Volume 17, Issue 6 (June 2019 2019)                   IJRM 2019, 17(6): 451-456 | Back to browse issues page

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Nazari M, Mehrjardi M Y V, Neghab N, Aghabagheri M, Ghasemi N. A novel mutation in CYP17A1 gene leads to congenital adrenal hyperplasia: A case report. IJRM 2019; 17 (6) :451-456
URL: http://ijrm.ir/article-1-1563-en.html
1- Department of Medical Genetics, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
2- Medical Genetics Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
3- Yazd Reproductive Sciences Institute, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
4- Meybod Nursing School, Yazd, Iran.
5- Abortion Research Centre, Yazd Reproductive Sciences Institute, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
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Congenital adrenal hyperplasia (CAH) is a group of rare disorders demonstrated by a failure in one of the five enzymes responsible for cortisol production in autosomal recessive pattern (1). In adrenal glands, Pregnenolone is made from cholesterol which later can be processed to either mineralocorticoids or glucocorticoids or to sex steroids in adrenals and gonads (2).
The p450c17 enzyme is encoded by the CYP17A1 gene located on 10q24.3 (3) and spans 6.6 kb, which comprises eight exons (4). "This gene transcribes 2.1-kb mRNA molecule, which expresses in both the adrenals and gonads and generates a 57-kDa microsomal cytochrome P450c17 enzyme. The CYP17A1 enzyme catalyzes both steroid 17-hydroxylase and 17,20-lyase activities" (5). Enzymatic failure of the P450c17 enzyme leads to both glucocorticoids and sex steroids deficiencies. After a reduction in blood glucocorticoids levels due to P450c17 defect, anterior pituitary tries to compensate for the insufficiency of glucocorticoids levels by producing extra Adrenocorticotropic hormone (ACTH). This results in the extra generation of steroid precursors and elevated ACTH level, which leads to some Congenital adrenal hyperplasia and result in hypertension, hypokalemia, and a suppressed renin-angiotensin system (6, 7). Moreover, due to the impairments in CYP17A1, the mineralocorticoid precursors (corticosterone and 11-deoxycorticosterone) accumulate, which demonstrate glucocorticoid activity, therefore defect in P450c17 does not associate with adrenal crisis, rather than other CAH variants (8). Mutations in the CYP17A1 gene are the rarest defects in CAH that yields to steroid 17-hydroxylase and 17,20-lyase deficiencies (9). Several mutations in the CYP17 gene have been reported that cause either complete or combined17-hydroxylase/17,20-lyase or isolated 17, 20-lyase enzyme deficiencies (10-14).
The purpose of this study was to investigate the molecular defects in CYP17A1 gene and its relationship with Congenital adrenal hyperplasia.
Case presentation
A 14-year-old female, the first child of consanguineous parents with normal family history was referred to the genetic clinic with high blood pressure, ambiguous genitalia, and lack of pubertal development. The blood sample was taken after receiving written informed consent from her parents. No pubic or axillary hair was seen by physical examination, and she had no clinical symptoms of Turner syndrome with 46, XX karyotype. In the sonographic survey, uterus was infantile. She was hypertensive (150/90 mmHg, 50th percentile for age) with high gonadotropins levels (LH, 19 mU/mL; FSH, 34 mU/mL). Moreover, low peripheral concentrations of sex steroids were seen (Table I).
Sequencing of CYP17A1 gene
Genomic DNA was purified from peripheral blood leukocytes (PBL) using QIAGEN Mini Blood kit. All the exons of CYP17A1 genewere proliferated by PCR (primers listed in Table II), which were designed with Primer3 software (http://primer3.sourceforge.net). All the PCR products were  sequenced in both directions by sanger sequencing. .
Mutational analysis
As shown in figure 1, a new in-frame homozygous deletion c.1052-1054CCT in exon 6 was identified that reported for the first time. 17α-hydroxylase deficiency was first pronounced by Biglieri and colleagues (15), who was phenotypically female and presented with sexual infantilism, primary amenorrhea and hypertension.

Table I. Clinical and hormonal characteristics

Table II. Primers for CYP17A1 amplification

Figure 1. (A) Schematic representation of CYP17A1 gene location on chr.10.
(B) Sanger sequence chromatogram of the CYP17A1 gene show three nucleotide deletion position 1552–1554 within exon 6 (deletion of 351Leu in protein and CCT deletion on cDNA sequence).

