Clinical Research
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Behçet Hastalığı Patogenezinde 21-Hidroksilaz Eksikliğinin Rolü

Year 2018, Volume: 81 Issue: 1, 11 - 16, 12.03.2018
https://doi.org/10.18017/iuitfd.390041

Abstract

Amaç: Akne benzeri deri lezyonlarının sıklığı
ve hastalığın erkeklerde daha ağır seyretmesi Behçet hastalığı (BH)
patogenezinde seks hormonlarının rolünün olabileceğini düşündürmektedir.
HLA-B51 BH için en önemli genetik duyarlılık faktörüdür. Konjenital adrenal
hiperplazilerin (KAH) çoğundan sorumlu olan CYP21A2 geni kromozom 6p21.3’deki
MHC bölgesinde yerleşimlidir. Bu çalışmada CYP21A2 genindeki olası bazı
mutasyonların HLA-B51 ile bağlantı dengesizliği göstererek 21-hidroksilaz
eksikliğine ve bunun sonucunda androjen fazlalığına yol açarak BH patogenezine
katkı yapabileceği hipotezini araştırmayı amaçladık.

Gereç ve Yöntem: Çalışma grubunu 18 sağlıklı
kontrol, 29 BH olan hasta ve 15 ankilozan spondilit (AS) hastası oluşturdu.
Bütün hastalara ACTH uyarı testi yapıldı. Bazal ve ACTH uyarısı sonrası serum
kortizol ve 17-OH-progesteron (17-OH-P) düzeyleri ve bazal
dehidroepiandrosteron sülfat (DHEA-S), total testosteron ve seks hormonu bağlayıcı
globulin (SHBG) düzeyleri ölçüldü.

Bulgular: Kılavuzların önerdiği şekilde,
klasik olmayan KAH tanısı için 17-OH-P için eşik değer olarak 10 ng/mL alındı.
ACTH uyarısı sonrası 3 BH (%10,3) ve 5 AS hastasının (%33,3) 17-OH-P düzeyleri
yüksek bulundu. Bu hastaların klasik olmayan KAH hastaları ya da KAH
mutasyonları için taşıyıcı olabileceği düşünüldü. Belirgin aknesi olan 8 BH’dan
üçünün biyokimyasal değerleri klasik olmayan KAH ile uyumluydu. BH olanların
ortalama total testosteron düzeylerinin sağlıklı kontrollerinkinden anlamlı
olarak düşük olduğu görüldü.  Bununla
birlikte 17-OH-P düzeyi yüksek olan hastalarda testosteron düzeyleri normaldi.







Sonuç: Bu pilot çalışmada BH ve AS hastalarının
bir grubunda ACTH uyarısı sonrası yüksek 17-OH-P değerleri gözlemledik.
Bulgularımız HLA-B allelleri ile bağlantı dengesizliği gösteren olası
21-hidroksilaz eksikliğinin patogeneze katkısının olabileceğini düşündürmekte
ve verilerin genetik çalışmalarla doğrulanmasını gerektirmektedir.

