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* p.P30L (rs9378251, CYP21A2*8).
* p.P30L (rs9378251, CYP21A2*8).


A point mutation in exon 7 of ''CYP21A2'' (p.<!--AWB, this is not a page-->V281L) accounts for the majority of LOCAH alleles worldwide.<ref name="pmid28541281">{{cite journal | name-list-style = vanc |last1=Hannah-Shmouni |first1=Fady |last2=Morissette |first2=Rachel |last3=Sinaii |first3=Ninet |last4=Elman |first4=Meredith |last5=Prezant |first5=Toni R |last6=Chen |first6=Wuyan |last7=Pulver |first7=Ann |last8=Merke |first8=Deborah P |title=Revisiting the prevalence of nonclassic congenital adrenal hyperplasia in US Ashkenazi Jews and Caucasians |journal=Genetics in Medicine |date=November 2017 |volume=19 |issue=11 |pages=1276–1279 |doi=10.1038/gim.2017.46 |pmid=28541281 |pmc=5675788 }}</ref> Carriers for this mild, p.<!--AWB, this is not a page-->V281L mutation, resulting in retaining of 20%–50% of 21-hydroxylase activity,<ref name="pmid2249999">{{cite journal | name-list-style = vanc | vauthors = Tusie-Luna MT, Traktman P, White PC | title = Determination of functional effects of mutations in the steroid 21-hydroxylase gene (CYP21) using recombinant vaccinia virus | journal = The Journal of Biological Chemistry | volume = 265 | issue = 34 | pages = 20916–22 | date = December 1990 | pmid = 2249999}}</ref><ref name="pmid28582566">{{cite journal | name-list-style = vanc | vauthors = Carmina E, Dewailly D, Escobar-Morreale HF, Kelestimur F, Moran C, Oberfield S, Witchel SF, Azziz R | 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 | url = https://academic.oup.com/humupd/article/23/5/580/3861391}}</ref> are at higher risk of symptoms of androgen excess than carriers of the severe mutations,<ref name="pmid23045419">{{cite journal | name-list-style = vanc | vauthors = Neocleous V, Shammas C, Phedonos AP, Karaoli E, Kyriakou A, Toumba M, Phylactou LA, Skordis N | title = Genetic defects in the cyp21a2 gene in heterozygous girls with premature adrenarche and adolescent females with hyperandrogenemia | journal = Georgian Medical News | volume = | issue = 210 | pages = 40–7 | date = September 2012 | pmid = 23045419 | doi = | url = }}</ref> and had higher [[ACTH stimulation test|adrenocorticotropic hormone (ACTH) stimulated]] [[17α-hydroxyprogesterone]].<ref name="pmid16712666">{{cite journal | name-list-style = vanc | vauthors = Admoni O, Israel S, Lavi I, Gur M, Tenenbaum-Rakover Y | title = Hyperandrogenism in carriers of CYP21 mutations: the role of genotype | journal = Clinical Endocrinology | volume = 64 | issue = 6 | pages = 645–51 | date = June 2006 | pmid = 16712666 | doi = 10.1111/j.1365-2265.2006.02521.x| s2cid = 37571628 }}</ref> Besides that, LOCAH due to 21-hydroxylase deficiency can be caused by duplications of CYP21A1P pseudogene and C4B gene. Due to the high degree of homology between the CYP21A2 gene and the CYP21A1P pseudogene, and the complexity of the locus, research on the 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 | pages = 165 | date = November 2020 | pmid = 33168061 | doi = 10.1186/s12902-020-00643-z| pmc = 7653887 }}</ref>
A point mutation in exon 7 of ''CYP21A2'' (p.<!--AWB, this is not a page-->V281L) accounts for the majority of LOCAH alleles worldwide.<ref name="pmid28541281">{{cite journal | name-list-style = vanc |last1=Hannah-Shmouni |first1=Fady |last2=Morissette |first2=Rachel |last3=Sinaii |first3=Ninet |last4=Elman |first4=Meredith |last5=Prezant |first5=Toni R |last6=Chen |first6=Wuyan |last7=Pulver |first7=Ann |last8=Merke |first8=Deborah P |title=Revisiting the prevalence of nonclassic congenital adrenal hyperplasia in US Ashkenazi Jews and Caucasians |journal=Genetics in Medicine |date=November 2017 |volume=19 |issue=11 |pages=1276–1279 |doi=10.1038/gim.2017.46 |pmid=28541281 |pmc=5675788 }}</ref><ref name="pmid33168061"/><ref>{{cite web |url=https://pubmed.ncbi.nlm.nih.gov/32647925/}}</ref> Carriers for this mild, p.<!--AWB, this is not a page-->V281L mutation, resulting in retaining of 20%–50% of 21-hydroxylase activity,<ref name="pmid2249999">{{cite journal | name-list-style = vanc | vauthors = Tusie-Luna MT, Traktman P, White PC | title = Determination of functional effects of mutations in the steroid 21-hydroxylase gene (CYP21) using recombinant vaccinia virus | journal = The Journal of Biological Chemistry | volume = 265 | issue = 34 | pages = 20916–22 | date = December 1990 | pmid = 2249999}}</ref><ref name="pmid28582566">{{cite journal | name-list-style = vanc | vauthors = Carmina E, Dewailly D, Escobar-Morreale HF, Kelestimur F, Moran C, Oberfield S, Witchel SF, Azziz R | 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 | url = https://academic.oup.com/humupd/article/23/5/580/3861391}}</ref> are at higher risk of symptoms of androgen excess than carriers of the severe mutations,<ref name="pmid23045419">{{cite journal | name-list-style = vanc | vauthors = Neocleous V, Shammas C, Phedonos AP, Karaoli E, Kyriakou A, Toumba M, Phylactou LA, Skordis N | title = Genetic defects in the cyp21a2 gene in heterozygous girls with premature adrenarche and adolescent females with hyperandrogenemia | journal = Georgian Medical News | volume = | issue = 210 | pages = 40–7 | date = September 2012 | pmid = 23045419 | doi = | url = }}</ref> and had higher [[ACTH stimulation test|adrenocorticotropic hormone (ACTH) stimulated]] [[17α-hydroxyprogesterone]].<ref name="pmid16712666">{{cite journal | name-list-style = vanc | vauthors = Admoni O, Israel S, Lavi I, Gur M, Tenenbaum-Rakover Y | title = Hyperandrogenism in carriers of CYP21 mutations: the role of genotype | journal = Clinical Endocrinology | volume = 64 | issue = 6 | pages = 645–51 | date = June 2006 | pmid = 16712666 | doi = 10.1111/j.1365-2265.2006.02521.x| s2cid = 37571628 }}</ref> Besides that, LOCAH due to 21-hydroxylase deficiency can be caused by duplications of CYP21A1P pseudogene and C4B gene. Due to the high degree of homology between the CYP21A2 gene and the CYP21A1P pseudogene, and the complexity of the locus, research on the 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 | pages = 165 | date = November 2020 | pmid = 33168061 | doi = 10.1186/s12902-020-00643-z| pmc = 7653887 }}</ref>


