Journal of Endocrinological Investigation

, Volume 27, Issue 6, pp 583–590 | Cite as

Clinical manifestations and hormonal profile of two women with Cushing’s disease and mild deficiency of 21-hydroxylase

  • M. Boronat
  • A. Carrillo
  • A. Ojeda
  • J. Estrada
  • B. Ezquieta
  • F. Marín
  • F. J. Nóvoa
Case Report


The development of Cushing’s disease among patients with deficiency of 21-hy-droxylase has not been observed to date. The clinical manifestations and the hormonal profile of this exceptional association are herein described through the study of two cases. The first one was a 39-yr-old woman who had undergone non-curative transsphenoidal surgery for a pituitary-dependent Cushing’s syndrome 12 yr before. She showed hypertension, central obesity, severe hirsutism, alopecia and hyperpigmentation. Urinary excretion of cortisol was normal, but ACTH levels were very high and hormonal dynamic studies (cortisol circadian rhythm, insulin-induced hypoglycemia and dexamethasone suppression tests) revealed the qualitative disturbances that characterize Cushing’s disease. Serum concen-trations of androstenedione, free testosterone and 17-hydroxyprogesterone were clearly increased. Reexamination of the tissue samples from previous surgery confirmed the presence of an ACTH-producing pituitary adenoma. CYP21 gene analysis found the splicing 655G mutation at intron 2 and the V281L mutation at exon 7. The second case was a 21-yr-old woman who was diagnosed with pituitary ACTH-dependent Cushing’s syndrome according to unequivocal clinical and laboratory findings. However, hirsutism was particularly severe and both serum androgens and 17-hydroxyprogesterone were elevated. The patient was heterozygote for a large conversion of CYP21 gene. In these cases, the clinical and biochemical expression of Cushing’s syndrome was determined by the different severity of 21-hy-droxylase deficiency and the subsequent residual ability of adrenal cortex to synthesize cortisol.


Pituitary adenoma 21-hydroxylase Cushing’s disease congenital adrenal hyperplasia 


