surveys in the last decade suggest that (1) sexual enjoyment is reduced in many women even after nerve-sparing procedures, and (2) women with CAH who have not had surgery also have a substantial rate of sexual dysfunction. (''See Intersex surgery for an overview of procedures and potential complications, and [[Biology:History of intersex surgery|History of intersex surgery]] for a fuller discussion of the controversies.'') Many patient advocates and surgeons argue for deferring surgery until adolescence or later, while some surgeons continue to argue that infant surgery has advantages.<ref name="newsnorthwesternedustories-2014">{{cite web | url=https://news.northwestern.edu/stories/2014/12/clitoridectomy-and-female-circumcision-in-america | title=Clitoridectomy and Female Circumcision in America }}</ref>

====Optimizing growth in CAH====
It is unclear what concentration of adrenal androgens is best for normal growth, puberty, and bone health.<ref name="pmid35086098">{{cite journal | vauthors = Nordenström A, Falhammar H, Lajic S | title = Current and novel treatment strategies in children with congenital adrenal hyperplasia | journal = Hormone Research in Paediatrics | volume =  96| issue =  6| pages = 560–572 | date = January 2022 | pmid = 35086098 | doi = 10.1159/000522260 | s2cid = 246360028 | doi-access = free }}</ref>

One of the challenging aspects of long-term management is optimizing growth so that a child with CAH achieves his or her height potential because both undertreatment and overtreatment can reduce growth or the remaining time for growth. While glucocorticoids are essential for health, dosing is always a matter of approximation. In even mildly excessive amounts, glucocorticoids slow growth. On the other hand, adrenal androgens are readily converted to [[Chemistry:Estradiol|estradiol]], which accelerates [[Medicine:Bone age|bone maturation]] and can lead to early [[Biology:Epiphysis|epiphyseal]] closure. This narrow target of optimal dose is made more difficult to obtain by the imperfect replication of normal diurnal plasma cortisol levels produced by 2 or 3 oral doses of hydrocortisone.<ref name="pmid35220302">{{cite journal | vauthors = Apsan J, Thomas C, Elnaas H, Lin-Su K, Lekarev O | title = Twice Daily Compared to Three Times Daily Hydrocortisone in Prepubertal Children with Congenital Adrenal Hyperplasia | journal = Hormone Research in Paediatrics | volume = 95 | issue = 1 | pages = 62–67 | date = 2022 | pmid = 35220302 | doi = 10.1159/000523808 | s2cid = 247131531 | doi-access = free }}</ref><ref name="pmid35817014">{{cite journal | vauthors = Sarafoglou K, Addo OY, Hodges JS, Brundage RC, Lightman SL, Hindmarsh PC, Miller BS | title = The Evidence for Twice-Daily Hydrocortisone Dosing in Children with Congenital Adrenal Hyperplasia Is Lacking | journal = Hormone Research in Paediatrics | volume = 95 | issue = 5 | pages = 499–504 | date = 2022 | pmid = 35817014 | doi = 10.1159/000525990 | s2cid = 250453213 | doi-access = free }}</ref> As a consequence, average height losses of about 4&nbsp;inches (10&nbsp;cm) have been reported with traditional management.<ref name="pmid30272171"/>

Traditionally, pediatric endocrinologists have tried to optimize growth by measuring a child every few months to assess current rate of growth, by checking the [[Medicine:Bone age|bone age]] every year or two, by periodically measuring 17OHP and [[Chemistry:Testosterone|testosterone]] levels as indicators of adrenal suppression, and by using hydrocortisone for glucocorticoid replacement rather than longer-acting [[Chemistry:Prednisone|prednisone]] or [[Biology:Dexamethasone|dexamethasone]].<ref name="pmid37902057"/>

