Abstract
Congenital adrenal hyperplasia (CAH) is an autosomal recessive disease caused by the deficiency of one of the enzymes involved in cortisol synthesis. Between 90% and 99% of cases of CAH are caused by 21-hydroxylase deficiency (21-OHD) caused by mutations in CYP21A2. Although 21-OHD has been historically divided into classical and non-classical forms, it is now thought to show a continuous phenotype. In the classical form, the external genitalia in females becomes virilized to varying degrees. If the disease is not recognized, salt wasting crises in the classical form may threaten life in neonates. Children experience accelerated somatic growth, increased bone age, and premature pubic hair in the simple virilizing form of classical 21-OHD. Female adolescents may present with severe acne, hirsutism, androgenic alopecia, menstrual irregularity or primary amenorrhea in the non-classical form. Diagnosis of CAH is made by clinical, biochemical and molecular genetic evaluation. In cases of 21-OHD, the diagnosis is based on the 17-hydroxyprogesterone (17-OHP) level being above 1000 ng/dL, measured early in the morning. In cases with borderline 17-OHP levels (200-1000 ng/dL), it is recommended to perform an adrenocorticotropic hormone (ACTH) stimulation test. Genotyping in cases with CAH should be performed if the adrenocortical profile is suspicious or if the ACTH stimulation test cannot be performed completely. After diagnosis, determining the carrier status of the parents and determining which parent the mutation was passed on from will help in interpreting the genetic results and determining the risk of recurrence in subsequent pregnancies.
Keywords: Congenital adrenal hyperplasia, 21-hydroxylase deficiency, children, adolescent, diagnosis
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References
Jha S, Turcu AF. Nonclassic congenital adrenal hyperplasia: what do endocrinologists need to know? Endocrinol Metab Clin North Am. 2021;50:151-165. Epub 2021 Jan 9
Claahsen-van der Grinten HL, Speiser PW, Ahmed SF, Arlt W, Auchus RJ, Falhammar H, Flück CE, Guasti L, Huebner A, Kortmann BBM, Krone N, Merke DP, Miller WL, Nordenström A, Reisch N, Sandberg DE, Stikkelbroeck NMML, Touraine P, Utari A, Wudy SA, White PC. Congenital adrenal hyperplasia-current insights in pathophysiology, diagnostics, and management. Endocr Rev. 2022;43:91-159.
Merke DP, Auchus RJ. Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency. N Engl J Med. 2020;383:1248-1261.
Balshem H, Helfand M, Schünemann HJ, Oxman AD, Kunz R, Brozek J, Vist GE, Falck-Ytter Y, Meerpohl J, Norris S, Guyatt GH. GRADE guidelines: 3. Rating the quality of evidence. J Clin Epidemiol. 2011;64:401-406. Epub 2011 Jan 5
Speiser PW, Arlt W, Auchus RJ, Baskin LS, Conway GS, Merke DP, Meyer-Bahlburg HFL, Miller WL, Murad MH, Oberfield SE, White PC. Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2018;103:4043-4088.
Güran T, Tezel B, Çakır M, Akıncı A, Orbak Z, Keskin M, Selver Eklioğlu B, Ozon A, Özbek MN, Karagüzel G, Hatipoğlu N, Gürbüz F, Çizmecioğlu FM, Kara C, Şimşek E, Baş F, Aydın M, Darendeliler F. Neonatal screening for congenital adrenal hyperplasia in Turkey: outcomes of extended pilot study in 241,083 infants. J Clin Res Pediatr Endocrinol. 2020;12:287-294. Epub 2020 Mar 11. Erratum in: J Clin Res Pediatr Endocrinol. 2021;13:250
Speiser PW, Dupont B, Rubinstein P, Piazza A, Kastelan A, New MI. High frequency of nonclassical steroid 21-hydroxylase deficiency. Am J Hum Genet. 1985;37:650-667.
Hannah-Shmouni F, Morissette R, Sinaii N, Elman M, Prezant TR, Chen W, Pulver A, Merke DP. Revisiting the prevalence of nonclassic congenital adrenal hyperplasia in US Ashkenazi Jews and Caucasians. Genet Med. 2017;19:1276-1279. Epub 2017 May 25
Carmina E, Dewailly D, Escobar-Morreale HF, Kelestimur F, Moran C, Oberfield S, Witchel SF, Azziz R. Non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency revisited: an update with a special focus on adolescent and adult women. Hum Reprod Update. 2017;23:580-599.
