Abstract
Congenital adrenal hyperplasia (CAH) is a group of disorders caused by mutations in genes that encode steroidogenic enzymes. The most frequent form of CAH is caused by defects in CYP21A2 gene leading to 21-hydroxylase deficiency (21-OHD). There are 3 clinical forms of CAH: classic (salt-wasting (SW), simple virilizing (SV)), and nonclassic (NCCAH). Classic forms of 21-OHD can be specifically detected by the measurement of 17-hydroxyprogesterone in blood. Nonclassic form is often characterized by equivocal level of 17-hydroxyprogesterone and non-specific symptoms, so the genotyping is essential for the diagnosis. Moreover, molecular analysis of CYP21A2 mutations is useful for predicting the severity of disease and important for genetic counseling. We discuss the structure of CYP21A2 gene, types of mutations, mechanisms of clinical manifestation of disorder, including clinical features of heterozygote carriers. We present results of the study of 85 patients with hyperandrogenemia that were genotyped by multiplex test detecting 15 most common mutations in CYP21A2.
Authors and affiliations
E.I. Koroleva(1), V.D. Nazarov(1), S.V. Lapin(1), A.V. Mazing(1), K.A. Malyshkin(1), A.V. Lisker(1), A. A. Wilhelmi(2), E.I. Morozov(2), N.E. Koshevaya(2), E.V. Emanuel(1) 1-I.P. Pavlov First Saint-Petersburg State Medical University, L’va Tolstogo Str., 6–8, Saint Petersburg, 197022, Russian Federation; 2-Laboratory of molecular diagnostics and genetics, OOO «Helix», B. Sampsoniyevsky pr., 20, Saint Petersburg, 194044, Russian Federation E-mail: katherinakoroleva@mail.ru
References
Hannah-Shmouni F., Chen W., Merke D.P. Genetics of Congenital Adrenal Hyper- plasia. Endocrinol. Metab. Clin. North. Am. 2017; 46 (2): 435–58. https://doi. org/10.1016/j.ecl.2017.01.008
Moran C., Azziz R., Weintrob N., Witchel S.F., Rohmer V., Dewailly D., Marcondes J.A., Pugeat M., Speiser P.W., Pignatelli D., Men- donca B.B., Bachega T.A., Escobar-Morre- ale H.F., Carmina E., Fruzzetti F., Kelestimur F. Reproductive Outcome of Women with 21-Hydroxylase-Deficient Nonclassic Adrenal Hyperplasia. J. Clin. Endocrinol. Metab. 2006; 91 (9): 3451–6. https://doi. org/10.1210/jc.2006-0062
Speiser P.W., Dupont B., Rubinstein P., Piazza A., Kastelan A., New M.I. High frequency of nonclassical steroid 21-hydroxylase deficiency. Am. J. Hum. Genet. 1985; 37 (4): 650–67
Carmina E., Dewailly D., Escobar-Morreale H.F., Kelestimur F., Moran C., Oberfield S., Witchel S.F., Azziz R. Non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency revisited: an update with a spe- cial focus on adolescent and adult women. Hum. Reprod. Update 2017; 23 (5): 580–99. https://doi.org/10.1093/humupd/dmx014
Turcu A.F., Auchus R.J. The next 150 years of congenital adrenal hyperplasia. J. Steroid. Biochem. Mol. Biol. 2015; 153: 63–71. https://doi.org/10.1016/j.jsbmb.2015.05.013
Turcu A.F., Auchus R.J. Adrenal steroido- genesis and congenital adrenal hyper- plasia. Endocrinol. Metab. Clin. North. Am. 2015; 44 (2): 275–96. https://doi. org/10.1016/j.ecl.2015.02.002
Witchel S.F., Azziz R. Nonclassic con- genital adrenal hyperplasia. Int. J. Pediatr. Endocrinol. 2010; 2010: 1–11. https://doi. org/10.1155/2010/625105
