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Case Reports
, 369 (2), 164-71

Delayed Puberty and Estrogen Resistance in a Woman With Estrogen Receptor α Variant

Case Reports

Delayed Puberty and Estrogen Resistance in a Woman With Estrogen Receptor α Variant

Samuel D Quaynor et al. N Engl J Med.


Although androgen resistance has been characterized in men with a normal chromosome complement and mutations in the androgen-receptor gene, a mutation in the gene encoding estrogen receptor α (ESR1) was previously described only in one man and not, to our knowledge, in a woman. We now describe an 18-year-old woman without breast development and with markedly elevated serum levels of estrogens and bilateral multicystic ovaries. She was found to have a homozygous loss-of-function ESR1 mutation in a completely conserved residue that interferes with estrogen signaling. Her clinical presentation was similar to that in the mouse orthologue knockout. This case shows that disruption of ESR1 causes profound estrogen resistance in women. (Funded by the National Institutes of Health.).


Figure 1
Figure 1. Phenotypic Features of a Female Patient with an ESR1 Mutation
Panel A shows the absence of breast development (Tanner stage 1) and the presence of pubic hair (Tanner stage 4) when the patient was examined at the age of 17 years 8 months. At the age of 17 years 5 months, when the patient’s weight was 44 kg, total-body dual-energy x-ray absorptiometry indicated that the total body fat was 11,834 g and the total lean mass was 30,459 g. Panel B shows enlarged cystic ovaries, with the right ovary measuring 8.4 by 4.7 by 8.3 cm and the left ovary measuring 2.9 by 2.7 by 3.1 cm at the age of 17 years 9 months. Panel C shows the patient’s growth velocity without the normal steroid-induced growth spurt at the time of puberty. Panel D shows linear percentiles for height (upper curve) and weight (lower curve).
Figure 2
Figure 2. Analysis of the ESRI Mutation in the Patient and Resulting Reduced Estrogen-Receptor Activity
A representative electropherogram obtained on DNA sequencing of ESR1 shows the location of the mutation found in the patient (Panel A). Alignment of the affected Gln (Q) 375 residue with other species indicates complete conservation in all 21 species (Panel B). Transactivation of an ERE-LUC (estrogen-response element upstream of luciferase) construct in transfected COS-7 cells revealed greatly reduced activity in the mutated estrogen receptor, as compared with the nonmutated estrogen receptor (Panel C).

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