The particularly mild clinical symptoms of LOCAH such as [[hyperandrogenism]], [[hirsutism]] and [[acne]] or [[infertility]] overlap with other diseases such as [[polycystic ovary syndrome]]. Biochemical parameters like [[17α-hydroxyprogesterone]] may not be elevated in very mild cases of LOCAH, and may vary between labs that makes interpretation difficult. It may not be possible to perform [[ACTH stimulation test|ACTH stimulation tests]] in all institutions, depending on the availability of the injectable [[adrenocorticotropic hormone]] medication. This is why a comprehensive ''CYP21A2'' genotyping (rather than variant-specific assays alone) is a good way to exclude/confirm 21-hydroxylase deficiency and heterozygosity (carrier) status.<ref name="pmid32616876">{{cite journal | name-list-style = vanc |last1=Baumgartner-Parzer |first1=Sabina |last2=Witsch-Baumgartner |first2=Martina |last3=Hoeppner |first3=Wolfgang |title=EMQN best practice guidelines for molecular genetic testing and reporting of 21-hydroxylase deficiency |journal=European Journal of Human Genetics |date=2 July 2020 |volume=28 |issue=10 |pages=1341–1367 |doi=10.1038/s41431-020-0653-5 |pmid=32616876 |pmc=7609334 |s2cid=220295067 }}</ref> Genetic testing can be used to exclude false positive diagnosis based on biochemical parameters alone, even with ACTH stimulation, since elevated 17-OHP levels may be also caused by [[Ovarian tumor|ovarian]] or [[Adrenal tumor|adrenal tumors]], rather than by the variants in the ''CYP21A2'' gene.<ref name="pmid33117272">{{cite journal | name-list-style = vanc | 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 = | pages = 526287 | date = 2020 | pmid = 33117272 | doi = 10.3389/fendo.2020.526287 | pmc = 7551200 | s2cid = 221979120 | url = }}</ref>
The particularly mild clinical symptoms of LOCAH such as [[hyperandrogenism]], [[hirsutism]] and [[acne]] or [[infertility]] overlap with other diseases such as [[polycystic ovary syndrome]]. Biochemical parameters like [[17α-hydroxyprogesterone]] may not be elevated in very mild cases of LOCAH, and may vary between labs that makes interpretation difficult. It may not be possible to perform [[ACTH stimulation test|ACTH stimulation tests]] in all institutions, depending on the availability of the injectable [[adrenocorticotropic hormone]] medication. This is why a comprehensive ''CYP21A2'' genotyping (rather than variant-specific assays alone) is a good way to exclude/confirm 21-hydroxylase deficiency and heterozygosity (carrier) status.<ref name="pmid32616876">{{cite journal | name-list-style = vanc |last1=Baumgartner-Parzer |first1=Sabina |last2=Witsch-Baumgartner |first2=Martina |last3=Hoeppner |first3=Wolfgang |title=EMQN best practice guidelines for molecular genetic testing and reporting of 21-hydroxylase deficiency |journal=European Journal of Human Genetics |date=2 July 2020 |volume=28 |issue=10 |pages=1341–1367 |doi=10.1038/s41431-020-0653-5 |pmid=32616876 |pmc=7609334 |s2cid=220295067 }}</ref> Genetic testing can be used to exclude false positive diagnosis based on biochemical parameters alone, even with ACTH stimulation, since elevated 17-OHP levels may be also caused by [[Ovarian tumor|ovarian]] or [[Adrenal tumor|adrenal tumors]], rather than by the variants in the ''CYP21A2'' gene.<ref name="pmid33117272">{{cite journal | name-list-style = vanc | 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 = | pages = 526287 | date = 2020 | pmid = 33117272 | doi = 10.3389/fendo.2020.526287 | pmc = 7551200 | s2cid = 221979120 | url = }}</ref>