The growth problem is even worse in the simple virilizing forms of CAH which are detected when premature pubic hair appears in childhood, because the [[Medicine:Bone age|bone age]] is often several years advanced at the age of diagnosis. While a boy (or girl) with simple virilizing CAH is taller than peers at that point, he will have far fewer years remaining to grow, and may go from being a very tall 7-year-old to a 62-inch 13-year-old who has completed growth. Even with adrenal suppression, many of these children will have already had central [[Medicine:Precocious puberty|precocious puberty]] triggered by the prolonged exposure of the [[Biology:Hypothalamus|hypothalamus]] to the adrenal androgens and estrogens. If this has begun, it may be advantageous to suppress puberty with a [[Biology:Gonadotropin-releasing hormone|gonadotropin-releasing hormone]] agonist such as leuprolide to slow continuing bone maturation.<ref name="pmid27318023">{{cite journal |vauthors=Schagen SE, Cohen-Kettenis PT, Delemarre-van de Waal HA, Hannema SE |title=Efficacy and Safety of Gonadotropin-Releasing Hormone Agonist Treatment to Suppress Puberty in Gender Dysphoric Adolescents |journal=J Sex Med |volume=13 |issue=7 |pages=1125–32 |date=July 2016 |pmid=27318023 |doi=10.1016/j.jsxm.2016.05.004 |url=}}</ref><ref>{{cite web | url=https://pedsendo.org/patient-resource/premature-adrenarche/ | title=Premature Adrenarche - Pediatric Endocrine Society | date=17 June 2020 }}</ref><ref>{{cite web | url=https://www.chop.edu/conditions-diseases/precocious-puberty-early-puberty | title=Precocious Puberty (Early Puberty) | date=23 August 2014 }}</ref>

In recent years some newer approaches to optimizing growth have been researched and are beginning to be used. It is possible to reduce the effects of androgens on the body by blocking the receptors with an antiandrogen such as [[Biology:Flutamide|flutamide]] and by reducing the conversion of testosterone to estradiol. This conversion is mediated by [[Biology:Aromatase|aromatase]] and can be inhibited by aromatase blockers such as [[Chemistry:Testolactone|testolactone]]. Blocking the effects and conversions of estrogens will allow use of lower doses of glucocorticoids with less risk of acceleration of bone maturation. Other proposed interventions have included bilateral adrenalectomy to remove the androgen sources, or growth hormone treatment to enhance growth.<ref name="pmid11344936">{{cite journal | vauthors = Migeon CJ, Wisniewski AB | title = Congenital adrenal hyperplasia owing to 21-hydroxylase deficiency. Growth, development, and therapeutic considerations | journal = Endocrinology and Metabolism Clinics of North America | volume = 30 | issue = 1 | pages = 193–206 | date = March 2001 | pmid = 11344936 | doi = 10.1016/S0889-8529(08)70026-4 }}</ref>

====Preventing hyperandrogenism and optimizing fertility====
As growth ends, management in girls with CAH changes focus to optimizing reproductive function. Both excessive androgens from the adrenals and excessive glucocorticoid treatment can disrupt ovulation, resulting in irregularity of [[Medicine:Menstrual cycle|menses]] or [[Medicine:Amenorrhea|amenorrhea]], as well as [[Medicine:Infertility|infertility]]. Continued monitoring of hormone balance and careful readjustment of glucocorticoid dose can usually restore fertility, but as a group, women with CAH have a lower fertility rate than a comparable population.<ref name="pmid30272171"/>

Classical CAH has little effect on male fertility unless an adult stops taking his glucocorticoid medication entirely for an extended time, in which case excessive adrenal androgens may reduce testicular production as well as spermatogenesis.<ref name="pmid30272171"/> Regarding nonclassic CAH, glucocorticoid therapy is typically not necessary for lifelong management. However, in certain cases, this treatment may be required to address fertility issues such as oligomenorrhea, amenorrhea, or difficulty conceiving. About 90% of women with nonclassic CAH remain undiagnosed. Once attempting to conceive, approximately 83% of women win nonclassic CAH successfully achieve pregnancy within one year, irrespective of whether they receive glucocorticoid therapy or not, but the therapy reduces risk of miscarriage.<ref name="pmid32966723"/>