Moran C, Azziz R, Carmina E, Dewailly D, Fruzzetti F, Ibañez L, Knochenhauer ES, Marcondes JA, Mendonca BB, Pignatelli D, Pugeat M, Rohmer V, Speiser PW, Witchel SF. 21-Hydroxylase-deficient nonclassic adrenal hyperplasia is a progressive disorder: a multicenter study. Am J Obstet Gynecol. 2000;183:1468-1474.
Nordenström A, Falhammar H. Management of endocrine disease: diagnosis and management of the patient with non-classic CAH due to 21-hydroxylase deficiency. Eur J Endocrinol. 2019;180:127-145.
Livadas S, Dracopoulou M, Dastamani A, Sertedaki A, Maniati-Christidi M, Magiakou AM, Kanaka-Gantenbein C, Chrousos GP, Dacou-Voutetakis C. The spectrum of clinical, hormonal and molecular findings in 280 individuals with nonclassical congenital adrenal hyperplasia caused by mutations of the CYP21A2 gene. Clin Endocrinol (Oxf). 2015;82:543-549. Epub 2014 Aug 3
Thilén A, Woods KA, Perry LA, Savage MO, Wedell A, Ritzén EM. Early growth is not increased in untreated moderately severe 21-hydroxylase deficiency. Acta Paediatr. 1995;84:894-898.
Bonfig W. Growth and development in children with classic congenital adrenal hyperplasia. Curr Opin Endocrinol Diabetes Obes. 2017;24:39-42.
Trapp CM, Oberfield SE. Recommendations for treatment of nonclassic congenital adrenal hyperplasia (NCCAH): an update. Steroids. 2012;77:342-346. Epub 2011 Dec 13
Özsu E, Şıklar Z, Bilici E, Ceran A, Uyanık R, Çetin T, Aycan Z, Berberoğlu M. Intramuscular short-term ACTH test for the determination of adrenal function in children: safe, effective and reliable. J Clin Res Pediatr Endocrinol. 2020;12:241-247. Epub 2019 Dec 17
Gundgurthi A, Garg MK, Dutta MK, Pakhetra R. Intramuscular ACTH stimulation test for assessment of adrenal function. J Assoc Physicians India. 2013;61320-324.
Sharma R, Madathil S, Maheshwari V, Roy K, Kumar B, Jain V. Long-acting intramuscular ACTH stimulation test for the diagnosis of secondary adrenal insufficiency in children. J Pediatr Endocrinol Metab. 2019;32:57-63.
Speiser PW, Azziz R, Baskin LS, Ghizzoni L, Hensle TW, Merke DP, Meyer-Bahlburg HF, Miller WL, Montori VM, Oberfield SE, Ritzen M, White PC; Endocrine Society. Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2010;95:4133-4160. Erratum in: J Clin Endocrinol Metab. 2010;95:5137. Erratum in: J Clin Endocrinol Metab. 2021;106:e2853.
Armengaud JB, Charkaluk ML, Trivin C, Tardy V, Bréart G, Brauner R, Chalumeau M. Precocious pubarche: distinguishing late-onset congenital adrenal hyperplasia from premature adrenarche. J Clin Endocrinol Metab. 2009;94:2835-2840. Epub 2009 May 19
Merke DP, Bornstein SR. Congenital adrenal hyperplasia. Lancet. 2005;365:2125-2136.
Azziz R, Hincapie LA, Knochenhauer ES, Dewailly D, Fox L, Boots LR. Screening for 21-hydroxylase-deficient nonclassic adrenal hyperplasia among hyperandrogenic women: a prospective study. Fertil Steril. 1999;72:915-925.
