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Horm Metab Res 2015; 47(09): 662-667
DOI: 10.1055/s-0035-1549911
Endocrine Care
© Georg Thieme Verlag KG Stuttgart · New York

Prevalence and Clinical Outcome of CYP21A2 Gene Mutations in Patients with Nonfunctional Adrenal Incidentalomas

B. Kiedrowicz
1   Department of Endocrinology, Metabolic and Internal Diseases, Pomeranian Medical University, Szczecin, Poland
,
A. Binczak-Kuleta
2   Department of Clinical and Molecular Biochemistry, Pomeranian Medical University, Szczecin, Poland
,
J. Lubikowski
3   Department of Surgery, West Pomeranian Oncology Center, Szczecin, Poland
,
M. Koziolek
1   Department of Endocrinology, Metabolic and Internal Diseases, Pomeranian Medical University, Szczecin, Poland
,
E. Andrysiak-Mamos
1   Department of Endocrinology, Metabolic and Internal Diseases, Pomeranian Medical University, Szczecin, Poland
,
M. Ostanek-Panka
2   Department of Clinical and Molecular Biochemistry, Pomeranian Medical University, Szczecin, Poland
,
A. Ciechanowicz
2   Department of Clinical and Molecular Biochemistry, Pomeranian Medical University, Szczecin, Poland
,
A. Syrenicz
1   Department of Endocrinology, Metabolic and Internal Diseases, Pomeranian Medical University, Szczecin, Poland
› Author Affiliations
Further Information

Publication History

received 22 September 2014

accepted 08 April 2015

Publication Date:
13 May 2015 (online)

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Abstract

Adrenal tumors, discovered incidentally in approximately 4.5% of imaging procedures, are known as adrenal incidentalomas. Nonclassic congenital adrenal hyperplasia, mild form of 21-hydroxylase deficiency, may lead to the development of adrenocortical tumors. The aim of the study was to evaluate prevalence of the most common nonclassic mutations of CYP21A2 gene in patients with adrenal incidentalomas and investigate possible relationship with clinical outcome. One hundred adult patients with such lesions were enrolled. Clinical, imaging and biochemical evaluation were performed to rule out hormonal overproduction or potential malignancy. All subjects and a control group of 100 neonates were genotyped for P30L, P453S, and V281L mutations of CYP21A2 gene using direct sequencing. Clinical and imaging features as well as hormone levels were analyzed. Heterozygous CYP21A2 gene mutations were detected in 8 subjects but not in the neonates. Thus, the risk of carrying mutant allele was significantly higher in subjects with adrenal tumors (OR=8.7; 95% CI=2.23–389.56; p=0.003). Mean concentrations of renin, basal, and stimulated 17-hydroxyprogesterone were higher and ACTH was lower in the carriers than in the remaining subjects. Furthermore, the carriers had higher incidence of hypertension (100 vs. 52.1%, p=0.008) and diabetes (50 vs. 11.9%, p=0.003). ACTH-stimulated 17-hydroxyprogesterone levels varied widely among the carriers. In summary, prevalence of P30L, P453S, and V281L mutations of CYP21A2 gene is increased in patients with adrenocortical tumors. In these subjects, carrying the analyzed mutant alleles may increase the risk of diabetes and hypertension. ACTH-stimulation test does not satisfactorily predict presence of heterozygous CYP21A2 mutations in patients with adrenal tumors.