====Psychosexual development and issues====
Nearly all [[Biology:Mammal|mammal]]s display [[Biology:Sexual dimorphism|sex-dimorphic]] reproductive and sexual behavior (e.g., [[Biology:Lordosis behavior|lordosis]] and mounting in [[Biology:Rodent|rodent]]s). Much research has made it clear that prenatal and early postnatal androgens play a role in the differentiation of most mammalian brains. Experimental manipulation of androgen levels in utero or shortly after birth can alter adult reproductive behavior.<ref name="pmid30272171"/>

Girls and women with CAH constitute the majority of genetic females with normal internal reproductive hormones who have been exposed to male levels of androgens throughout their prenatal lives. Milder degrees of continuing androgen exposure continue throughout childhood and adolescence as a consequence of the imperfections of current glucocorticoid treatment for CAH. The psychosexual development of these girls and women has been analyzed as evidence of the role of androgens in human sex-dimorphic behaviors.<ref name="pmid30272171"/>

In comparison to unaffected individuals, patients with classical CAH exhibit a greater prevalence of anxiety disorders, depressive disorders, alcohol misuse, personality disorders, and suicidal tendencies in males, while females are more prone to adjustment disorders.<ref name="pmid32966723"/> In comparison to the general population, individuals with CAH have a higher prevalence of substance abuse and attention deficit–hyperactivity disorder (ADHD). This is particularly observed in females with the most severe null genotype and males who receive a diagnosis after the neonatal period.<ref name="pmid32966723"/>

Girls with CAH have repeatedly been reported to spend more time with "sex-atypical" toys and "rough-and-tumble" play than unaffected sisters. These differences continue into adolescence, as expressed in social behaviors, leisure activities, and career interests. Interest in babies and becoming mothers is significantly lower by most measures.<ref name="pmid32966723"/> Avoidance of romantic relationships is common in women and men with classical CAH.<ref name="pmid32966723"/>

Gender identity of girls and women with CAH is most frequently observed to be female. Sexual orientation is more mixed, though the majority are heterosexual.<ref name="pmid32966723"/> In one study, 27% of women with CAH were rated as bisexual in their orientations.<ref name="pmid32231525">{{cite journal | vauthors = Daae E, Feragen KB, Waehre A, Nermoen I, Falhammar H | title = Sexual Orientation in Individuals With Congenital Adrenal Hyperplasia: A Systematic Review | journal = Frontiers in Behavioral Neuroscience | volume = 14 | issue =  | page = 38 | date = 2020 | pmid = 32231525 | pmc = 7082355 | doi = 10.3389/fnbeh.2020.00038 | doi-access = free }}</ref>

A 2020 survey of 57 females with life-long experience of CAH and 132 parents of females with CAH in the United States revealed that majority of participants do not consider females with CAH to be [[Biology:Intersex|intersex]], and oppose a legal intersex designation of females with CAH.<ref name="pmid33041207">{{cite journal | vauthors = Szymanski KM, Rink RC, Whittam B, Hensel DJ | title = Majority of females with a life-long experience of CAH and parents do not consider females with CAH to be intersex | journal = Journal of Pediatric Urology | volume = 17 | issue = 2 | pages = 210.e1–210.e9 | date = April 2021 | pmid = 33041207 | doi = 10.1016/j.jpurol.2020.09.009 | hdl-access = free | s2cid = 222300981 | hdl = 1805/27714 }}</ref>

Cognitive effects are less clear. Altered fetal and postnatal exposure to androgens, as well as glucocorticoid therapy, affect brain development and function. Compared to healthy girls, those with classical CAH have more aggressive behavior but have better spatial navigation abilities, and the amygdala activation patterns differ between affected and healthy girls. Glucocorticoid therapy in CAH impairs working memory and causes brain changes, including white matter hyperintensities, suggesting a reduction in white matter structural integrity.<ref name="pmid32966723"/> Cognitive impairment, when observed, has occasionally been attributed to hypoglycemia and electrolyte imbalances at the initial presentation.<ref name="pmid32966723"/> A 2023 population-based cohort study of 714 patients with classical CAH and 71400 control subjects predict that patients with CAH have an increased prevalence of injuries and accidents, especially females, but the cause is not known.<ref name="pmid37862468">{{cite journal |vauthors=Falhammar H, Hirschberg AL, Nordenskjöld A, Larsson H, Nordenström A |title=Increased Prevalence of Accidents and Injuries in Congenital Adrenal Hyperplasia: A Population-Based Cohort Study |journal=J Clin Endocrinol Metab |volume= |issue= |pages= |date=October 2023 |pmid=37862468 |doi=10.1210/clinem/dgad624 |url=|doi-access=free }}</ref>