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  1. 1.
    Kubota T, Hayashi M, Kabuto M, et al. Corticotroph cell hyperplasia in a patient with Addison disease: a case report. Surg Neurol 1992, 37: 441–7.PubMedCrossRefGoogle Scholar
  2. 2.
    Krautli B, Muller J, Landolt AM, von Schulthess F. ACTH-pro-ducing pituitary adenomas in Addison’s disease: two cases treated by transsphenoidal microsurgery. Acta Endocrinol (Copenh) 1982, 99: 357–63.Google Scholar
  3. 3.
    White PC, Speiser PW. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Endocr Rev 2000, 21: 245–91.PubMedGoogle Scholar
  4. 4.
    White PC, New MI, Dupont B. Molecular cloning of steroid 21-hydroxylase. Ann N Y Acad Sci 1985, 458: 273–87.CrossRefGoogle Scholar
  5. 5.
    Ezquieta B, Oliver A, Gracia R, Gancedo PG. Analysis of steroid 21-hydroxylase gene in the Spanish population. Hum Genet 1995, 96: 198–204.PubMedCrossRefGoogle Scholar
  6. 6.
    López J, Barceló B, Lucas T, et al. Petrosal sinus sampling for diagnosis of Cushing’s disease: evidence of false negative results. Clin Endocrinol (Oxf) 1996, 45: 147–56.CrossRefGoogle Scholar
  7. 7.
    Estrada J, Boronat M, Mielgo M, et al. The long-term outcome of pituitary irradiation after unsuccessful transsphenoidal surgery in Cushing’s disease. N Engl J Med 1997, 336: 172–7.PubMedCrossRefGoogle Scholar
  8. 8.
    Frisch H, Parth K, Schober E, Swoboda W. Circadian patterns of plasma cortisol, 17-hydroxyprogesterone and testosterone in congenital adrenal hyperplasia. Arch Dis Child 1981, 56: 208–13.PubMedCrossRefPubMedCentralGoogle Scholar
  9. 9.
    Estrada J, García-Uría J, Lamas C, et al. The complete normalization of the adrenocortical function as the criterion of cure after transsphenoidal surgery for Cushing’s disease. J Clin Endocrinol Metab 2001, 86: 5696–9.Google Scholar
  10. 10.
    Al-Saadi N, Diederich S, Oelkers W. A very high dose dex-amethasone suppression test for differential diagnosis of Cushing’s syndrome. Clin Endocrinol (Oxf) 1998, 48: 45–51.CrossRefGoogle Scholar
  11. 11.
    Thorner MO, Lee Vance M, Laws ER, Horvath E, Kovacs K. The anterior pituitary. In: Wilson JD, Foster DW, Kronenberg HM, Larsen PR eds. Williams Textbook of Endocrinology. 9th ed. Philadelphia: Saunders. 1998, 249–340.Google Scholar
  12. 12.
    Moran C, Azziz R, Carmina E, et al. 21-Hydroxylase-deficient nonclassic adrenal hyperplasia is a progressive disorder: a multicenter study. Am J Obstet Gynecol 2000, 183: 1468–74.PubMedCrossRefGoogle Scholar
  13. 13.
    Falke TH, van Seters AP, Schaberg A, Moolenaar AJ. Computed tomography in untreated adults with virilizing congenital adrenal cortical hyperplasia. Clin Radiol 1986, 37: 155–60.PubMedCrossRefGoogle Scholar
  14. 14.
    Jaresch S, Kornely E, Kley HK, Schlaghecke R. Adrenal inci-dentaloma and patients with homozygous or heterozygous congenital adrenal hyperplasia. J Clin Endocrinol Metab 1992, 74: 685–9.PubMedGoogle Scholar
  15. 15.
    Witchel SF, Lee PA, Suda-Hartman M, Hoffman EP. Hyperan-drogenism and manifesting heterozygotes for 21-hydroxy-lase deficiency. Biochem Mol Med 1997, 62: 151–8.PubMedCrossRefGoogle Scholar
  16. 16.
    Kaltsas GA, Korbonits M, Isidori AM, et al. How common are polycystic ovaries and the polycystic ovarian syndrome in women with Cushing’s syndrome? Clin Endocrinol (Oxf) 2000, 53: 493–500.CrossRefGoogle Scholar
  17. 17.
    Barbetta L, Dall’Asta C, Re T, Colombo P, Travaglini P, Ambrosi B. Androgen secretion in ectopic ACTH syndrome and in Cushing’s disease: modifications before and after surgery. Horm Metab Res 2001, 33: 596–601.PubMedCrossRefGoogle Scholar
  18. 18.
    Zarrilli L, Colao A, Merola B, et al. Corticotropin-releasing hormone test: improvement of the diagnostic accuracy of simultaneous and bilateral inferior petrosal sinus sampling in patients with Cushing syndrome. World J Surg 1995, 19: 150–3.PubMedCrossRefGoogle Scholar
  19. 19.
    Bonelli FS, Huston J 3rd, Carpenter PC, Erickson D, Young WF Jr, Meyer FB. Adrenocorticotropic hormone-dependent Cushing’s syndrome: sensitivity and specificity of inferior petrosal sinus sampling. Am J Neuroradiol 2000, 21: 690–6.PubMedGoogle Scholar

Copyright information

© Italian Society of Endocrinology (SIE) 2004

Authors and Affiliations

  • M. Boronat
    • 1
  • A. Carrillo
    • 1
  • A. Ojeda
    • 1
  • J. Estrada
    • 2
  • B. Ezquieta
    • 3
  • F. Marín
    • 4
  • F. J. Nóvoa
    • 1
  1. 1.Section of Endocrinology and NutritionHospital Universitario InsularLas Palmas de Gran CanariaSpain
  2. 2.Service of EndocrinologyCliníca Puerta de HierroOkayamaJapan
  3. 3.Service of BiochemistryHospital Gregorio MarañónMadridSpain
  4. 4.Department of Cell Biology, Faculty of MedicineUniversidad ComplutenseMadridSpain

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