17α-hydroxylase and 17, 20-lyase deficiencies are rare types of CAH which make up ~1% of all CAH patients (16). "In general, the majority of patients with CAH present with hypertension and primary gonadal failure during adolescence and adulthood, however, a few individuals are reported to be normotensive at the time of diagnosis" (7, 9). The deficiency of 17a-hydroxylase is a rare reason of CAH, with little more than 100 cases reported (17). 17α-hydroxylase deficiency was first described in a 35-year-old patient in 1966 by Biglieri and co-workers, who was phenotypically female and presented with hyperten­sion, sexual infantilism, and primary amenorrhea. In the complete deficiency of CYP17A1(CDC), the hormonal alterations are summed up as sex steroids and cortisol insufficiencies with mineralocorticoids excessiveness. All afflicted individuals were born with sexual infantilism and incapable of  secondary sexual characteristics development (18). Isolated 17,20-lyase deficiency (ILD) was first described in boys with a disorder of sex development (DSD) (11, 19). In addition to CYP17A1gene, mutations in its redox partner POR gene, which encodes protein P450 oxidoreductase, can eliminate the 17,20-lyase activity (ILD) of CYP17A1, which is characterized by abnormal sexual development and hypertension (20). lastly, the purest form of ILD results from defects in the CYB5A gene (21), encoding the allosteric activator b5, which selectively give rise to the ILD. These individuals maintain a hint of ILD, about 10% of normal, which leads to DSD in 46, XY males.
Symptoms can be briefly listed as hypertension, primary amenorrhea, and ambiguous genitalia. In this case, unlike CDC, the levels of most 17-hydroxysteroids were elevated, suggesting exclusive impairment of ILD. Moreover, the level of cortisol as opposed to in CDC patients exists in the normal range which further rules out the impairment of 17-hydroxylase activity. The alteration in 351Leu which lies in the redox partner-binding domain of P450c17 leads to an impairment in lyase activity of P450c17 (14, 19), in other words, disrupt interactions of redox partner proteins with CYP17A1.
In sum, this case manifested typical feature of 17α-hydroxylase and 17,20-lyase deficiencies (e.g., hypertension and ambiguous genitalia). This study is the first paper to report an in-frame deletion which results in isolated 17, 20-lyase deficiency, and this mutation might be used for diagnosis in other patients with distinctive clinical symptoms. Identification of 17α-hydroxylase/17,20 lyase deficiency was confirmed by the particular profile of adrenal steroid levels, and further confirmation by CYP17A mutation analysis.
Our research group thanks the patients and their families for their cooperation.
Conflict of Interest
The authors declare no conflict of interest.
Type of Study: Case Report |