Revision as of 23:33, 26 November 2020

Late onset congenital adrenal hyperplasia
Other namesNonclassic onset congenital adrenal hyperplasia
Frequency0.1%–2%

Late onset congenital adrenal hyperplasia (LOCAH), also known as nonclassic congenital adrenal hyperplasia (NCCAH or NCAH), is a milder form of congenital adrenal hyperplasia (CAH), a group of autosomal recessive disorders characterized by impaired cortisol synthesis that leads to variable degrees of postnatal androgen excess.[1][2][3]

The causes of LOCAH are the same as of classic CAH, and in the majority of the cases are the mutations in the CYP21A2 gene resulting in corresponding activity changes in the associated P450c21 (21-hydroxylase) protein enzyme which ultimately leads to excessive androgen production. Other causes, albeit less frequent, are mutations in genes affecting other enzymes involved in steroid metabolism, like 11β-hydroxylase or 3β-hydroxysteroid dehydrogenase. It has 0.1%–2% prevalence depending on population,[1] and is one of the most common autosomal recessive genetic diseases in humans.[4][5][6] The pathophysiology is complex and not all individuals are symptomatic.[1]

Presentation

Patients with LOCAH usually present with signs of hyperandrogenism rather than of glucocorticoid deficiency.[7] Females may present with symptoms like hirsutism, oligomenorrhea, acne, infertility,[8] and male-pattern baldness.[9][10][11] Males are generally asymptomatic,[12][7] but may present with acne[13][14][15], early balding[16][17][18] and testicular adrenal rest tumors.[8][16] While symptoms are usually diagnosed after puberty, children may present with premature adrenarche.[7]

The degree of hormonal disorder in patients with LOCAH is relatively mild. Such patients have not been extensively studied. However, alterations in the hypothalamic–pituitary–adrenal axis are present even in this mild form of the disease and might contribute to psychiatric vulnerability.[19]

LOCAH was originally characterized in 1957 by French biochemist Jacques Decourt.[20]

Molecular genetics

LOCAH is most commonly attributed to mutations in the CYP21A2 gene, which encodes the 21-hydroxylase enzyme. Cases of LOCAH due to deficiencies in other enzymes that are known causes of CAH (3β-hydroxysteroid dehydrogenase, steroid 11β-hydroxylase, etc.) are rare and have no established prevalence estimates.[21]

The following three mutations to the CYP21A2 gene are mostly associated with LOCAH:[22]

  • p.V281L (rs6471, CYP21A2*15);
  • p.P453S (rs6445, CYP21A2*19);
  • p.P30L (rs9378251, CYP21A2*8).

