Adrenogenital syndrome: molecular mechanisms of development

V.P. Pishak, M.O. Ryznychuk

Abstract


On the long multistage pathway of biosynthesis of steroid hormones from cholesterol to cortisol, testo­sterone and estradiol, due to mutations in genes, there is the deficiency of steroidogenesis enzymes in the adrenal glands: cholesterol desmolase, 3β-hydroxysteroid dehydrogenase, 17α-hydroxylase, 21-hydroxylase, and enzymes of steroidogenesis in the testis: 17,20-desmolasis, 17β-hydroxystyrol dehydroreductase and others, as well as a complex of widespread congenital diseases of heterogeneous group with autosomal recessive type of inheritance — adrenogenital syndrome (AGS). Deficiency of any of these enzymes or transport proteins leads to partial or complete loss of their activity. Phenotypic manifestations of AGS are quite polymorphic: phenomenon of hypoadrenocorticism; violation of the nature and rates of sexual development; bilateral increasing of adrenal glands; hypercorticotropinemia sensitive to dexamethasone; oligo- or amenorrhea; anovulatory infertility, miscarriage in early pregnancy. Pathogenetic component of these signs is congenital disorder of steroidogenesis caused by 11β-hydroxylase deficiency and symptoms of androgen excess. In AGS, there are distinguished a phenotype and nonclassical forms of steroidogenesis enzyme deficiency. In most cases, both types of diseases occur in persons of both sexes with different course — from mild to severe forms of the disease.

Keywords


adrenogenital syndrome; diagnosis; adrenal cortex; virilization

References


Osinovskaya NS, Ivashchenko TE, Soboleva EL et al. Analysis of spectrum of mutational damages of 21-hydroxylasae gene in patients with a сongenital adrenal hyperplasia. Russian Journal of Genetics. 2000;36(8): 955-7.

Newsbaum RL, McInnes RR, Villard HV. Meditsinskaia genetika [Medical genetics]. Moscow: GEOTAR-Media; 2010. 624 p. (Russian).

Pankiv VI. Insufficiency of mineralocorticors: epidemiology, pathogenesis, diagnostics, treatment. Mezhdunarodnyi Nevrologicheskii Zhurnal. 2012;3(49):102-108 (Russian).

Pishak VP, Myslytskyi VF, Tkachuk SS. The inherited syndromes with bases of phenotypic diagnostics. Chernivtsi: Meduniversytet, 2010; 608 s. (Ukrainian).

Vikhlieva EM. Rukovodstvo po endokrinnoi ginekologii [Guidance on endocrine gynaecology]. М.: Med. Inform. Agentstvo, 2006; 784 s. (Russian).

Chernushin SU, Livshyts LA. Methodology of analysis of mutations of gene of CYP21A2 in patients with сongenital adrenal hyperplasia. Biotechnologia Acta. 2014;7(1):75-79 (Ukrainian).

Meimaridou E, Hughes CR, Kowalczyk J, Chan LF, Clark AJ, Metherell LA. ACTH resistance: genes and mechanisms. Endocr Rev. 2013;24:57-66. doi: 10.1159/000342504.

Harrington J, Peña AS, Gent R. Adolescents with congenital adrenal hyperplasia because of 21-hydroxylase deficiency have vascular dysfunction. Clin Endocrinol (Oxf). 2012;76:837-842. doi: 10.1111/j.1365-2265.2011.04309.x.

Völkl TM, Simm D, Dötsch J et al. Altered 24-hour blood pressure profiles in children and adolescents with classical congenital adrenal hyperplasia due to 21-hydroxylase deficiency. J Clin Endocrinol Metab. 2006;91:4888-95. doi: 10.1210/jc.2006-1069. PMID: 17003094

. Auchus RJ. Steroid 17-hydroxylase and 17,20-lyase deficiencies, genetic and pharmacologic. J Steroid Biochem Mol Biol. 2017;165:71-78. doi: 10.1016/j.jsbmb.2016.02.002.

Brett EM, Auchus RJ. Genetic forms of adrenal insufficiency. Endocr Pract. 2015;21(4):395-399. doi: 10.4158/EP14503.RA.

