ESPE Yearbook of Paediatric Endocrinology

J Clin Endocrinol Metab. 2018 Oct 1;103(10):3748–3756.

doi: 10.1210/jc.2018-00769. PubMed PMID: 30113650

This case report describes a 16 year old girl with 46,XX karyotype, no pubertal development and streak gonads. The girl was 150 cm tall and had closed epiphyses and osteoporosis. Genetic investigation by whole exome sequencing showed a loss-of-function mutation in the Estrogen Receptor β gene (ESR2).

This ESR2 variant was a loss-of-function heterozygous mutation in a highly conserved residue of the gene. It disrupts estradiol-dependent signaling and has a dominant negative effect. Functional transactivation studies were performed using different cell types of known interest for estrogen function. When stimulated with estradiol, mutant ESR2 in breast cells or osteoblasts had a much lower basal transactivation potential than the wild type receptor. In ovarian cells, the mutant ESR2 did show any expression and had a dominant negative effect on the wild-type allele, consistent with its pathological heterozygote effects. The effect was not rescued by increasing estradiol concentrations, suggesting a complete loss of function.

The bone phenotype is difficult to understand. Osteoporosis is expected with estrogen deficiency, however, the epiphyseal closure is unexpected. There are conflicting reports on the localization and function of ESR1 and ESR2 in growth plate chondrocytes, and whether predominantly ESR1 or ESR2 or both are required. A 2-year follow up during treatment with estrogen, calcium and vitamin D showed some improvement in bone density parameters but the effect was much less notable compared with her changes in breast and uterus size. This suggests a more complex or slower influence of estrogens on bone.

These novel findings suggest that ESR2 is necessary for human ovarian determination and/or maintenance and that ESR1 is not sufficient to sustain ovarian function in humans. The results add to the understanding of the function of estrogen in the processes of sex differentiation and development.