A point mutation in exon 7 of CYP21A2 (p.V281L) accounts for the majority of LOCAH alleles worldwide.[22][23][24] Carriers for this mild, p.V281L mutation, resulting in retaining of 20%–50% of 21-hydroxylase activity,[25][12] are at higher risk of symptoms of androgen excess than carriers of the severe mutations,[26] and had higher adrenocorticotropic hormone (ACTH) stimulated 17α-hydroxyprogesterone.[27] Besides that, LOCAH due to 21-hydroxylase deficiency can be caused by duplications of CYP21A1P pseudogene and C4B gene. Due to the high degree of homology between the CYP21A2 gene and the CYP21A1P pseudogene, and the complexity of the locus, research on the molecular level is difficult.[23]

The particularly mild clinical symptoms of LOCAH such as hyperandrogenism, hirsutism and acne or infertility overlap with other diseases such as polycystic ovary syndrome. Biochemical parameters like 17α-hydroxyprogesterone may not be elevated in very mild cases of LOCAH, and may vary between labs that makes interpretation difficult. It may not be possible to perform ACTH stimulation tests in all institutions, depending on the availability of the injectable adrenocorticotropic hormone medication. This is why a comprehensive CYP21A2 genotyping (rather than variant-specific assays alone) is a good way to exclude/confirm 21-hydroxylase deficiency and heterozygosity (carrier) status.[28] Genetic testing can be used to exclude false positive diagnosis based on biochemical parameters alone, even with ACTH stimulation, since elevated 17-OHP levels may be also caused by ovarian or adrenal tumors, rather than by the variants in the CYP21A2 gene.[29]

Diagnosis

LOCAH differs from classic CAH in that it does not cause atypical neonatal genital morphology, is not life threatening and presents after birth. Unlike classic CAH, LOCAH generally cannot be reliably detected with neonatal screening.[30] Many individuals (both male and female) present no symptoms during childhood and adolescence and only become aware of the possibility of LOCAH due to the diagnosis of another family member. In young females, premature pubarche is generally the first symptom to present.[10] The earliest known diagnosis was in a 6 month old female who developed pubic hair.[31] Additional symptoms include acne, menstrual irregularities and hirsutism in females as well as alopecia in males. LOCAH is often misdiagnosed as polycystic ovarian disease (PCOS).[32]

LOCAH is sometimes diagnosed during an evaluation for oligomenorrhea or amenorrhea and infertility. However, an estimated 90% of women with LOCAH never receive a diagnosis. Once they start trying to conceive, roughly 83% of women with known LOCAH become pregnant within 1 year, with or without glucocorticoid therapy. Such women have consistently been found to be at increased risk for miscarriage.[19]

The diagnostic procedure varies according to the specific enzyme deficiency causing LOCAH and the precise serum androgen levels required for diagnosis are the subject to variance from different measurement methods, refinement in specific cases and are under active research. Some protocols are based on measuring 17α-hydroxyprogesterone levels, with or without ACTH stimulation test.[30]

21-Hydroxylase deficiency

Screening

Main article: Congenital adrenal hyperplasia due to 21-hydroxylase deficiency

The condition of 21-hydroxylase deficiency is screened by measuring serum levels of 17α-hydroxyprogesterone (17-OHP) in the morning and between day 3 and 5 of the menstrual cycle (for females) to reduce the possibility of false positive results.[19] 17-OHP is used as a marker of the 21-hydroxylase enzyme activity since the 1980s.[33] 17-OHP between 1.7 and 3.0 ng/mL is sufficient for diagnosis while higher levels suggest further investigation. Randomly timed measurements of 17-OHP have not been shown to be useful for screening since they are often normal and are known to be very high in the luteal phase of the female menstrual cycle. After basal levels have been measured, confirmation is done by administering ACTH, and comparing 17-OHP pre and post test. 17-OHP levels over 10 ng/mL at the 60th minute post stimulation is considered diagnostic for LOCAH.[30]

Androgen backdoor pathway

Main article: Androgen backdoor pathway

In 21-hydroxylase deficiency, especially in mild cases (LOCAH), the androgen "backdoor" pathway may be the reason of androgen excess.[34] This backdoor pathway is not always considered in the clinical evaluation of patients with hyperandrogenism conditions such as LOCAH and may be a source of diagnostic pitfalls and confusion.[35] One case study demonstrated the importance of considering serum 5α-dihydrotestosterone (DHT) levels and the androgen backdoor pathway in a LOCAH diagnosis that would have not been apparent from testosterone levels alone.[35]