Witchel S.F. Congenital Adrenal Hyper- plasia. J. Pediatr. Adolesc. Gynecol. 2017; 30 (5): 520–34. https://doi.org/10.1016/j. jpag.2017.04.001
Kamrath C., Hochberg Z., Hartmann M.F., Re- mer T., Wudy S.A. Increased Activation of the Alternative «Backdoor» Pathway in Patients with 21-Hydroxylase Deficiency: Evidence from Urinary Steroid Hormone Analysis. J. Clin. Endocrinol. Metab. 2012; 97 (3): 367–75. https://doi.org/10.1210/jc.2011-1997
Dacou-Voutetakis C., Dracopoulou M. High Incidence of Molecular Defects of the CYP21 Gene in Patients with Pre- mature Adrenarche. J. Clin. Endocrinol. Metab. 1999; 84 (5): 1570–4. https://doi. org/10.1210/jcem.84.5.5683
Speiser P.W., Azziz R., Baskin L.S., Ghizzoni L., Hensle T.W., Merke D.P., Meyer-Bahlburg H.F., Miller W.L., Montori V.M., Oberfield S.E., Ritzen M., White P.C. Congenital Adrenal Hyperpla- sia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clin. Practice Guide- line. J. Clin. Endocrinol. Metab. 2010; 95 (9): 4133–60. https://doi.org/10.1210/jc.2009-2631
Moran C., Azziz R., Carmina E., Dewailly D., Fruzzetti F., Ibañez L., Knochenhauer E.S., Marcondes J.A., Mendonca B.B., Pignatelli D., Pugeat M., Rohmer V., Speiser P.W., Witchel S.F. 21-Hydroxylase–deficient non- classic adrenal hyperplasia is a progressive disorder: A multicenter study. Am. J. Obstet. Gynecol. 2000; 183 (6): 1468–74. https:// doi.org/10.1067/mob.2000.108020
Bidet M., Bellanné-Chantelot C., Galand- Portier M.B., Golmard J.L., Tardy V., Morel Y., Clauin S., Coussieu C., Boudou P., Mow- zowicz I., Bachelot A., Touraine P., Kuttenn F. Fertility in Women with Nonclassical Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency. J. Clin. Endo crinol. Metab. 2010; 95 (3): 1182–90. https:// doi.org/10.1210/jc.2009-1383
Yang Z., Mendoza A.R., Welch T.R., Zipf W.B., Yu C.Y. Modular Variations of the Human Major Histocompatibility Complex Class III Genes for Serine/Threonine Kinase RP, Complement Component C4, Steroid 21-Hydroxylase CYP21, and Tenascin TNX (the RCCX Mod- ule). J. Biol. Chem. 1999; 274 (17): 12147–56. https://doi.org/10.1074/jbc.274.17.12147
Lee H. CYP21 mutations and congenital adrenal hyperplasia. Clin. Genet. 2002; 59 (5): 293–301. https://doi.org/10.1034/j.1399- 0004.2001.590501.x
Tusie-Luna M.T., White P.C. Gene conversions and unequal crossovers between CYP21 (steroid 21-hydroxylase gene) and CYP21P involve different mechanisms. Proc. Natl. Acad. Sci. U.S.A. 1995; 92 (23): 10796–800. https://doi.org/10.1073/pnas.92.23.10796
Higashi Y., Yoshioka H., Yamane M., Gotoh O., Fujii-Kuriyama Y. Complete nucleotide se- quence of two steroid 21-hydroxylase genes tandemly arranged in human chromosome: a pseudogene and a genuine gene. Proc. Natl. Acad. Sci. U.S.A. 1986; 83 (9): 2841–5. https://doi.org/10.1073/pnas.83.9.2841
Lee H. The chimeric CYP21P/CYP21 gene and 21-hydroxylase deficiency. J. Hum. Genet. 2004; 49 (2): 65–72. https://doi. org/10.1007/s10038-003-0115-2
Narasimhan M.L., Khattab A. Genet- ics of congenital adrenal hyperplasia and genotype-phenotype correlation. Fertil. Steril. 2019; 111 (1): 24–9. https://doi. org/10.1016/j.fertnstert.2018.11.007
Parajes S., Krone N. Molecular Genetics of 21-Hydroxylase Deficiency. In eLS. 2014. https://doi.org/10.1002/9780470015902. a0023845
