Estrogen alpha receptor inactivation: Different phenotypic severities among different studies and within the same family - 13/12/22
Résumé |
Context and objective |
Action of estrogen is mediated by nuclear alpha and beta receptors (ER) and by membrane receptors. Only three female and two male patients, from three families, with a loss of ERα function have been reported to date. All affected women had a rather homogeneous phenotype, combining a complete absence of puberty, a small prepubertal uterus, enlarged polycystic ovaries with high estradiol levels and high gonadotropin levels. Both male individuals identified had delayed bone maturation, with high estradiol and gonadotropin levels. One had normal gonadal development and a normal plasma testosterone concentration, whereas the other had a complete absence of puberty associated with unilateral cryptorchidism and low plasma testosterone levels. All patients complained of continued growth due to delayed epiphyseal maturation. Metabolic phenotypes were variable across studies.
We describe two sisters how display endocrine and ovarian defects of different severities despite carrying the same homozygous variant of the ESR1 gene.
Results |
A 36-year-old woman from a consanguineous Jordanian family presented primary amenorrhea and no breast development, with high plasma levels of 17β-estradiol, FSH and LH and enlarged multifollicular ovaries, strongly suggesting estrogen resistance. Her 18-year-old sister did not enter puberty and had moderately high levels of 17β-estradiol, high plasma gonadotropin levels and normal ovaries. Genetic analysis identified a homozygous variant of ESR1 leading to the replacement of a highly conserved glutamic acid with a valine (ERα-E385V). In-vitro analysis revealed highly impaired ERE-dependent transcriptional activation by 17β-estradiol. The analysis of the KISS1 promoter activity revealed that the E385V substitution induced a ligand independent activation of ERα.
Conclusion |
These two new cases are remarkable, given the difference in the severity of their phenotypes. This discrepancy may be due to a mechanism partially compensating for the ERα loss of function.
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Vol 83 - N° 6
P. 454 - décembre 2022 Retour au numéroBienvenue sur EM-consulte, la référence des professionnels de santé.
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