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

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 microg/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 microg/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 Ala(571) 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.

In humans, early cortisol biosynthesis provides a mechanism to safeguard female sexual development

“…In support of this model, loss of cortisol feedback by inactivation of the GR has previously been associated with disrupted female sexual differentiation and ambiguous genitalia at birth (although the patient also carried 1 disrupted allele of the CYP21 gene, this would be insufficient by itself to generate an intersex phenotype; ref. 24).…”

Genotype–phenotype correlation in a family with primary cortisol resistance: possible modulating effect of the ER22/23EK polymorphism.

“…At present, five different mutations have been identified in five different kindreds: C1844T (V571A), A2054T (D641V), G2317A (V729I), T2373G (I747M), and a 4-bp deletion at the 3 0 boundary of exon 6. In addition, five more mutations were described in sporadic cases: G1430A (R477H), G2035A (G679S), T1808A (I559N), T2318C (L773P), and T2209C (F737L) (7)(8)(9)(10)(11)(12)(13). The genotype has been identified as either homozygous mutation with autosomal recessive or heterozygous mutation with autosomal dominant transmission in the familial cases.…”

“…Although all such mutations in the LBD would lead to a decrease in ligand-binding affinity, some mutations were associated with delayed translocation to the nucleus after exposure to ligand (V571A, D641V, V729I, R477H, and G679S) or delayed interaction with certain coactivators (I559N, V571A, D641V, V729I, and I747M) (7)(8)(9)(10)(11)(12)(13). The ability of a heterozygous GR-a gene mutation (I559N and I747M) to exert a dominantnegative effect on the transcriptional activity of wildtype GR-a was due to the inhibition of nuclear translocation of the wild-type receptor (14).…”

Causas raras de pseudo-hermafroditismo feminino: quando suspeitar?

“…Até o momento, 6 mutações no gene do GR foram descritas, dentre os 30 casos ou membros assintomáticos de 10 famílias com SRGG relatados. Todas estas mutações localizam-se nos exons 5 a 9 do gene do GR (57)(58)(59)(60)(61)(62).…”

“…Mais recentemente, tivemos a oportunidade de estudar uma menina mulata nascida com genitália ambígua de um casamento cujos pais eram primos (62). Sua genitália caracterizava-se por clitoromegalia, fusão labioescrotal e presença de seio urogenital.…”