Key words

adrenogenital syndrome (AGS) - incidentaloma - adrenal tumor - adrenal adenoma - CYP21A2
 

  • References

  • 1 Mansmann G, Lau J, Balk E, Rothberg M, Miyachi Y, Bornstein SR. The clinically inapparent adrenal mass: update in diagnosis and management. Endocr Rev 2004; 25: 309-340
    CrossrefPubMedGoogle Scholar
  • 2 Hammarstedt L, Muth A, Wängberg B, Björneld L, Sigurjónsdóttir HA, Götherström G, Almqvist E, Widell H, Carlsson S, Ander S, Hellström M. Adrenal Study Group of Western Sweden . Adrenal lesion frequency: A prospective, cross-sectional CT study in a defined region, including systematic re-evaluation. Acta Radiol 2010; 51: 1149-1156
    CrossrefPubMedGoogle Scholar
  • 3 White PC, Speiser PW. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Endocr Rev 2000; 21: 245-291
    CrossrefPubMedGoogle Scholar
  • 4 Speiser PW, Azziz R, Baskin LS, Ghizzoni L, Hensle TW, Merke DP, Meyer-Bahlburg HFL, Miller WL, Montori VM, Oberfield SE, Ritzen M, White PC. Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2010; 95: 4133-4160
    CrossrefPubMedGoogle Scholar
  • 5 Witchel SF, Lee PA. Identification of heterozygotic carriers of 21-hydroxylase deficiency: sensitivity of ACTH stimulation tests. Am J Med Genet 1998; 76: 337-342
    CrossrefPubMedGoogle Scholar
  • 6 Ravichandran R, Lafferty F, McGinniss MJ, Taylor HC. Congenital adrenal hyperplasia presenting as massive adrenal incidentalomas in the sixth decade of life: report of two patients with 21-hydroxylase deficiency. J Clin Endocrinol Metab 1996; 81: 1776-1779
    CrossrefPubMedGoogle Scholar
  • 7 Kurtoğlu S, Atabek ME, Keskin M, Patiroglu TE. Adrenocortical adenoma associated with inadequately treated congenital adrenal hyperplasia. J Pediatr Endocrinol Metab 2003; 16: 1311-1314
    PubMedGoogle Scholar
  • 8 Moskvina V, Holmans P, Schmidt KM, Craddock N. Design of case-controls studies with unscreened controls. Ann Hum Genet 2005; 69: 566-576
    CrossrefPubMedGoogle Scholar
  • 9 American Diabetes Association . Standards of medical care in diabetes – 2008. Diabetes Care 2008; 31 (Suppl. 01) S12-S54
    CrossrefPubMedGoogle Scholar
  • 10 Mancia G, De Backer G, Dominiczak A, Cifkova R, Fagard R, Germano G, Grassi G, Heagerty AM, Kjeldsen SE, Laurent S, Narkiewicz K, Ruilope L, Rynkiewicz A, Schmieder RE, Boudier HAS, Zanchetti A. ESH-ESC Task Force on the Management of Arterial Hypertension . 2007 ESH-ESC Practice Guidelines for the Management of Arterial Hypertension: ESH-ESC Task Force on the Management of Arterial Hypertension. J Hypertens 2007; 25: 1751-1762
    CrossrefPubMedGoogle Scholar
  • 11 Terzolo M, Stigliano A, Chiodini I, Loli P, Furlani L, Arnaldi G, Reimondo G, Pia A, Toscano V, Zini M, Borretta G, Papini E, Garofalo P, Allolio B, Dupas B, Mantero F, Tabarin A. AME position statement on adrenal incidentaloma. Eur J Endocrinol 2011; 164: 851-870
    CrossrefPubMedGoogle Scholar
  • 12 Funder JW, Carey RM, Fardella C, Gomez-Sanchez CE, Mantero F, Stowasser M, Young WF, Montori VM. Case Detection, Diagnosis, and Treatment of Patients with Primary Aldosteronism: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2008; 93: 3266-3281
    Google Scholar