Subbarayan A, Dattani MT, Peters CJ, Hindmarsh PS. Cardiovascular risk factors in children and adolescents with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Clin Endocrinol (Oxf). 2014;80:471-477. doi:10.1111/cen.12265.

Sahakitrungruang T, Soccio RE, Lang-Muritano M et al. Clinical, genetic, and functional characterization of four patients carrying partial loss-of-function mutations in the steroidogenic acute regulatory protein (StAR). J Clin Endocrinol Metab. 2010;95(7):3352-9. doi: 10.1210/jc.2010-0437.

Lekarev O, Mallet D, Yuen T. Congenital lipoid adrenal hyperplasia (a rare form of adrenal insufficiency and ambiguous genitalia) caused by a novel mutation of the steroidogenic acute regulatory protein gene. Eur J Pediatr. 2012;171:787-793.

Meimaridou E, Hughes C, Kowalczyk J et al. Familial glucocorticoid deficiency: new genes and mechanisms. Mol Cell Endocrinol. 2013;371:195-200. doi: 10.1016/j.mce.2012.12.010

Gangaher A, Jyotsna VP, Chauhan V et al. Gender of rearing and psychosocial aspect in 46 XX congenital adrenal hyperplasia. Indian J Endocrinol Metab. 2016;20(6):870-7 doi: 10.4103/2230-8210.192922.

Hauffa B, Hiort O. P450 side-chain cleavage deficiency — a rare cause of congenital adrenal hyperplasia. Endocr Rev. 2011;20:54-62. doi: 10.1159/000321215.

Krawczak M1, Ball EV, Fenton I, et al. Human gene mutation database — a biomedical information and research resource. Hum Mutat. 2000;15(1):45-51. doi: 10.1002/(SICI)1098-1004(200001)15:1<45::AID-HUMU10>3.0.CO;2-T.

Wasniewska M, Balsamo A, Valenzise M et al. Increased large artery intima media thickness in adolescents with either classical or non-classical congenital adrenal hyperplasia. J Endocrinol Invest. 2013;36:12-15. doi: 10.3275/8194.

Kim CJ. Congenital lipoid adrenal hyperplasia. Ann Pediatr Endocrinol Metab. 2014;19(4):179-183. doi: 10.6065/apem.2014.19.4.179.

Kaur J, Casas L, Bose HS. Lipoid congenital adrenal hyperplasia due to STAR mutations in a Caucasian patient. Endocrinol Diabetes Metab Case Rep. 2016;2016:150119. doi: 10.1530/EDM-15-0119.

Aydin Z, Ozturk S, Gursu M. Male pseudohermaphroditism as a cause of secondary hypertension: a case report. Endocrine. 2010;38(1):100-103. doi: 10.1007/s12020-010-9357-x.

Marsh CA, Auchus RJ. Fertility in patients with genetic deficiencies of cytochrome P450c17 (CYP17A1): combined 17-hydroxylase/17,20-lyase deficiency and isolated 17,20-lyase deficiency. Fertil Steril. 2014;101(2):317-322. doi: 10.1016/j.fertnstert.2013.11.011.

Miller WL, Bose HS. Early steps in steroidogenesis: intracellular cholesterol trafficking. J Lipid Res. 2011;52(12):2111-2135. doi: 10.1194/jlr.R016675.

Miller WL, Tee MK. The post-translational regulation of 17,20 lyase activity. Mol Cell Endocrinol. 2015;408(15):99-106. doi: 10.1016/j.mce.2014.09.010.

Miller WL. The syndrome of 17,20 lyase deficiency. J Clin Endocrinol Metab. 2012;97(1):59-67. doi: 10.1210/jc.2011-2161.

Bose HS, Sato S, Aisenberg J. Mutations in the steroidogenic acute regulatory protein (StAR) in six patients with congenital lipoid adrenal hyperplasia. J Clin Endocrinol Metab. 2000;85(10):3636-9. doi: 10.1210/jcem.85.10.6896.

Lutfallah C, Wan W, Mason JI. Newly proposed hormonal criteria via genotypic proof for type II 3-beta-hydroxysteroid dehydrogenase deficiency. J Clin Endocr Metab. 2002;87:2611-22. doi: 10.1210/jcem.87.6.8615.