Chen W., Xu Z., Sullivan A., Finkielstain G.P., Van Ryzin C., Merke D.P., McDon- nell N.B. Junction site analysis of chimeric CYP21A1P/CYP21A2 genes in 21-hy- droxylase deficiency. Clin. Chem. 2012; 58 (2): 421–30. https://doi.org/10.1373/ clinchem.2011.174037
Cargill M., Altshuler D., Ireland J., Sklar P., Ardlie K., Patil N., Shaw N., Lane C.R., Lim E.P., Kalyanaraman N., Nemesh J., Ziaugra L., Friedland L., Rolfe A., Warrington J., Lipshutz R., Daley G.Q., Lander E.S. Charac- terization of single-nucleotide polymor- phisms in coding regions of human genes. Nat Genet. 1999; 22 (3): 231–8. https://doi. org/10.1038/10290
Ajlamazjan E.K., Soboleva E.L., Potin V.V., Osinovskaja N.S. Diagnostika i lechenie neklassicheskoj formy vrozhdennoj giperplazii kory nadpochechnikov. Zhurnal akusherstva i zhenskih boleznej. 2011; LX (1): 88–96. [Aylamazyan E.K., Soboleva E.L., Potin V.V., Osinovskaya N.S. Diagnosis and treatment of non-classical form of congenital adrenal hyperplasia. Zhurnal akusherstva i zhenskih boleznej. 2011; LX (1): 88–96 (in Russian)]
Weintrob N., Brautbar C., Pertzelan A., Josefsberg Z., Dickerman Z., Kauschan- sky A., Lilos P., Peled D., Phillip M., Israel S.Genotype-phenotype associations in non- classical steroid 21-hydroxylase deficiency. Eur. J. Endocrinol. 2000; 143 (3): 397–403https://doi.org/10.1530/eje.0.1430397
Deneux C., Tardy V., Dib A., Mornet E., Billaud L., Charron D., Morel Y., Kuttenn F. Phenotype-Genotype Correlation in 56 Women with Nonclassical Congeni- tal Adrenal Hyperplasia due to 21-Hy- droxylase Deficiency. J. Clin. Endocrinol. Metab. 2001; 86 (1): 207–13. https://doi. org/10.1210/jcem.86.1.7131
Speiser P.W, Dupont J., Zhu D., Serrat J., Buegeleisen M., Tusie-Luna M.T., Lesser M., New M.I., White P.C. Disease expression and molecular genotype in congenital adrenal hyperplasia due to 21-hydroxy- lase deficiency. J. Clin. Invest. 1992; 90 (2): 584–95. https://doi.org/10.1172/JCI115897
Haider S., Islam B., D’Atri V., Sgobba M., Poojari C., Sun L., Yuen T., Zaidi M., NewM.I. Structure-phenotype correlations of human CYP21A2 mutations in congenital adrenal hyperplasia. Proc. Natl. Acad. Sci. U.S.A. 2013; 110 (7): 2605–10. https://doi. org/10.1073/pnas.1221133110
New M.I., Abraham M., Gonzalez B., Dumic M., Razzaghy-Azar M., Chitayat D., Sun L., Zaidi M., Wilson R.C., Yuen T. Genotype- phenotype correlation in 1,507 families with congenital adrenal hyperplasia owingto 21-hydroxylase deficiency. Proc. Natl. Acad. Sci. U.S.A. 2013; 110 (7): 2611–6.https://doi.org/10.1073/pnas.1300057110
Koyama S., Toyoura T., Saisho S., Shimozawa K., Yata J. Genetic Analysis of Japanese Patients with 21-Hydroxylase Deficiency: Identification of a Patient with a New Mutation of a Homozygous Deletion of Ad- enine at Codon 246 and Patients without Demonstrable Mutations within the Struc- tural Gene for CYP21. J. Clin. Endocrinol. Metab. 2002; 87 (6): 2668–73. https://doi. org/10.1210/jcem.87.6.8522
Tajima T., Fujieda K., Nakae J., Mikami A., Cutler G.B. Jr. Mutations of the CYP21Gene in Nonclassical Steroid 21-Hydroxy- lase Deficiency in Japan. Endocr. J. 1998; 45 (4): 493–7. https://doi.org/10.1507/en- docrj.45.493