Dundar A, Bayramov R, Onal MG, Akkus M, Dogan ME, Kenanoglu S, Cerrah Gunes M, Kazimli U, Ozbek MN, Ercan O, Yildirim R, Celmeli G, Parlak M, Dundar I, Hatipoglu N, Unluhizarci K, Akalin H, Ozkul Y, Saatci C, Dundar M. The molecular basis and genotype-phenotype correlations of congenital adrenal hyperplasia (CAH) in Anatolian population. Mol Biol Rep. 2019;46:3677-3690. Epub 2019 Apr 20
Maffazioli GDN, Bachega TASS, Hayashida SAY, Gomes LG, Valassi HPL, Marcondes JAM, Mendonca BB, Baracat EC, Maciel GAR. Steroid screening tools differentiating nonclassical congenital adrenal hyperplasia and polycystic ovary syndrome. J Clin Endocrinol Metab. 2020;105:dgaa369.
Pall M, Azziz R, Beires J, Pignatelli D. The phenotype of hirsute women: a comparison of polycystic ovary syndrome and 21-hydroxylase-deficient nonclassic adrenal hyperplasia. Fertil Steril. 2010;94:684-689. Epub 2009 Sep 1
Rudnicka E, Kunicki M, Radowicki S. Stezenie hormonów androgennych oraz 17-hydroksyprogesteronu w surowicy krwi a wzorzec miesiaczkowania u pacjentek z zespołem policystycznych jajników [Androgen and 17-hydroxyprogesterone concentrations in blood serum versus menstrual patterns in women with polycystic ovary syndrome (PCOS)]. Ginekol Pol. 2010;81:745-749.
Falhammar H. Non-functioning adrenal incidentalomas caused by 21-hydroxylase deficiency or carrier status? Endocrine. 2014;47:308-314. Epub 2014 Jan 23
Turcu AF, Rege J, Auchus RJ, Rainey WE. 11-Oxygenated androgens in health and disease. Nat Rev Endocrinol. 2020;16:284-296. Epub 2020 Mar 16
Skordis N, Shammas C, Phedonos AA, Kyriakou A, Toumba M, Neocleous V, Phylactou LA. Genetic defects of the CYP21A2 gene in girls with premature adrenarche. J Endocrinol Invest. 2015;38:535-539. Epub 2014 Dec 7
Foster C, Diaz-Thomas A, Lahoti A. Low prevalence of organic pathology in a predominantly black population with premature adrenarche: need to stratify definitions and screening protocols. Int J Pediatr Endocrinol. 2020;2020:5. Epub 2020 Mar 9
Binay C, Simsek E, Cilingir O, Yuksel Z, Kutlay O, Artan S. Prevalence of nonclassic congenital adrenal hyperplasia in Turkish children presenting with premature pubarche, hirsutism, or oligomenorrhoea. Int J Endocrinol. 2014;2014:768506. Epub 2014 Mar 23
Turan I, Tastan M, Boga DD, Gurbuz F, Kotan LD, Tuli A, Yüksel B. 21-Hydroxylase deficiency: Mutational spectrum and Genotype-Phenotype relations analyses by next-generation sequencing and multiplex ligation-dependent probe amplification. Eur J Med Genet. 2020;63:103782. Epub 2019 Oct 2
Concolino P, Costella A. Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency: a comprehensive focus on 233 pathogenic variants of CYP21A2 gene. Mol Diagn Ther. 2018;22:261-280.
New MI, Abraham M, Gonzalez B, Dumic M, Razzaghy-Azar M, Chitayat D, Sun L, Zaidi M, Wilson RC, Yuen T. Genotype-phenotype correlation in 1,507 families with congenital adrenal hyperplasia owing to 21-hydroxylase deficiency. Proc Natl Acad Sci U S A. 2013;110:2611-2616. Epub 2013 Jan 28
Falhammar H, Nordenström A. Nonclassic congenital adrenal hyperplasia due to 21-hydroxylase deficiency: clinical presentation, diagnosis, treatment, and outcome. Endocrine. 2015;50:32-50. Epub 2015 Jun 17
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; AQUAPE CAH Study Group. Genotype/phenotype correlations in 538 congenital adrenal hyperplasia patients from Germany and Austria: discordances in milder genotypes and in screened versus prescreening patients. Endocr Connect. 2019;8:86-94.