The increased prevalence of depressive and anxiety disorders, along with the prescription of antidepressants by medical practitioners, among youth with CAH in comparison to the general population indicates the potential necessity for screening for symptoms of depression and anxiety in this specific population.<ref name="pmid37664854">{{cite journal |vauthors=Harasymiw LA, Grosse SD, Cullen KR, Bitsko RH, Perou R, Sarafoglou K |title=Depressive and anxiety disorders and antidepressant prescriptions among insured children and young adults with congenital adrenal hyperplasia in the United States |journal=Front Endocrinol (Lausanne) |volume=14 |issue= |pages=1129584 |date=2023 |pmid=37664854 |pmc=10470620 |doi=10.3389/fendo.2023.1129584 |url= |doi-access=free }}</ref>

Given that people with CAH exhibit a higher incidence and severity of behavioral symptoms,<ref name="pmid32966723"/> and that the manifestation of these behavioral problems can be attributed to excessive endogenous androgen exposure and side effects of glucucorticoid therapy,<ref name="pmid32966723"/> emphasis should be placed on early optimization of CAH management to mitigate the psychological ramifications that may ensue.<ref name="pmid32740726">{{cite journal |vauthors=Hamed SA, Attiah FA, Abd Elaal RF, Fawzy M |title=Behavioral assessment of females with congenital adrenal hyperplasia |journal=Hormones (Athens) |volume=20 |issue=1 |pages=131–141 |date=March 2021 |pmid=32740726 |doi=10.1007/s42000-020-00232-8 |s2cid=220907439 |url=}}</ref>

==Prognosis==
The outcomes and prognosis for CAH (Congenital Adrenal Hyperplasia) can vary depending on several factors, such as the specific type of CAH, its severity, early detection, and proper management. With appropriate medical care and ongoing treatment, individuals with CAH can lead healthy lives. Consistent monitoring and adherence to treatment are crucial for optimal outcomes.<ref name="pmid30272171"/>

Children with CAH often experience increased height during early childhood, but their final adult height tends to be shorter than expected. Advanced bone age and early fusion of growth plates due to excess androgens contribute to this outcome. Additionally, glucocorticoid treatment for CAH can affect growth and result in decreased final height. Experimental treatments using growth hormone and luteinizing hormone-releasing hormone analogs have shown some success in increasing average height gains by approximately 7.3&nbsp;cm. Most children with CAH have normal neuropsychological development, although there may be differences in gendered play activities influenced by prenatal sex steroid exposure.<ref name="pmid29630216"/>

While bone density is typically normal in most patients, metabolic abnormalities such as obesity, insulin resistance, dyslipidemia (abnormal blood lipid levels), and polycystic ovarian syndrome are more prevalent either due to the disease itself or long-term glucocorticoid treatment.<ref name="pmid30272171"/>

Fertility is possible for both males and females with CAH but may be reduced due to multiple factors encompassing biology, psychology, social influences, and sexual aspects.<ref name="pmid30272171"/>

Management of CAH requires collaboration among different subspecialty professionals considering the complex nature of the disease's complications and long-term consequences.<ref name="pmid29630216"/>

