Cushing's disease preceded by generalized glucocorticoid resistance

clinical consequences of a novel, dominant-negative glucocorticoid receptor mutation.

M. Karl, S. W. Lamberts, J. W. Koper, D. A. Katz, N. E. Huizenga, Tomoshige Kino, B. R. Haddad, M. R. Hughes, G. P. Chrousos

Research output: Contribution to journalArticle

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Abstract

Generalized glucocorticoid resistance is associated with chronic hyperactivation of the hypothalamic-pituitary-adrenal axis, compensating for impaired glucocorticoid receptor function. We report a unique patient with sporadic generalized glucocorticoid resistance who, at age 33, presented with infertility and hypertension and, at 38, developed pituitary Cushing's disease. Leukocyte-binding studies revealed normal affinity of the glucocorticoid receptor but a reduction of binding sites by 50%. [3H]thymidine incorporation by this patient's lymphocytes was not suppressible by dexamethasone. He had a novel heterozygous missense mutation in the glucocorticoid receptor gene (isoleucine 559 to asparagine 559). The mutant receptor exhibited a strong dominant-negative effect on the ability of the wild-type receptor to induce gene transcription in vitro. The mutation was present in all of the patient's cultured lymphoblasts and fibroblasts as well as in 50% of his sperm, as demonstrated by single-cell polymerase chain reaction; it was not present in his parents and seven siblings. This novel mutation was thus both de novo and present in the germ line. Immunohistochemical staining of this patient's pituitary corticotropinoma revealed accumulation of p53 protein, indicating the presence of a putative somatic oncogenic mutation in the p53 gene in the tumor cells. Investigation of the lymphoblast and skin fibroblast cultures for p53 abnormalities did not show any aberration. Thus, a novel de novo germ line mutation of the glucocorticoid receptor with strong dominant-negative activity caused severe sporadic generalized glucocorticoid resistance, which preceded corticotroph adenoma formation. The latter probably was due to the combined effects of chronic corticotroph hyperstimulation, decreased glucocorticoid negative feedback, and at least one subsequent somatic defect in the control of the cell cycle.

Original languageEnglish
Pages (from-to)296-307
Number of pages12
JournalProceedings of the Association of American Physicians
Volume108
Issue number4
Publication statusPublished - Jul 1996
Externally publishedYes

Fingerprint

Pituitary ACTH Hypersecretion
Glucocorticoid Receptors
Mutation
ACTH-Secreting Pituitary Adenoma
Fibroblasts
Corticotrophs
Aptitude
Germ-Line Mutation
Isoleucine
Asparagine
p53 Genes
Missense Mutation
Cell Cycle Checkpoints
Germ Cells
Thymidine
Infertility
Dexamethasone
Glucocorticoids
Genes
Spermatozoa

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Cushing's disease preceded by generalized glucocorticoid resistance : clinical consequences of a novel, dominant-negative glucocorticoid receptor mutation. / Karl, M.; Lamberts, S. W.; Koper, J. W.; Katz, D. A.; Huizenga, N. E.; Kino, Tomoshige; Haddad, B. R.; Hughes, M. R.; Chrousos, G. P.

In: Proceedings of the Association of American Physicians, Vol. 108, No. 4, 07.1996, p. 296-307.

Research output: Contribution to journalArticle

Karl, M. ; Lamberts, S. W. ; Koper, J. W. ; Katz, D. A. ; Huizenga, N. E. ; Kino, Tomoshige ; Haddad, B. R. ; Hughes, M. R. ; Chrousos, G. P. / Cushing's disease preceded by generalized glucocorticoid resistance : clinical consequences of a novel, dominant-negative glucocorticoid receptor mutation. In: Proceedings of the Association of American Physicians. 1996 ; Vol. 108, No. 4. pp. 296-307.
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