11β-Hydroxylase deficiency

Main article: Congenital adrenal hyperplasia due to 11β-hydroxylase deficiency

The activity of 11β-hydroxylase can be determined by observing the basal 11-deoxycortisol level. A level over 10 ng/mL, indicates followup with ACTH stimulation test. The 60th minute post-stimulation 11-deoxycortisol levels higher than 18 ng/mL are diagnostic of LOCAH.[30]

3β-Hydroxysteroid dehydrogenase deficiency

Main article: Congenital adrenal hyperplasia due to 3β-hydroxysteroid dehydrogenase deficiency

The activity of 3β-hydroxysteroid dehydrogenase can be determined by observing the basal 17α-hydroxypregnenolone level. A level above 30 ng/mL and 17α-hydroxypregnenolone/cortisol ratio above 10 SD are diagnostic of LOCAH.[30]

Management

Management and treatment of LOCAH is case specific and the application of glucocorticoid treatment is not standard as it is in classic CAH. Recent reviews emphasize treatment that is specific to each case rather than merely abnormal hormone levels.[21][30][36] LOCAH is not a life-threatening medical condition and the risks of treatment given prenatally or to asymptomatic children outweigh potential benefits.[37][38][39] In appropriate cases, glucocorticoids (usually hydrocortisone in children) are administered to suppress secretion of hypothalmic corticotropin releasing hormone (CRH) and pituitary ACTH which will reduce serum concentrations of adrenal sex steroids. Some of the main considerations in treatment include the watchful waiting of symptom severity as well as adverse responses to exogenous glucocorticoids seen in patient bone density, height and weight.[40] For women, an oral contraceptive pill and spironolactone or cyproterone acetate, are alternatives to glucocorticoids for managing symptoms of androgen excess.[19]

Incidence

According to haplotype association studies, the prevalence of LOCAH in the general white population is estimated to be 1:500 to 1:1000, but in people with a high rate of marriage between relatives, the prevalence rate is as high as 1:50 to 1:100. A 2017 CYP21A2 genotype analysis predicted that the total frequency of LOCAH in the US caucasian population is about 1:200 (95% confidence level, from 1:100 to 1:280).[1][41]

LOCAH-affected individuals account for 88% of Anne Fausto-Sterling's 1.7% prevalence estimate of intersex conditions,[42] which is cited by a number of prominent intersex advocacy organizations.[43][44][45][46] From the clinical perspective, LOCAH is not an intersex condition[47] and including LOCAH in intersex prevalence estimates has been cited as an example of dubious statistical practice.[48]