References

  • 1. Gul A. Pathogenesis of Behcet's disease: autoinflammatory features and beyond. Semin Immunopathol 2015;37 (4): 413-8.
  • 2. Gul A. Genetics of Behcet's disease: lessons learned from genomewide association studies. Curr Opin Rheumatol 2014;26 (1): 56-63.
  • 3. Yazici H, Tuzun Y, Pazarli H, Yurdakul S, Ozyazgan Y, Ozdogan H, et al. Influence of age of onset and patient's sex on the prevalence and severity of manifestations of Behcet's syndrome. Ann Rheum Dis 1984;43 (6): 783-9.
  • 4. Tugal-Tutkun I, Onal S, Altan-Yaycioglu R, Altunbas HH, Urgancioglu M. Uveitis in Behcet disease: an analysis of 880 patients. Am J Ophthalmol 2004;138 (3): 373-80.
  • 5. Yazici H, Mat C, Deniz S, Iscimen A, Yurdakul S, Tuzun Y, Hekim N, Yazici Y. Sebum production is increased in Behçet's syndrome and even more so in rheumatoid arthritis. Clin Exp Rheumatol 1987;5 (4): 371-4.
  • 6. Dupont B, Oberfield SE, Smithwick EM, Lee TD, Levine LS. Close genetic linkage between HLA and congenital adrenal hyperplasia (21-hydroxylase deficiency). Lancet 1977;2 (8052-8053): 1309-12.
  • 7. Speiser PW, Azziz R, Baskin LS, Ghizzoni L, Hensle TW, Merke DP, et al. Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2010;95 (9): 4133-60.
  • 8. Witchel SF, Azziz R. Nonclassic congenital adrenal hyperplasia. Int J Pediatr Endocrinol 2010;2010 625105.
  • 9. Levine LS, Zachmann M, New MI, Prader A, Pollack MS, O'Neill GJ, et al. Genetic mapping of the 21-hydroxylase-deficiency gene within the HLA linkage group. N Engl J Med 1978;299 (17): 911-5.
  • 10. Bercovici JP, Khoury S, Le Fur JM, Saleun JP, Nahoul K, Scholler R. Hormonal profiles of heterozygotes in humans for 21-hydroxylase deficiency defined by HLA B typing. J Steroid Biochem 1981;14 (10): 1049-54.
  • 11. Pollack MS, Keenan B, Christiansen FT, Cobain TJ, Dawkins RL, Clayton G. The immunological detection of a 21-OH deficiency mutation HLA supratype. Am J Hum Genet 1986;38 (5): 688-98.
  • 12. White PC, Werkmeister J, New MI, Dupont B. Steroid 21-hydroxylase deficiency and the major histocompatibility complex. Hum Immunol 1986;15 (4): 404-15.
  • 13. Velasco FJ, Pico AM, Munoz C, Mauri M, de la Sen ML. [A genetic and hormonal study of 5 patients with the nonclassical form of congenital adrenal hyperplasia due to 21-hydroxylase deficiency]. Med Clin (Barc) 1992;99 (3): 81-6.
  • 14. Parlato F, Pisano G, Misiano G, Cosentini E, Cacciapuoti C, Cavalcanti MR, et al. HLADR5 and C4BQO high frequency and antinuclear antibodies positivity in patients with 21 hydroxylase deficiency from Campania region. J Endocrinol Invest 1992;15 (6): 429-36.
  • 15. Carmina E, Dewailly D, Escobar-Morreale HF, Kelestimur F, Moran C, Oberfield S, et al. 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 (5): 580-99.
  • 16. Sahin Y, Kelestimur F. The frequency of late-onset 21-hydroxylase and 11 beta-hydroxylase deficiency in women with polycystic ovary syndrome. Eur J Endocrinol 1997;137 (6): 670-4.
  • 17. Yarman S, Dursun A, Oguz F, Alagol F. The prevalence, molecular analysis and HLA typing of late-onset 21-hydroxylase deficiency in Turkish woman with hirsutism and polycystic ovary. Endocr J 2004;51 (1): 31-6.
  • 18. Unluhizarci K, Kula M, Dundar M, Tanriverdi F, Israel S, Colak R, et al. The prevalence of non-classic adrenal hyperplasia among Turkish women with hyperandrogenism. Gynecol Endocrinol 2010;26 (2): 139-43.
  • 19. 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.
  • 20. Kirac D, Guney AI, Akcay T, Guran T, Ulucan K, Turan S, et al. The frequency and the effects of 21-hydroxylase gene defects in congenital adrenal hyperplasia patients. Ann Hum Genet 2014;78 (6): 399-409.
  • 21. Escobar-Morreale HF, Sanchon R, San Millan JL. A prospective study of the prevalence of nonclassical congenital adrenal hyperplasia among women presenting with hyperandrogenic symptoms and signs. J Clin Endocrinol Metab 2008;93 (2): 527-33.
  • 22. Ghizzoni L, Cappa M, Vottero A, Ubertini G, Carta D, Di Iorgi N, et al. Relationship of CYP21A2 genotype and serum 17-hydroxyprogesterone and cortisol levels in a large cohort of Italian children with premature pubarche. Eur J Endocrinol 2011;165 (2): 307-14.
  • 23. Azziz R, Dewailly D, Owerbach D. Clinical review 56: Nonclassic adrenal hyperplasia: current concepts. J Clin Endocrinol Metab 1994;78 (4): 810-5.
  • 24. Gooren LJ, Giltay EJ, van Schaardenburg D, Dijkmans BA. Gonadal and adrenal sex steroids in ankylosing spondylitis. Rheum Dis Clin North Am 2000;26 (4): 969-87.
  • 25. Gerencer M, Tajic M, Kerhin-Brkljacic V, Kastelan A. An association between serum testosterone level and HLA phenotype. Immunol Lett 1982;4 (3): 155-8.