==Incidence==
According to most studies, the global incidence of classical forms range from about 1:14,000 to 1:18,000 births, based on newborn screening programs and national case registries, but this situation is more common in small genetically isolated populations with small gene pools.<ref name="pmid30272171"/> 10% of patients with classical forms of CAH have CAH-X syndrome, that is marked by the presence of CAH features along with features indicative of hypermobility-type Ehlers-Danlos syndrome. This condition results from a contiguous gene deletion that impacts both ''CYP21A2'' and ''TNXB'' genes.<ref name="pmid32291442">{{cite journal |vauthors=Gao Y, Lu L, Yu B, Mao J, Wang X, Nie M, Wu X |title=The Prevalence of the Chimeric TNXA/TNXB Gene and Clinical Symptoms of Ehlers-Danlos Syndrome with 21-Hydroxylase Deficiency |journal=J Clin Endocrinol Metab |volume=105 |issue=7 |pages= 2288–2299|date=July 2020 |pmid=32291442 |doi=10.1210/clinem/dgaa199 |url=|doi-access=free }}</ref><ref name="pmid35476220">{{cite journal |vauthors=Concolino P, Falhammar H |title=CAH-X Syndrome: Genetic and Clinical Profile |journal=Mol Diagn Ther |volume=26 |issue=3 |pages=293–300 |date=May 2022 |pmid=35476220 |doi=10.1007/s40291-022-00588-0 |s2cid=248402892 |url=}}</ref>

The incidence of [[Medicine:Late onset congenital adrenal hyperplasia|nonclassical forms]] of CAH is 1:200 to 1:1000 based on various estimates, and is also higher in groups people with a high rate of marriage between relatives, up to 1:50.<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 | pmc = 5675788 | doi = 10.1038/gim.2017.46 | s2cid = 4630175 }}</ref><ref name="pmid16912124">{{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 = 4205–4214 | date = November 2006 | pmid = 16912124 | doi = 10.1210/jc.2006-1645 | doi-access = free }}</ref> Nonclassic CAH may be identified incidentally during the assessment of oligomenorrhea, [[Medicine:Amenorrhea|amenorrhea]], and infertility in females. However, a significant proportion, approximately 90%, of women with nonclassic CAH remain undiagnosed. As for men with nonclassic CAH, their asymptomatic nature commonly leads to underdiagnosis.<ref name="pmid32966723"/>

== History ==
In 19th Century, cases of CAH were reported, leading to the understanding that the adrenal gland influenced sexual phenotypes as well as being mysteriously required for survival.<ref name="pmid36446323"/>

In 1865, CAH in its non-salt-wasting form was thoroughly described for the first time by a Neapolitan pathologist Luigi De Crecchio.<ref name="pmid25635623">{{cite journal | vauthors = Delle Piane L, Rinaudo PF, Miller WL | title = 150 years of congenital adrenal hyperplasia: translation and commentary of De Crecchio's classic paper from 1865 | journal = Endocrinology | volume = 156 | issue = 4 | pages = 1210–1217 | date = April 2015 | pmid = 25635623 | doi = 10.1210/en.2014-1879 | s2cid = 36312972 | doi-access = free }}</ref> However, significant strides in understanding and treating the condition have been made over the years.

In the early 20th Century, numerous adrenal steroids were isolated, and bioassays eventually distinguished glucocorticoids, mineralocorticoids, and androgens.<ref name="pmid36446323"/>

In 1950, Wilkins, Bartter, and Albright revolutionized clinical endocrinology with the use of cortisone to treat CAH and ushered in a productive era of pediatric adrenal research. Through careful clinical research, Wilkins established modern methods of treating CAH.<ref name="pmid36446323">{{cite journal | vauthors = Miller WL, White PC | title = A Brief History of Congenital Adrenal Hyperplasia | journal = Hormone Research in Paediatrics | volume = 95 | issue = 6 | pages = 529–545 | date = 2022 | pmid = 36446323 | doi = 10.1159/000526468 | s2cid = 254095026 | doi-access = free }}</ref>

In 1957, Alfred Bongiovanni noticed a defect in 21-hydroxylation in CAH, followed by defects in 3β-hydroxysteroid dehydrogenase and 11β-hydroxylase.<ref name="pmid36446323"/>

P450 enzymes were described from 1962 to 1964, and 21-hydroxylation was the first identified activity of P450s.<ref name="pmid36446323"/>

In the last quarter of the 20th Century, notable scholars who have contributed to the development of CAH knowledge include Hans Selye, who studied stress responses and adrenal function,<ref name="pmid36446323"/> as well as Maria New, who conducted extensive research on prenatal treatment options for CAH.