See also

References

  1. ^ a b c d Speiser PW, Arlt W, Auchus RJ, Baskin LS, Conway GS, Merke DP, Meyer-Bahlburg HFL, Miller WL, Murad MH, Oberfield SE, White PC (2018). "Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clinical Practice Guideline". The Journal of Clinical Endocrinology and Metabolism. 103 (11): 4043–4088. doi:10.1210/jc.2018-01865. PMC 6456929. PMID 30272171.
  2. ^ Hattori N, Ishihara T, Moridera K, Hino M, Ikekubo K, Kurahachi H (February 1993). "A case of late-onset congenital adrenal hyperplasia due to partial 3 beta-hydroxysteroid dehydrogenase deficiency". Endocrine Journal. 40 (1): 107–9. doi:10.1507/endocrj.40.107. PMID 7951484.
  3. ^ "Congenital adrenal hyperplasia due to 11-beta-hydroxylase deficiency".
  4. ^ Speiser PW, Dupont B, Rubinstein P, Piazza A, Kastelan A, New MI (July 1985). "High frequency of nonclassical steroid 21-hydroxylase deficiency". American Journal of Human Genetics. 37 (4): 650–67. PMC 1684620. PMID 9556656.
  5. ^ Krone N, Arlt W (April 2009). "Genetics of congenital adrenal hyperplasia". Best Practice & Research. Clinical Endocrinology & Metabolism. 23 (2): 181–92. doi:10.1016/j.beem.2008.10.014. PMC 5576025. PMID 19500762.
  6. ^ Turcu AF, Nanba AT, Chomic R, Upadhyay SK, Giordano TJ, Shields JJ, Merke DP, Rainey WE, Auchus RJ (May 2016). "Adrenal-derived 11-oxygenated 19-carbon steroids are the dominant androgens in classic 21-hydroxylase deficiency". European Journal of Endocrinology. 174 (5): 601–9. doi:10.1530/EJE-15-1181. PMC 4874183. PMID 26865584.
  7. ^ a b c Witchel SF, Azziz R (2010). "Nonclassic Congenital Adrenal Hyperplasia". International Journal of Pediatric Endocrinology. 2010: 625105. doi:10.1155/2010/625105. PMC 2910408. PMID 20671993.
  8. ^ a b Miller WL, Auchus RJ (April 2019). "The "backdoor pathway" of androgen synthesis in human male sexual development". PLOS Biology. 17 (4): e3000198. doi:10.1371/journal.pbio.3000198. PMC 6464227. PMID 30943210. S2CID 92999312.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  9. ^ Pignatelli D (2013). "Non-classic adrenal hyperplasia due to the deficiency of 21-hydroxylase and its relation to polycystic ovarian syndrome". Frontiers of Hormone Research. 40: 158–70. doi:10.1159/000342179. ISBN 978-3-318-02238-4. PMID 24002412.
  10. ^ a b Livadas S, Bothou C (2019). "Management of the Female With Non-classical Congenital Adrenal Hyperplasia (NCCAH): A Patient-Oriented Approach". Frontiers in Endocrinology. 10: 366. doi:10.3389/fendo.2019.00366. PMC 6563652. PMID 31244776. S2CID 174798615.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  11. ^ Powell D, Inoue T, Bahtiyar G, Fenteany G, Sacerdote A (2017). "Treatment of Nonclassic 11-Hydroxylase Deficiency with Ashwagandha Root". Case Reports in Endocrinology. 2017: 1869560. doi:10.1155/2017/1869560. PMC 5496100. PMID 28713602.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  12. ^ a b Carmina E, Dewailly D, Escobar-Morreale HF, Kelestimur F, Moran C, Oberfield S, Witchel SF, Azziz R (September 2017). "Non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency revisited: an update with a special focus on adolescent and adult women". Human Reproduction Update. 23 (5): 580–599. doi:10.1093/humupd/dmx014. PMID 28582566.
  13. ^ Degitz K, Placzek M, Arnold B, Schmidt H, Plewig G (June 2003). "Congenital adrenal hyperplasia and acne in male patients". The British Journal of Dermatology. 148 (6): 1263–6. doi:10.1046/j.1365-2133.2003.05369.x. PMID 12828760. S2CID 42921625.
  14. ^ Sharquie KE, Noaimi AA, Saleh BO, Anbar ZN (December 2009). "The frequency of 21-alpha hydroxylase enzyme deficiency and related sex hormones in Iraqi healthy male subjects versus patients with acne vulgaris". Saudi Medical Journal. 30 (12): 1547–50. PMID 19936418.
  15. ^ Falhammar H, Nordenström A (September 2015). "Nonclassic congenital adrenal hyperplasia due to 21-hydroxylase deficiency: clinical presentation, diagnosis, treatment, and outcome". Endocrine. 50 (1): 32–50. doi:10.1007/s12020-015-0656-0. PMID 26082286. S2CID 23469344.
  16. ^ a b New MI (1 November 2006). "Nonclassical 21-Hydroxylase Deficiency". The Journal of Clinical Endocrinology & Metabolism. 91 (11): 4205–4214. doi:10.1210/jc.2006-1645. PMID 16912124. Loss of scalp hair in females and males is embarrassing, requiring treatment with 5α-reductase inhibitors
