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Female Pseudohermaphroditism Caused by a Novel Homozygous Missense Mutation of the GR Gene

Unidade de Endocrinologia do Desenvolvimento e Laboratório de Hormônios e Genética Molecular, Disciplina de Endocrinologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo (B.B.M., T.A.S.B., A.E.C.B., I.J.P.A., A.C.L.), and Departamento de Fisiologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo (M.C., L.L.K.E.), 05403-900 São Paulo, Brazil; Universidade Federal do Rio Grande do Norte (M.V.L.), 59022-020 Natal, Brazil; and Pediatric and Reproductive Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health (T.K., G.P.C.), Bethesda, Maryland 20814

Address all correspondence and requests for reprints to: Berenice B. Mendonca, M.D., Hospital das Clínicas, Laboratório de Hormônios, Avenue Dr. Eneas de Carvalho Aguiar 155 PAMB, 2 andar Bloco 6, 05403-900, Sao Paulo Brazil. E-mail: . beremen{at}usp.br

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.

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