Riedl S., Röhl F.W., Bonfig W., Brämswig J., Richter-Unruh A., Fricke-Otto S., Bettendorf M., Riepe F., Kriegshäuser G., Schönau E., Even G., Hauffa B., Dörr H.G., Holl R.W., 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 (2): 86–94. https://doi.org/10.1530/ EC-18-0281
Neocleous V., Fanis P., Toumba M., Phedonos A.A.P., Picolos M., Andreou E., Kyriakides T.C., Tanteles G.A., Shammas C., Phylactou L.A., Skordis N. Variations in the 3’UTR of the CYP21A2 Gene in Heterozy- gous Females with Hyperandrogenaemia. Int. J. Endocrinol. 2017; 8984365. https:// doi.org/10.1155/2017/8984365
Knochenhauer E.S., Cortet-Rudelli C., Cunnigham R.D., Conway-Myers B.A., Dewailly D., Azziz R. Carriers of 21-Hydroxy- lase Deficiency Are Not at Increased Risk for Hyperandrogenism. J. Clin. Endocrinol. Metab. 1997; 82 (2): 479–85. https://doi. org/10.1210/jcem.82.2.3759
Neocleous V., Shammas C., Phedonos A.A., Phylactou L.A., Skordis N. Pheno- typic variability of hyperandrogenemia in females heterozygous for CYP21A2 muta- tions. Indian J. Endocrinol. Metab. 2014; 18 (1): 72–9. https://doi.org/10.4103/2230- 8210.145077
Paris F., Tardy V., Chalançon A., Picot M.C.,Morel Y., Sultan C. Premature pubarche in Mediterranean girls: high prevalence of heterozygous CYP21 mutation carriers. Gy- necol. Endocrinol. 2010; 26 (5): 319–24. htt- ps://doi.org/10.3109/09513590903511505
Dacou-Voutetakis C., Dracopoulou M. High Incidence of Molecular Defects of the CYP21 Gene in Patients with Pre- mature Adrenarche. J. Clin. Endocrinol. Metab. 1999; 84 (5): 1570–4. https://doi. org/10.1210/jcem.84.5.5683
Admoni O., Israel S., Lavi I., Gur M., Tenenbaum-Rakover Y. Hyperandrogenism in carriers of CYP21 mutations: the role of genotype. Clin. Endocrinol. (Oxf) 2006; 64 (6): 645–51. https://doi.org/10.1111/j.1365- 2265.2006.02521.x
Concolino P., Costella A. Congenital Adre- nal Hyperplasia (CAH) due to 21-Hydroxy- lase Deficiency: A Comprehensive Focus on 233 Pathogenic Variants of CYP21A2 Gene. Mol. Diagn. Ther. 2018; 22 (3): 261–80. https://doi.org/10.1007/s40291-018- 0319-y
Kleinle S., Lang R., Fischer G.F., Vierhapper H., Waldhauser F., Födinger M., Baum- gartner-Parzer S.M. Duplications of the Functional CYP21A2 Gene Are Primarily Restricted to Q318X Alleles: Evidencefor a Founder Effect. J. Clin. Endocrinol. Metab. 2009; 94 (10): 3954–8. https://doi. org/10.1210/jc.2009-0487
Lekarev O., Tafuri K., Lane A.H., Zhu G., Nakamoto J.M., Buller-Burckle A.M., Wilson T.A., New M.I. Erroneous prenatal diagnosis of congenital adrenal hyperplasia owing to a duplication of the CYP21A2 gene. J. Perinatol. 2013; 33 (1): 76–8. https://doi. org/10.1038/jp.2012.5
Kolahdouz M., Hashemipour M., Khanah- mad H., Rabbani B., Salehi M., Rabbani A., Ansari A., Naseri M.M. Mutation detection of CYP21A2 gene in nonclassical con- genital adrenal hyperplasia patients with premature pubarche. Adv. Biomed. Res. 2016; 5: 33. https://doi.org/10.4103/2277- 9175.178794
Binay C., Simsek E., Cilingir O., Yuksel Z., Kutlay O., Artan S. Prevalence of nonclas- sic congenital adrenal hyperplasia in Turkish children presenting with premature pubarche, hirsutism, or oligomenorrhoea. Int. J. Endocrinol. 2014; 768506. https://doi. org/10.1155/2014/768506