  17. ^ Bernal González C, Fernández Salas C, Martínez S, Ezquieta Zubicaray B (October 2006). "[Premature androgenetic alopecia in adult male with nonclassic 21-OH deficiency. A novel nonsense CYP21A2 mutation (Y336X) in 2 affected siblings]". Medicina Clinica (in European Spanish). 127 (16): 617–21. doi:10.1016/s0025-7753(06)72688-4. PMID 17145028.
  18. ^ "Congenital Adrenal Hyperplasia: Diagnosis and Emergency Treatment".
  19. ^ a b c d Merke DP, Auchus RJ (September 2020). "Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency". The New England Journal of Medicine. 383 (13): 1248–1261. doi:10.1056/NEJMra1909786. PMID 32966723.
  20. ^ Decourt J, Jayle MF, Baulieu E (May 1957). "Virilisme cliniquement tardif avec excrétion de prégnanetriol et insuffisance de la production du cortisol" [Clinically late virilism with excretion of pregnanetriol and insufficiency of cortisol production]. Annales d'endocrinologie (in French). 18 (3): 416–22. PMID 13470408.
  21. ^ a b Speiser PW (9 August 2008). "Nonclassic adrenal hyperplasia". Reviews in Endocrine and Metabolic Disorders. 10 (1): 77–82. doi:10.1007/s11154-008-9097-x. PMID 18690539. S2CID 30469525.
  22. ^ a b Hannah-Shmouni F, Morissette R, Sinaii N, Elman M, Prezant TR, Chen W, Pulver A, Merke DP (November 2017). "Revisiting the prevalence of nonclassic congenital adrenal hyperplasia in US Ashkenazi Jews and Caucasians". Genetics in Medicine. 19 (11): 1276–1279. doi:10.1038/gim.2017.46. PMC 5675788. PMID 28541281.
  23. ^ a b Espinosa Reyes TM, Collazo Mesa T, Lantigua Cruz PA, Agramonte Machado A, Domínguez Alonso E, Falhammar H (November 2020). "Molecular diagnosis of patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency". BMC Endocrine Disorders. 20 (1): 165. doi:10.1186/s12902-020-00643-z. PMC 7653887. PMID 33168061.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  24. ^ https://pubmed.ncbi.nlm.nih.gov/32647925/. {{cite web}}: Missing or empty |title= (help)
  25. ^ Tusie-Luna MT, Traktman P, White PC (December 1990). "Determination of functional effects of mutations in the steroid 21-hydroxylase gene (CYP21) using recombinant vaccinia virus". The Journal of Biological Chemistry. 265 (34): 20916–22. PMID 2249999.
  26. ^ Neocleous V, Shammas C, Phedonos AP, Karaoli E, Kyriakou A, Toumba M, Phylactou LA, Skordis N (September 2012). "Genetic defects in the cyp21a2 gene in heterozygous girls with premature adrenarche and adolescent females with hyperandrogenemia". Georgian Medical News (210): 40–7. PMID 23045419.
  27. ^ Admoni O, Israel S, Lavi I, Gur M, Tenenbaum-Rakover Y (June 2006). "Hyperandrogenism in carriers of CYP21 mutations: the role of genotype". Clinical Endocrinology. 64 (6): 645–51. doi:10.1111/j.1365-2265.2006.02521.x. PMID 16712666. S2CID 37571628.
  28. ^ Baumgartner-Parzer S, Witsch-Baumgartner M, Hoeppner W (2 July 2020). "EMQN best practice guidelines for molecular genetic testing and reporting of 21-hydroxylase deficiency". European Journal of Human Genetics. 28 (10): 1341–1367. doi:10.1038/s41431-020-0653-5. PMC 7609334. PMID 32616876. S2CID 220295067.
  29. ^ Tsai WH, Wong CH, Dai SH, Tsai CH, Zeng YH (2020). "Adrenal Tumor Mimicking Non-Classic Congenital Adrenal Hyperplasia". Frontiers in Endocrinology. 11: 526287. doi:10.3389/fendo.2020.526287. PMC 7551200. PMID 33117272. S2CID 221979120.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  30. ^ a b c d e f Kurtoğlu S, Hatipoğlu N (7 March 2017). "Non-Classical Congenital Adrenal Hyperplasia in Childhood". Journal of Clinical Research in Pediatric Endocrinology. 9 (1): 1–7. doi:10.4274/jcrpe.3378. PMC 5363159. PMID 27354284.
  31. ^ Kohn B, Levine LS, Pollack MS, Pang S, Lorenzen F, Levy D, Lerner AJ, Rondanini GF, Dupont B, New MI (November 1982). "Late-Onset Steroid 21-Hydroxylase Deficiency: A Variant of Classical Congenital Adrenal Hyperplasia". The Journal of Clinical Endocrinology & Metabolism. 55 (5): 817–827. doi:10.1210/jcem-55-5-817. PMID 6288753.
  32. ^ Chrousos GP, Loriaux DL, Mann DL, Cutler GB J (1 February 1982). "Late-Onset 21-Hydroxylase Deficiency Mimicking Idiopathic Hirsutism or Polycystic Ovarian Disease: An Allelic Variant of Congenital Virilizing Adrenal Hyperplasia with a Milder Enzymatic Defect". Annals of Internal Medicine. 96 (2): 143–8. doi:10.7326/0003-4819-96-2-143. PMID 6977282.