From 1984 to 2004, the techniques of molecular genetics were applied to elucidate the genetic and biochemical bases of CAH.<ref name="pmid36446323"/>

== Society and culture ==
Society's understanding of CAH can vary widely, leading to different perceptions and attitudes toward individuals with the condition. Lack of awareness or misconceptions about CAH may contribute to stigma or discrimination.<ref name="pmid31823183">{{cite journal |vauthors=Carroll L, Graff C, Wicks M, Diaz Thomas A |title=Living with an invisible illness: a qualitative study exploring the lived experiences of female children with congenital adrenal hyperplasia |journal=Qual Life Res |volume=29 |issue=3 |pages=673–681 |date=March 2020 |pmid=31823183 |doi=10.1007/s11136-019-02350-2 |s2cid=208957761 |url=}}</ref><ref>{{Citation |last1=Liamputtong |first1=Pranee |title=Stigma, Discrimination, and Social Exclusion |date=2021 |url=https://link.springer.com/10.1007/978-3-030-48277-0_6-2 |work=Handbook of Social Inclusion |pages=1–17 |editor-last=Liamputtong |editor-first=Pranee |access-date=2023-11-15 |place=Cham |publisher=Springer International Publishing |language=en |doi=10.1007/978-3-030-48277-0_6-2 |isbn=978-3-030-48277-0 |last2=Rice |first2=Zoe Sanipreeya}}</ref>

Discussions around [[Biology:Intersex|intersex]] conditions have evolved over time as societal understanding has progressed. There is consensus that classical CAH is an intersex condition. However, for the nonclassical CAH, there is a debate on whether it can be considered an intersex condition. Anne Fausto-Sterling, an American sexologist, in a 2000 book "Sexing the Body" came up with an estimate that people with [[Biology:Intersex|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|publisher=Basic Books}}</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 [[Biology:Intersex|intersex]] individuals, according to Fausto-Sterling, 88% have nonclassical CAH.<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, nonclassical CAH 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 nonclassical CAH in intersex prevalence estimates has been cited by Joel Best, is a professor of sociology and criminal justice, in a 2013 book "Stat-Spotting: A Field Guide to Identifying Dubious Data" 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|publisher=University of California Press}}</ref>

Different cultural contexts may shape views on [[Philosophy:Gender identity|gender identity]], sexuality, and medical interventions for intersex conditions. Individuals with visible differences or unique health needs associated with CAH may face social stigmatization due to a lack of awareness, prejudice, or preconceived notions about intersexuality.<ref name="pmid30322770">{{cite journal | vauthors = Gondim R, Teles F, Barroso U | title = Sexual orientation of 46, XX patients with congenital adrenal hyperplasia: a descriptive review | journal = Journal of Pediatric Urology | volume = 14 | issue = 6 | pages = 486–493 | date = December 2018 | pmid = 30322770 | doi = 10.1016/j.jpurol.2018.08.004 | s2cid = 53507149 }}</ref><ref name="pmid11344934">{{cite journal | vauthors = Meyer-Bahlburg HF | title = Gender and sexuality in classic congenital adrenal hyperplasia | journal = Endocrinology and Metabolism Clinics of North America | volume = 30 | issue = 1 | pages = 155–71, viii | date = March 2001 | pmid = 11344934 | doi = 10.1016/s0889-8529(08)70024-0 }}</ref><ref name="pmid23507003">{{cite journal | vauthors = Zainuddin AA, Grover SR, Shamsuddin K, Mahdy ZA | title = Research on quality of life in female patients with congenital adrenal hyperplasia and issues in developing nations | journal = Journal of Pediatric and Adolescent Gynecology | volume = 26 | issue = 6 | pages = 296–304 | date = December 2013 | pmid = 23507003 | doi = 10.1016/j.jpag.2012.08.004 }}</ref><ref name="pmid37694439">{{cite journal | vauthors = Finkielstain GP, Rey RA | title = Challenges in managing disorders of sex development associated with adrenal dysfunction | journal = Expert Review of Endocrinology & Metabolism | volume = 18 | issue = 5 | pages = 427–439 | date = 2023 | pmid = 37694439 | doi = 10.1080/17446651.2023.2256393 | s2cid = 261575934 }}</ref>
Activists, such as Hida Viloria, who was born with a form of CAH, advocate for compassionate care for people born intersex.<ref>{{Cite web |last=PhD |first=Hida Viloria and Professor Maria Nieto |title=Intersex Activist Hida Viloria and Maria Nieto PhD announce 'The Spectrum of Sex' Book |url=https://www.prweb.com/releases/intersex-activist-hida-viloria-and-maria-nieto-phd-announce-the-spectrum-of-sex-book-846476662.html |access-date=2023-11-15 |website=www.prweb.com |language=en}}</ref><ref>{{Cite web |date=2023-07-06 |title=These are the 10 best memoirs and autobiographies to read now |url=https://www.harpersbazaar.com/uk/culture/entertainment/g37950787/memoirs-autobiographies/ |access-date=2023-11-15 |website=Harper's BAZAAR |language=en-GB}}</ref>