  • 13 Diagnosis and Treatment of Subclinical Hypercortisolism. J Clin Endocrinol Metab 2011; 96: 1223-1236
    CrossrefPubMedGoogle Scholar
  • 14 Jaresch S, Kornely E, Kley HK, Schlaghecke R. Adrenal incidentaloma and patients with homozygous or heterozygous congenital adrenal hyperplasia. J Clin Endocrinol Metab 1992; 74: 685-689
    CrossrefPubMedGoogle Scholar
  • 15 Barzon L, Maffei P, Sonino N, Pilon C, Baldazzi L, Balsamo A, Del Maschio O, Masi G, Trevisan M, Pacenti M, Fallo F. The role of 21-hydroxylase in the pathogenesis of adrenal masses: review of the literature and focus on our own experience. J Endocrinol Invest 2007; 30: 615-623
    CrossrefPubMedGoogle Scholar
  • 16 Seppel T, Schlaghecke R. Augmented 17 alpha-hydroxyprogesterone response to ACTH stimulation as evidence of decreased 21-hydroxylase activity in patients with incidentally discovered adrenal tumours (‘incidentalomas’). Clin Endocrinol (Oxf) 1994; 41: 445-451
    CrossrefPubMedGoogle Scholar
  • 17 Dall’Asta C, Barbetta L, Libé R, Passini E, Ambrosi B. Coexistence of 21-hydroxylase and 11 beta-hydroxylase deficiency in adrenal incidentalomas and in subclinical Cushing’s syndrome. Horm Res 2002; 57: 192-196
    CrossrefPubMedGoogle Scholar
  • 18 Grossrubatscher E, Vignati F, Possa M, Lohi P. The natural history of incidentally discovered adrenocortical adenomas: a retrospective evaluation. J Endocrinol Invest 2001; 24: 846-855
    Google Scholar
  • 19 Mantero F, Terzolo M, Arnaldi G, Osella G, Masini AM, Alì A, Giovagnetti M, Opocher G, Angeli A. A survey on adrenal incidentaloma in Italy. Study Group on Adrenal Tumors of the Italian Society of Endocrinology. J Clin Endocrinol Metab 2000; 85: 637-644
    CrossrefPubMedGoogle Scholar
  • 20 Patócs A, Tóth M, Barta C, Sasvári-Székely M, Varga I, Szücs N, Jakab C, Gláz E, Rácz K. Hormonal evaluation and mutation screening for steroid 21-hydroxylase deficiency in patients with unilateral and bilateral adrenal incidentalomas. Eur J Endocrinol 2002; 147: 349-355
    CrossrefPubMedGoogle Scholar
  • 21 Beuschlein F, Schulze E, Mora P, Gensheimer HP, Maser-Gluth C, Allolio B, Reincke M. Steroid 21-hydroxylase mutations and 21-hydroxylase messenger ribonucleic acid expression in human adrenocortical tumors. J Clin Endocrinol Metab 1998; 83: 2585-2588
    CrossrefPubMedGoogle Scholar
  • 22 Baumgartner-Parzer SM, Pauschenwein S, Waldhäusl W, Pölzler K, Nowotny P, Vierhapper H. Increased prevalence of heterozygous 21-OH germline mutations in patients with adrenal incidentalomas. Clin Endocrinol (Oxf) 2002; 56: 811-816
    CrossrefPubMedGoogle Scholar
  • 23 Wagnerova H, Lazúrová I, Habalová V, Dudásová D, Vrzgula A. The prevalence of 21-hydroxylase deficiency in adrenal incidentalomas – hormonal and mutation screening. Exp Clin Endocrinol Diabetes 2008; 116: 272-275
    Article in Thieme ConnectPubMedGoogle Scholar
  • 24 Kjellman M, Holst M, Bäckdahl M, Larsson C, Farnebo LO, Wedell A. No overrepresentation of congenital adrenal hyperplasia in patients with adrenocortical tumours. Clin Endocrinol (Oxf) 1999; 50: 343-346
    CrossrefPubMedGoogle Scholar
  • 25 Fitness J, Dixit N, Webster D, Torresani T, Pergolizzi R, Speiser PW, Day DJ. Genotyping of CYP21, linked chromosome 6p markers, and a sex-specific gene in neonatal screening for congenital adrenal hyperplasia. J Clin Endocrinol Metab 1999; 84: 960-966
