Female pseudohermaphroditism caused by a novel homozygous missense mutation of the GR gene

Berenice B. Mendonca, Maristela V. Leite, Margaret De Castro, Tomoshige Kino, Lucila L K Elias, Tania A S Bachega, Ivo J P Arnhold, George P. Chrousos, Ana Claudia Latronico

Research output: Contribution to journalArticle

87 Citations (Scopus)

Abstract

Familial glucocorticoid resistance is characterized by increased cortisol secretion without clinical evidence of hypercortisolism, but with manifestations of androgen and mineralocorticoid excess. This condition is mainly caused by mutations of the GR gene that cause inadequate transduction of the glucocorticoid signal in glucocorticoid target tissues. The clinical features of glucocorticoid resistance in females include hirsutism, acne, male pattern baldness, oligomenorrhea, and oligoanovulation. We describe here a new phenotype, female pseudohermaphroditism and severe hypokalemia, caused by a homozygous inactivating mutation of the GR gene. The proband was born with ambiguous genitalia from consanguineous parents and was mistreated as a 21-hydroxylase deficiency case since the age of 5 yr. She had very high levels of plasma ACTH (759 pg/ml or 167 pmol/liter) and high levels of cortisol (28-54 μg/dl or 772-1490 nmol/liter), androstenedione (5-14 ng/ml or 17-48 nmol/liter), T (174-235 ng/dl or 7-8 nmol/liter), and 17-hydroxyprogesterone (8-12 ng/ml or 24-36 nmol/liter). Her cortisol and 17-hydroxyprogesterone levels were not compatible with the diagnosis of classic congenital adrenal hyperplasia; furthermore, cortisol was not properly suppressed after dexamethasone administration (28 μg/d or 772 nmol/liter). Her laboratory evaluation indicated a diagnosis of glucocorticoid resistance. To investigate this puzzling clinical and biochemical picture, we analyzed both GR and CYP21 genes. Indeed, a homozygous T to C substitution at nucleotide 1844 in exon 5 of the GR gene was identified in the patient that caused a valine to alanine substitution at amino acid 571 in the ligand domain of the receptor. Her parents and an older sister were heterozygous for this mutation. A whole Epstein-Barr virus-transformed cell dexamethasone-binding assay revealed that this Ala571 mutant had a 6-fold reduction in binding affinity compared with the wild-type receptor. In a functional assay using mouse mammary tumor virus promoter-driven luciferase reporter gene, the mutant receptor displayed 10- to 50-fold less trans-activation activity than the wild-type receptor. In addition, a large heterozygous CYP21 conversion was identified in the patient and her father. In conclusion, we described the first case of female pseudohermaphroditism caused by a novel homozygous GR gene mutation. This phenotype indicates that pre- and postnatal virilization can occur in females with the glucocorticoid resistance syndrome.

Original languageEnglish
Pages (from-to)1805-1809
Number of pages5
JournalJournal of Clinical Endocrinology and Metabolism
Volume87
Issue number4
DOIs
Publication statusPublished - 2002
Externally publishedYes

Fingerprint

XX Disorders of Sex Development 46
Missense Mutation
Glucocorticoids
Genes
Hydrocortisone
17-alpha-Hydroxyprogesterone
Mutation
Dexamethasone
Viruses
Parents
Oligomenorrhea
Assays
Mouse mammary tumor virus
Virilism
Substitution reactions
Phenotype
Disorders of Sex Development
Congenital Adrenal Hyperplasia
Hirsutism
Mineralocorticoids

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Medicine(all)
  • Endocrinology
  • Clinical Biochemistry
  • Biochemistry, medical

Cite this

Mendonca, B. B., Leite, M. V., De Castro, M., Kino, T., Elias, L. L. K., Bachega, T. A. S., ... Latronico, A. C. (2002). Female pseudohermaphroditism caused by a novel homozygous missense mutation of the GR gene. Journal of Clinical Endocrinology and Metabolism, 87(4), 1805-1809. https://doi.org/10.1210/jc.87.4.1805

Female pseudohermaphroditism caused by a novel homozygous missense mutation of the GR gene. / Mendonca, Berenice B.; Leite, Maristela V.; De Castro, Margaret; Kino, Tomoshige; Elias, Lucila L K; Bachega, Tania A S; Arnhold, Ivo J P; Chrousos, George P.; Latronico, Ana Claudia.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 87, No. 4, 2002, p. 1805-1809.

Research output: Contribution to journalArticle

Mendonca, BB, Leite, MV, De Castro, M, Kino, T, Elias, LLK, Bachega, TAS, Arnhold, IJP, Chrousos, GP & Latronico, AC 2002, 'Female pseudohermaphroditism caused by a novel homozygous missense mutation of the GR gene', Journal of Clinical Endocrinology and Metabolism, vol. 87, no. 4, pp. 1805-1809. https://doi.org/10.1210/jc.87.4.1805
Mendonca, Berenice B. ; Leite, Maristela V. ; De Castro, Margaret ; Kino, Tomoshige ; Elias, Lucila L K ; Bachega, Tania A S ; Arnhold, Ivo J P ; Chrousos, George P. ; Latronico, Ana Claudia. / Female pseudohermaphroditism caused by a novel homozygous missense mutation of the GR gene. In: Journal of Clinical Endocrinology and Metabolism. 2002 ; Vol. 87, No. 4. pp. 1805-1809.
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