1. Merke DP, Bornstein SR, Avila NA, Chrousos GP. NIH conference. Future directions in the study and management of congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Ann Intern Med 2002; 136: 320-334. [DOI:10.7326/0003-4819-136-4-200202190-00012] [PMID]
2. DeVore NM, Scott EE. Structures of cytochrome P450 17A1 with prostate cancer drugs abiraterone and TOK-001. Nature 2012; 482: 116-119. [DOI:10.1038/nature10743] [PMID] [PMCID]
3. Matteson KJ, Picado-Leonard J, Chung BC, Mohandas TK, Miller WL. Assignment of the gene for adrenal p450cl7 (steroid 17α-hydr0xylase⁄ 17, 20 lyase) to human chromosome 10. J Clin Endocrinol Metab 1986; 63: 789-791. [DOI:10.1210/jcem-63-3-789] [PMID]
4. Picado-Leonard J, Miller WL. Cloning and sequence of the human gene for P450cl7 (steroid 17α-hydroxylase/17, 20 lyase): similarity with the gene for P450c21. DNA 1987; 6: 439-448. [DOI:10.1089/dna.1987.6.439] [PMID]
5. Chung BC, Picado-Leonard J, Haniu M, Bienkowski M, Hall PF, Shively JE, et al. Cytochrome P450c17 (steroid 17 alpha-hydroxylase/17, 20 lyase): cloning of human adrenal and testis cDNAs indicates the same gene is expressed in both tissues. Proc Nati Acad Sci USA 1987; 84: 407-411. [DOI:10.1073/pnas.84.2.407] [PMID] [PMCID]
6. Miller WL, Auchus RJ. The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders. Endocr Rev 2011; 32: 81-151. [DOI:10.1210/er.2010-0013] [PMID] [PMCID]
7. Yanase T, Simpson ER, Waterman MR. 17α-hydroxylase/17, 20-lyase deficiency: from clinical investigation to molecular definition. Endocr Rev 1991; 12: 91-108. [DOI:10.1210/edrv-12-1-91] [PMID]
8. Krone N, Dhir V, Ivison HE, Arlt W. Congenital adrenal hyperplasia and P450 oxidoreductase deficiency. Clin Endocrinol 2007; 66: 162-172. [DOI:10.1111/j.1365-2265.2006.02740.x] [PMID]
9. Auchus RJ. The genetics, pathophysiologx, and management of human deficiencies of P450c17. Endocrinol Metab Clin North Am 2001; 30: 101-119. [DOI:10.1016/S0889-8529(08)70021-5]
10. Biason-Lauber A, Leiberman E, Zachmann M. A single amino acid substitution in the putative redox partner-binding site of P450c17 as cause of isolated 17, 20-lyase deficiency. J Clin Endocrinol Metab 1997; 82: 3807-3812. [DOI:10.1210/jc.82.11.3807]
11. Sherbet DP, Tiosano D, Kwist KM, Hochberg Z, Auchus RJ. CYP17 mutation E305G causes isolated 17, 20-lyase deficiency by selectively altering substrate binding. J Biol Chem 2003; 278: 48563-48569. [DOI:10.1074/jbc.M307586200] [PMID]
12. Turkkahraman D, Guran T, Ivison H, Griffin A, Vijzelaar R, Krone N. Identification of a novel large CYP17A1 deletion by MLPA analysis in a family with classic 17α-hydroxylase deficiency. Sex Dev 2015; 9: 91-97. [DOI:10.1159/000375183] [PMID]
13. Brooke AM, Taylor NF, Shepherd JH, Gore ME, Ahmad T, Lin L, et al. A novel point mutation in P450c17 (CYP17) causing combined 17α-hydroxylase/17, 20-lyase deficiency. J Clin Endocrinol Metab 2006; 91: 2428-2431. [DOI:10.1210/jc.2005-2653] [PMID]
14. van Den Akker EL, Koper JW, Boehmer AL, Themmen AP, Verhoef-Post M, Timmerman MA, et al. Differential inhibition of 17α-hydroxylase and 17, 20-lyase activities by three novel missense CYP17 mutations identified in patients with P450c17 deficiency. J Clin Endocrinol Metabo 2002; 87: 5714-5721. [DOI:10.1210/jc.2001-011880] [PMID]
15. Oh YK, Ryoo U, Kim D, Cho SY, Jin DK, Yoon BK, et al. 17α-hydroxlyase/17, 20-lyase deficiency in three siblings with primary amenorrhea and absence of secondary sexual development. J Pediatr Adolesc Gynecol 2012; 25: e103-e105. [DOI:10.1016/j.jpag.2012.05.008] [PMID]
16. Biglieri EG, Herron MA, Brust N. 17-hydroxylation deficiency in man. J Clin Invest 1966; 45: 1946-1954. [DOI:10.1172/JCI105499] [PMID] [PMCID]
17. Speroff L, Fritz MA. Clinical gynecologic endocrinology and infertility. 8th ed. Philadelphia: Lipppincott Williams & Wilkins; 2011.
18. Attard G, Reid AH, Auchus RJ, Hughes BA, Cassidy AM, Thompson E, et al. Clinical and biochemical consequences of CYP17A1 inhibition with abiraterone given with and without exogenous glucocorticoids in castrate men with advanced prostate cancer. J Clin Endocrinol Metab 2012; 97: 507-516. [DOI:10.1210/jc.2011-2189] [PMID]
19. Geller DH, Auchus RJ, Mendonça BB, Miller WL. The genetic and functional basis of isolated 17, 20-lyase deficiency. Nat Genet 1997; 17: 201-205. [DOI:10.1038/ng1097-201] [PMID]
20. Hershkovitz E, Parvari R, Wudy SA, Hartmann MF, Gomes LG, Loewental N, et al. Homozygous mutation G539R in the gene for P450 oxidoreductase in a family previously diagnosed as having 17, 20-lyase deficiency. J Clin Endocrinol Metab 2008; 93: 3584-3588. [DOI:10.1210/jc.2008-0051] [PMID] [PMCID]
21. Kok RC, Timmerman MA, Wolffenbuttel KP, Drop SL, de Jong FH. Isolated 17, 20-lyase deficiency due to the cytochrome b5 mutation W27X. J Clin Endocrinol Metab 2010; 95: 994-999. [DOI:10.1210/jc.2008-1745] [PMID]

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