  33. ^ Azziz R, Zacur HA (September 1989). "21-Hydroxylase deficiency in female hyperandrogenism: screening and diagnosis". The Journal of Clinical Endocrinology and Metabolism. 69 (3): 577–84. doi:10.1210/jcem-69-3-577. PMID 2547827.
  34. ^ White PC (June 2018). "Update on diagnosis and management of congenital adrenal hyperplasia due to 21-hydroxylase deficiency". Current Opinion in Endocrinology, Diabetes and Obesity. 25 (3): 178–184. doi:10.1097/MED.0000000000000402. PMID 29718004. S2CID 26072848.
  35. ^ a b Sumińska M, Bogusz-Górna K, Wegner D, Fichna M (29 June 2020). "Non-Classic Disorder of Adrenal Steroidogenesis and Clinical Dilemmas in 21-Hydroxylase Deficiency Combined with Backdoor Androgen Pathway. Mini-Review and Case Report". International Journal of Molecular Sciences. 21 (13): 4622. doi:10.3390/ijms21134622. PMC 7369945. PMID 32610579.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  36. ^ Kelestimur F (August 2006). "Non-classic congenital adrenal hyperplasia". Pediatric Endocrinology Reviews : PER. 3 Suppl 3: 451–4. PMID 17551465. NCAH is not characterized by cortisol insufficiency and these patients do not need glucocorticoid replacement before and/or during surgery unless they have been treated chronically with glucocorticoids.
  37. ^ Miller WL, Witchel SF (May 2013). "Prenatal treatment of congenital adrenal hyperplasia: risks outweigh benefits". American Journal of Obstetrics and Gynecology. 208 (5): 354–359. doi:10.1016/j.ajog.2012.10.885. PMID 23123167.
  38. ^ Clayton PE, Miller WL, Oberfield SE, Ritzén EM, Sippell WG, Speiser PW, ESPE/ LWPES CAH Working Group (2002). "Consensus Statement on 21-Hydroxylase Deficiency from The European Society for Paediatric Endocrinology and The Lawson Wilkins Pediatric Endocrine Society". Hormone Research in Paediatrics. 58 (4): 188–195. doi:10.1159/000065490. PMID 12324718. S2CID 41346214.
  39. ^ Joint LWPES/ESPE CAH Working Group (September 2002). "Consensus Statement on 21-Hydroxylase Deficiency from The Lawson Wilkins Pediatric Endocrine Society and The European Society for Paediatric Endocrinology". The Journal of Clinical Endocrinology & Metabolism. 87 (9): 4048–4053. doi:10.1210/jc.2002-020611. PMID 12213842.
  40. ^ Van Ryzin C (December 2009). "Nonclassic congenital adrenal hyperplasia: an overview". Journal of Pediatric Nursing. 24 (6): 535–7. doi:10.1016/j.pedn.2009.09.004. PMID 19946984.
  41. ^ Hannah-Shmouni F, Morissette R, Sinaii N, Elman M, Prezant TR, Chen W, Pulver A, Merke DP (November 2017). "Revisiting the prevalence of nonclassic congenital adrenal hyperplasia in US Ashkenazi Jews and Caucasians". Genetics in Medicine. 19 (11): 1276–1279. doi:10.1038/gim.2017.46. PMID 28541281. S2CID 4630175.
  42. ^ Fausto-Sterling A. Sexing the body : gender politics and the construction of sexuality. [New York]. ISBN 9781549104480.
  43. ^ "Intersex babies are perfect just as they are!". UN Free & Equal. p 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!
  44. ^ "Its Intersex Awareness Day - here are 5 myths we need to shatter". www.amnesty.org. According to experts, around 1.7% of the population is born with intersex traits - comparable to the number of people born with red hair.
  45. ^ "How common is intersex? | Intersex Society of North America". isna.org. Below we provide a summary of statistics drawn from an article by Brown University researcher Anne Fausto-Sterling...Late onset adrenal hyperplasia one in 66 individuals
  46. ^ "Intersex population figures". Intersex Human Rights Australia. 28 September 2013. 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.
  47. ^ Sax L (August 2002). "How common is lntersex? A response to Anne Fausto‐Sterling". Journal of Sex Research. 39 (3): 174–178. doi:10.1080/00224490209552139. PMID 12476264. S2CID 33795209. 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.
  48. ^ Best J (14 September 2013). Stat-spotting : a field guide to identifying dubious data (Updated and expand ed.). Berkeley. pp. 12–13. ISBN 978-0520279988.{{cite book}}: CS1 maint: location missing publisher (link)
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