The Role of 21-Hydroxylase Deficiency in The Pathogenesis of Behçet Disease

Year 2018, Volume: 81 Issue: 1, 11 - 16, 12.03.2018
https://doi.org/10.18017/iuitfd.390041

Abstract

Objective: Acne-like skin lesions and more
severe disease course in males suggest a role for sex hormones in the
pathogenesis of Behçet disease (BD). HLA-B51 is the main genetic susceptibility
factor for BD, and CYP21A2 gene responsible for most of congenital adrenal
hyperplasia (CAH) is located within the MHC locus on chromosome 6p21.3. We
aimed to investigate the possible role of 21-hydroxylase deficiency in linkage
disequilibrium with HLA-B51 and causing androgen excess.

Materials and Methods: We studied 18
healthy controls, 29 BD patients and 15 patients with ankylosing spondylitis
(AS). All subjects underwent ACTH stimulation test. Basal and stimulated serum
cortisol and 17-OH-progesterone (17-OH-P) levels and basal
dehydroepiandrosterone sulfate (DHEA-S), total testosterone and sex hormone
binding globulin (SHBG) levels were measured.

Results: According to current guidelines,
we accepted 10 ng/mL as the cut-off point for 17-OH-P to define non-classic CAH
(NCAH). After ACTH stimulation 3 of BD patients (10.3%) and 5 AS patients
(33.3%) had high 17-OH-P concentrations. Those individuals were considered as
NCAH or possible carriers for CAH mutations. Three out of 8 BD patients with
prominent acne were identified as NCAH biochemically. Mean total testosterone
levels of BD patients were significantly lower than those of healthy controls,
however these levels were normal in BD patients with high 17-OH-P.







Conclusion: This preliminary work
documented high 17-OH-P levels following ACTH stimulation in a subset of BD and
AS patients, and genetic studies are necessary to investigate the role of
21-hydroxylase deficiency in association with HLA-B alleles in their
pathogenesis.