    CrossrefPubMedGoogle Scholar
  • 26 Baumgartner-Parzer SM, Nowotny P, Heinze G, Waldhäusl W, Vierhapper H. Carrier frequency of congenital adrenal hyperplasia (21-hydroxylase deficiency) in a middle European population. J Clin Endocrinol Metab 2005; 90: 775-778
    CrossrefPubMedGoogle Scholar
  • 27 Ezquieta B, Ruano MLF, Dulín E, Arnao DR, Rodríguez A. Prevalence of frequent recessive diseases in the Spanish population through DNA analyses on samples from the neonatal screening. Med Clínica 2005; 125: 493-495
    PubMedGoogle Scholar
  • 28 Ezquieta B, Oyarzabal M, Barrio R, Luzuriaga C, Hermoso F, Lechuga JL, Quinteiro S, Rodríguez A, Labarta JI, Gutierrez Macias A, Gallego M, Bellón JM. Monogenic and Polygenic Models Detected in Steroid 21-Hydroxylase Deficiency-Related Paediatric Hyperandrogenism. Horm Res 2009; 71: 28-37
    PubMedGoogle Scholar
  • 29 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
    CrossrefPubMedGoogle Scholar
  • 30 Bachega TASS, Brenlha EML, Billerbeck AEC, Marcondes JAM, Madureira G, Arnhold IJP, Mendonca BB. Variable ACTH-stimulated 17-hydroxyprogesterone values in 21-hydroxylase deficiency carriers are not related to the different CYP21 gene mutations. J Clin Endocrinol Metab 2002; 87: 786-790
    CrossrefPubMedGoogle Scholar
  • 31 Speiser PW, Serrat J, New MI, Gertner JM. Insulin insensitivity in adrenal hyperplasia due to nonclassical steroid 21-hydroxylase deficiency. J Clin Endocrinol Metab 1992; 75: 1421-1424
    CrossrefPubMedGoogle Scholar
  • 32 Paula FJ, Gouveia LM, Paccola GM, Piccinato CE, Moreira AC, Foss MC. Androgen-related effects on peripheral glucose metabolism in women with congenital adrenal hyperplasia. Horm Metab Res 1994; 26: 552-556
    Article in Thieme ConnectPubMedGoogle Scholar
  • 33 Saygili F, Oge A, Yilmaz C. Hyperinsulinemia and insulin insensitivity in women with nonclassical congenital adrenal hyperplasia due to 21-hydroxylase deficiency: the relationship between serum leptin levels and chronic hyperinsulinemia. Horm Res 2005; 63: 270-274
    CrossrefPubMedGoogle Scholar
  • 34 Zhang H-J, Yang J, Zhang M-N, Liu C-Q, Xu M, Li X-J, Yang S-Y, Li X-Y. Metabolic disorders in newly diagnosed young adult female patients with simple virilizing 21-hydroxylase deficiency. Endocrine 2010; 38: 260-265
    CrossrefPubMedGoogle Scholar
  • 35 Peppa M, Boutati E, Koliaki C, Papaefstathiou N, Garoflos E, Economopoulos T, Hadjidakis D, Raptis SA. Insulin resistance and metabolic syndrome in patients with nonfunctioning adrenal incidentalomas: a cause-effect relationship?. Metabolism 2010; 59: 1435-1441
    CrossrefPubMedGoogle Scholar
  • 36 Morelli V, Donadio F, Eller-Vainicher C, Cirello V, Olgiati L, Savoca C, Cairoli E, Salcuni AS, Beck-Peccoz P, Chiodini I. Role of glucocorticoid receptor polymorphism in adrenal incidentalomas. Eur J Clin Invest 2010; 40: 803-811
    CrossrefPubMedGoogle Scholar
  • 37 Midorikawa S, Sanada H, Hashimoto S, Suzuki T, Watanabe T. The improvement of insulin resistance in patients with adrenal incidentaloma by surgical resection. Clin Endocrinol (oxf) 2001; 54: 797-804
    CrossrefPubMedGoogle Scholar