Ludwig K, Lai F, Wiley V, Ravine A, Srinivasan S. Genotyping in patients with congenital adrenal hyperplasia by sequencing of newborn bloodspot samples. J Pediatr Endocrinol Metab. 2023;36:966-973.
de Carvalho DF, Miranda MC, Gomes LG, Madureira G, Marcondes JA, Billerbeck AE, Rodrigues AS, Presti PF, Kuperman H, Damiani D, Mendonca BB, Bachega TA. Molecular CYP21A2 diagnosis in 480 Brazilian patients with congenital adrenal hyperplasia before newborn screening introduction. Eur J Endocrinol. 2016;175:107-116. Epub 2016 May 16
Krone N, Riepe FG, Grötzinger J, Partsch CJ, Sippell WG. Functional characterization of two novel point mutations in the CYP21 gene causing simple virilizing forms of congenital adrenal hyperplasia due to 21-hydroxylase deficiency. J Clin Endocrinol Metab. 2005;90:445-454. Epub 2004 Oct 13
Pignatelli D, Carvalho BL, Palmeiro A, Barros A, Guerreiro SG, Macut D. The complexities in genotyping of congenital adrenal hyperplasia: 21-hydroxylase deficiency. Front Endocrinol (Lausanne). 2019;10:432. Erratum in: Front Endocrinol (Lausanne). 2020;11:113.
Dolzan V, Sólyom J, Fekete G, Kovács J, Rakosnikova V, Votava F, Lebl J, Pribilincova Z, Baumgartner-Parzer SM, Riedl S, Waldhauser F, Frisch H, Stopar-Obreza M, Krzisnik C, Battelino T. Mutational spectrum of steroid 21-hydroxylase and the genotype-phenotype association in Middle European patients with congenital adrenal hyperplasia. Eur J Endocrinol. 2005;153:99-106.
Karaoğlan M, Nacarkahya G, Aytaç EH, Keskin M. Challenges of CYP21A2 genotyping in children with 21-hydroxylase deficiency: determination of genotype-phenotype correlation using next generation sequencing in Southeastern Anatolia. J Endocrinol Invest. 2021;44:2395-2405. Epub 2021 Mar 6
Sadeghi F, Yurur-Kutlay N, Berberoglu M, Cetinkaya E, Aycan Z, Kara C, Ilgin Ruhi H, Ocal G, Siklar Z, Elhan A, Tukun A. Identification of frequency and distribution of the nine most frequent mutations among patients with 21-hydroxylase deficiency in Turkey. J Pediatr Endocrinol Metab. 2008;21:781-787.
Baş F, Kayserili H, Darendeliler F, Uyguner O, Günöz H, Yüksel Apak M, Atalar F, Bundak R, Wilson RC, New MI, Wollnik B, Saka N. CYP21A2 gene mutations in congenital adrenal hyperplasia: genotype-phenotype correlation in Turkish children. J Clin Res Pediatr Endocrinol. 2009;1:116-128. Epub 2009 Feb 2
Toraman B, Ökten A, Kalay E, Karagüzel G, Dinçer T, Açıkgöz EG, Karagüzel A. Investigation of CYP21A2 mutations in Turkish patients with 21-hydroxylase deficiency and a novel founder mutation. Gene. 2013;513:202-208. Epub 2012 Nov 7
Moran C, Azziz R, Weintrob N, Witchel SF, Rohmer V, Dewailly D, Marcondes JA, Pugeat M, Speiser PW, Pignatelli D, Mendonca BB, Bachega TA, Escobar-Morreale HF, Carmina E, Fruzzetti F, Kelestimur F. Reproductive outcome of women with 21-hydroxylase-deficient nonclassic adrenal hyperplasia. J Clin Endocrinol Metab. 2006;91:3451-3456. Epub 2006 Jul 5
Bidet M, Bellanné-Chantelot C, Galand-Portier MB, Golmard JL, Tardy V, Morel Y, Clauin S, Coussieu C, Boudou P, Mowzowicz I, Bachelot A, Touraine P, Kuttenn F. Fertility in women with nonclassical congenital adrenal hyperplasia due to 21-hydroxylase deficiency. J Clin Endocrinol Metab. 2010;95:1182-1190. Epub 2010 Jan 15