References

  • 1. Gul A. Pathogenesis of Behcet's disease: autoinflammatory features and beyond. Semin Immunopathol 2015;37 (4): 413-8.
  • 2. Gul A. Genetics of Behcet's disease: lessons learned from genomewide association studies. Curr Opin Rheumatol 2014;26 (1): 56-63.
  • 3. Yazici H, Tuzun Y, Pazarli H, Yurdakul S, Ozyazgan Y, Ozdogan H, et al. Influence of age of onset and patient's sex on the prevalence and severity of manifestations of Behcet's syndrome. Ann Rheum Dis 1984;43 (6): 783-9.
  • 4. Tugal-Tutkun I, Onal S, Altan-Yaycioglu R, Altunbas HH, Urgancioglu M. Uveitis in Behcet disease: an analysis of 880 patients. Am J Ophthalmol 2004;138 (3): 373-80.
  • 5. Yazici H, Mat C, Deniz S, Iscimen A, Yurdakul S, Tuzun Y, Hekim N, Yazici Y. Sebum production is increased in Behçet's syndrome and even more so in rheumatoid arthritis. Clin Exp Rheumatol 1987;5 (4): 371-4.
  • 6. Dupont B, Oberfield SE, Smithwick EM, Lee TD, Levine LS. Close genetic linkage between HLA and congenital adrenal hyperplasia (21-hydroxylase deficiency). Lancet 1977;2 (8052-8053): 1309-12.
  • 7. Speiser PW, Azziz R, Baskin LS, Ghizzoni L, Hensle TW, Merke DP, et al. Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2010;95 (9): 4133-60.
  • 8. Witchel SF, Azziz R. Nonclassic congenital adrenal hyperplasia. Int J Pediatr Endocrinol 2010;2010 625105.
  • 9. Levine LS, Zachmann M, New MI, Prader A, Pollack MS, O'Neill GJ, et al. Genetic mapping of the 21-hydroxylase-deficiency gene within the HLA linkage group. N Engl J Med 1978;299 (17): 911-5.
  • 10. Bercovici JP, Khoury S, Le Fur JM, Saleun JP, Nahoul K, Scholler R. Hormonal profiles of heterozygotes in humans for 21-hydroxylase deficiency defined by HLA B typing. J Steroid Biochem 1981;14 (10): 1049-54.
  • 11. Pollack MS, Keenan B, Christiansen FT, Cobain TJ, Dawkins RL, Clayton G. The immunological detection of a 21-OH deficiency mutation HLA supratype. Am J Hum Genet 1986;38 (5): 688-98.
  • 12. White PC, Werkmeister J, New MI, Dupont B. Steroid 21-hydroxylase deficiency and the major histocompatibility complex. Hum Immunol 1986;15 (4): 404-15.
  • 13. Velasco FJ, Pico AM, Munoz C, Mauri M, de la Sen ML. [A genetic and hormonal study of 5 patients with the nonclassical form of congenital adrenal hyperplasia due to 21-hydroxylase deficiency]. Med Clin (Barc) 1992;99 (3): 81-6.
  • 14. Parlato F, Pisano G, Misiano G, Cosentini E, Cacciapuoti C, Cavalcanti MR, et al. HLADR5 and C4BQO high frequency and antinuclear antibodies positivity in patients with 21 hydroxylase deficiency from Campania region. J Endocrinol Invest 1992;15 (6): 429-36.
  • 15. Carmina E, Dewailly D, Escobar-Morreale HF, Kelestimur F, Moran C, Oberfield S, et al. 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 (5): 580-99.
  • 16. Sahin Y, Kelestimur F. The frequency of late-onset 21-hydroxylase and 11 beta-hydroxylase deficiency in women with polycystic ovary syndrome. Eur J Endocrinol 1997;137 (6): 670-4.
  • 17. Yarman S, Dursun A, Oguz F, Alagol F. The prevalence, molecular analysis and HLA typing of late-onset 21-hydroxylase deficiency in Turkish woman with hirsutism and polycystic ovary. Endocr J 2004;51 (1): 31-6.
  • 18. Unluhizarci K, Kula M, Dundar M, Tanriverdi F, Israel S, Colak R, et al. The prevalence of non-classic adrenal hyperplasia among Turkish women with hyperandrogenism. Gynecol Endocrinol 2010;26 (2): 139-43.
  • 19. 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.
  • 20. Kirac D, Guney AI, Akcay T, Guran T, Ulucan K, Turan S, et al. The frequency and the effects of 21-hydroxylase gene defects in congenital adrenal hyperplasia patients. Ann Hum Genet 2014;78 (6): 399-409.
  • 21. Escobar-Morreale HF, Sanchon R, San Millan JL. A prospective study of the prevalence of nonclassical congenital adrenal hyperplasia among women presenting with hyperandrogenic symptoms and signs. J Clin Endocrinol Metab 2008;93 (2): 527-33.
  • 22. Ghizzoni L, Cappa M, Vottero A, Ubertini G, Carta D, Di Iorgi N, et al. Relationship of CYP21A2 genotype and serum 17-hydroxyprogesterone and cortisol levels in a large cohort of Italian children with premature pubarche. Eur J Endocrinol 2011;165 (2): 307-14.
  • 23. Azziz R, Dewailly D, Owerbach D. Clinical review 56: Nonclassic adrenal hyperplasia: current concepts. J Clin Endocrinol Metab 1994;78 (4): 810-5.
  • 24. Gooren LJ, Giltay EJ, van Schaardenburg D, Dijkmans BA. Gonadal and adrenal sex steroids in ankylosing spondylitis. Rheum Dis Clin North Am 2000;26 (4): 969-87.
  • 25. Gerencer M, Tajic M, Kerhin-Brkljacic V, Kastelan A. An association between serum testosterone level and HLA phenotype. Immunol Lett 1982;4 (3): 155-8.
There are 25 citations in total.