Osinovskaja N, Ivaschenko T, Soboleva E. CYP21-B–CYP21-P chimeric molecule as a possible cause of nonclassical form of congenital adrenal hyperplasia. European human genetic conference. Praga, 2005; 270 p.

Flück CE, Pandey AV, Huang N. P450 oxidoreductase deficiency — a new form of congenital adrenal hyperplasia. Endocr Dev. 2008;13:67-81. doi: 10.1159/000134826. doi: 10.1159/000134826.

Sahakitrungruang T, Tee MK, Blackett PR, Miller WL. Partial defect in the cholesterol side-chain cleavage enzyme P450scc (CYP11A1) resembling nonclassic congenital lipoid adrenal hyperplasia. J Clin Endocrinol Metab. 2011;96(3):792-8. doi: 10.1210/jc.2010-1828.

Joshi R, Das D, Tamhankar P, Shaikh S. Phenotypic variability in congenital lipoid adrenal hyperplasia. Indian Pediatr. 2014;51(5):399-400.

Tsai SL, Green J, Metherell LA. Primary Adrenocortical Insufficiency Case Series: Genetic Etiologies More Common than Expected. Horm Res Paediatr. 2016;85(1):35-42. doi: 10.1159/000441843.

Mermejo LM, Elias LL, Marui S. Refining hormonal diagnosis of type II 3beta-hydroxysteroid dehydrogenase deficiency in patients with premature pubarche and hirsutism based on HSD3B2 genotyping. J Clin Endocrinol Metab. 2005;90(3):1287-93. doi: 10.1210/jc.2004-1552.

Kim CJ, Lin L, Huang N, et al. Severe combined adrenal and gonadal deficiency caused by novel mutations in the cholesterol side chain cleavage enzyme, P450scc. J Clin Endocrinol Metab. 2008;93(3):696-702. doi: 10.1210/jc.2007-2330.

Speiser PW. Congenital Adrenal Hyperplasia. F1000Res. 2015;20(4) (F1000 Faculty Rev):601. doi: 10.12688/f1000research.6543.1.

Haider S, Islam B, D’Atri V. Structure-phenotype correlations of human CYP21A2 mutations in congenital adrenal hyperplasia. Proc Natl Acad Sci. 2013;110:2605-10. doi: 10.1073/pnas.1221133110.

Gomes LG, Huang N, Agrawal V. The common P450 oxidoreductase variant A503V is not a modifier gene for 21-hydroxylase deficiency. J Clin Endocrinol Metab. 2008;93(7):2913-2916. doi: 10.1210/jc.2008-0304.

Baquedano MS, Guercio G, Marino R. Unique dominant negative mutation in the N-terminal mitochondrial targeting sequence of StAR, causing a variant form of congenital lipoid adrenal hyperplasia. J Clin Endocrinol Metab. 2013;98:153-61.

Arlt W, Willis DS, Wild SH, United Kingdom Congenital Adrenal Hyperplasia Adult Study Executive (CaHASE). Health status of adults with congenital adrenal hyperplasia: a cohort study of 203 patients. J Clin Endocrinol Metab. 2010;95:5110-21. doi: 10.1210/jc.2010-0917.

Tee MK, Abramsohn M, Loewenthal N, et al. Varied clinical presentations of seven patients with mutations in CYP11A1 encoding the cholesterol side-chain cleavage enzyme, P450sc. J Clin Endocrinol Metab. 2013;98(2):713-20. doi: 10.1210/jc.2012-2828.

White PC. Congenital adrenal hyperplasia owing to 11β-hydroxylase deficiency. Adv Exp Med Biol. 2011;707:7-8. doi: 10.1007/978-1-4419-8002-1_2.

White PC. Steroid 11 beta-hydroxylase deficiency and related disorders. Endocrinol Metab Clin North Am. 2001;30(1):61-79. PMID: 11344939.




DOI: https://doi.org/10.22141/2224-0721.13.2.2017.100612

Refbacks

  • There are currently no refbacks.


Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.

 

© "Publishing House "Zaslavsky", 1997-2017

 

 Яндекс.МетрикаSeo анализ сайта Рейтинг@Mail.ru