== Research directions ==

Currently, gene replacement therapy for CAH is still at an early stage of research and development. Various approaches are being explored, including using viral vectors carrying a healthy copy of the CYP21A2 gene to deliver it into target cells. Another approach is based on utilizing human embryonic stem cells (hESCs) or induced pluripotent stem cells (iPSCs) to generate steroid-producing cells that can potentially replace or supplement dysfunctional adrenal tissue in individuals with CAH. However,  it remains unclear how new approaches can be tested,  as there are even no experimental models yet for this disease for gene therapy.<ref name="pmid36982440">{{cite journal | vauthors = Glazova O, Bastrich A, Deviatkin A, Onyanov N, Kaziakhmedova S, Shevkova L, Sakr N, Petrova D, Vorontsova MV, Volchkov P | display-authors = 6 | title = Models of Congenital Adrenal Hyperplasia for Gene Therapies Testing | journal = International Journal of Molecular Sciences | volume = 24 | issue = 6 | date = March 2023 | page = 5365 | pmid = 36982440 | pmc = 10049562 | doi = 10.3390/ijms24065365 | doi-access = free }}</ref>

== See also ==
* [[Medicine:Inborn errors of steroid metabolism|Inborn errors of steroid metabolism]]
* [[Medicine:Congenital adrenal hyperplasia|Congenital adrenal hyperplasia]]
* Adrenal insufficiency
* Disorders of sexual development
* [[Biology:Intersex|Intersex]]uality, [[Medicine:Pseudohermaphroditism|pseudohermaphroditism]], and ambiguous genitalia
* [[Biology:21-Hydroxylase|21-Hydroxylase]]

== References ==
{{Reflist}}

== External links ==
* [https://www.ncbi.nlm.nih.gov/books/NBK1171/ GeneReviews/NCBI/NIH/UW entry on 21-Hydroxylase-Deficient Congenital Adrenal Hyperplasia]
* [https://omim.org/entry/201910 OMIM entry on 21-Hydroxylase-Deficient Congenital Adrenal Hyperplasia]

{{Medical resources
| ICD11           = {{ICD11|5A71.01}}
| ICD10           = {{ICD10|E25.0}}
| ICD10CM         = <!-- {{ICD10CM|Xxx.xxxx}} -->
| ICD9            = {{ICD9|255.2}}
| ICDO            = 
| OMIM            = 201910
| MeshID          = C535979
| DiseasesDB      = 1854
| SNOMED CT       = 717261006
| Curlie          = 
| MedlinePlus     = 
| eMedicineSubj   = 
| eMedicineTopic  = 
| PatientUK       =
| NCI             = 
| GeneReviewsNBK  = NBK1171
| GeneReviewsName = 21-Hydroxylase-Deficient Congenital Adrenal Hyperplasia
| NORD            = 
| GARDNum         = 12665
| GARDName        = Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency
| RP              = 
| AO              = 
| WO              = 
| OrthoInfo       = 
| Orphanet        = 90794
| Scholia         = Q4127185
| OB              =
}}

{{Defects of cholesterol and steroid metabolism}}

[[Category:Autosomal recessive disorders]]

{{Sourceattribution|Congenital adrenal hyperplasia due to 21-hydroxylase deficiency}}