Details

Primary Language English
Subjects Health Care Administration
Journal Section Clinical Research
Authors

Nurdan Gül 0000-0002-1187-944X

Ahmet Gül This is me 0000-0001-8219-3720

Murat İnanç This is me 0000-0002-6376-5583

Lale Öçal 0000-0003-3615-256X

Orhan Aral This is me 0000-0001-8550-9970

Faruk Alagöl This is me 0000-0002-6141-9038

Publication Date March 12, 2018
Submission Date February 5, 2018
Published in Issue Year 2018 Volume: 81 Issue: 1

Cite

APA Gül, N., Gül, A., İnanç, M., Öçal, L., et al. (2018). The Role of 21-Hydroxylase Deficiency in The Pathogenesis of Behçet Disease. Journal of Istanbul Faculty of Medicine, 81(1), 11-16. https://doi.org/10.18017/iuitfd.390041
AMA Gül N, Gül A, İnanç M, Öçal L, Aral O, Alagöl F. The Role of 21-Hydroxylase Deficiency in The Pathogenesis of Behçet Disease. İst Tıp Fak Derg. March 2018;81(1):11-16. doi:10.18017/iuitfd.390041
Chicago Gül, Nurdan, Ahmet Gül, Murat İnanç, Lale Öçal, Orhan Aral, and Faruk Alagöl. “The Role of 21-Hydroxylase Deficiency in The Pathogenesis of Behçet Disease”. Journal of Istanbul Faculty of Medicine 81, no. 1 (March 2018): 11-16. https://doi.org/10.18017/iuitfd.390041.
EndNote Gül N, Gül A, İnanç M, Öçal L, Aral O, Alagöl F (March 1, 2018) The Role of 21-Hydroxylase Deficiency in The Pathogenesis of Behçet Disease. Journal of Istanbul Faculty of Medicine 81 1 11–16.
IEEE N. Gül, A. Gül, M. İnanç, L. Öçal, O. Aral, and F. Alagöl, “The Role of 21-Hydroxylase Deficiency in The Pathogenesis of Behçet Disease”, İst Tıp Fak Derg, vol. 81, no. 1, pp. 11–16, 2018, doi: 10.18017/iuitfd.390041.
ISNAD Gül, Nurdan et al. “The Role of 21-Hydroxylase Deficiency in The Pathogenesis of Behçet Disease”. Journal of Istanbul Faculty of Medicine 81/1 (March 2018), 11-16. https://doi.org/10.18017/iuitfd.390041.
JAMA Gül N, Gül A, İnanç M, Öçal L, Aral O, Alagöl F. The Role of 21-Hydroxylase Deficiency in The Pathogenesis of Behçet Disease. İst Tıp Fak Derg. 2018;81:11–16.
MLA Gül, Nurdan et al. “The Role of 21-Hydroxylase Deficiency in The Pathogenesis of Behçet Disease”. Journal of Istanbul Faculty of Medicine, vol. 81, no. 1, 2018, pp. 11-16, doi:10.18017/iuitfd.390041.
Vancouver Gül N, Gül A, İnanç M, Öçal L, Aral O, Alagöl F. The Role of 21-Hydroxylase Deficiency in The Pathogenesis of Behçet Disease. İst Tıp Fak Derg. 2018;81(1):11-6.

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