ESR1 – Estrogen Resistance Syndrome

Estrogen resistance syndrome is an autosomal recessive disorder caused by loss-of-function variants in the estrogen receptor α gene ESR1. Affected individuals present with primary amenorrhea, incomplete pubertal development, elevated estradiol and gonadotropin levels, multicystic ovaries, delayed skeletal maturation, tall stature, insulin resistance, osteoporosis, and infertility.

In three unrelated consanguineous families, six individuals from Jordanian, Algerian, and French pedigrees were homozygous for ESR1 variants and manifested estrogen resistance. Two sisters with a homozygous c.1153G>T (p.Glu385Ter) variant exhibited variable ovarian and hormonal phenotypes (PMID:35134944). Three siblings carrying homozygous c.1180C>T (p.Arg394Cys) and c.1181G>A (p.Arg394His) variants demonstrated delayed bone maturation and multicystic ovaries (PMID:27754803). A woman with a novel homozygous c.1628T>C (p.Met543Thr) missense change showed tall stature, delayed bone age, insulin resistance, and severe osteoporosis unresponsive to estrogen therapy (PMID:40032016).

Segregation analysis confirmed co-segregation of homozygous ESR1 variants with disease in each family, consistent with autosomal recessive inheritance. Six probands across three pedigrees support a moderate level of clinical validity under ClinGen criteria, with clear segregation and concordant endocrine dysfunction.

Functional studies of the c.1153G>T (p.Glu385Ter) and c.1180C>T (p.Arg394Cys) variants demonstrated severely impaired estrogen response element (ERE)-dependent transcription, altered nuclear translocation, and disrupted ligand binding in cell models, confirming loss of receptor function and a mechanism of pathogenicity through receptor inactivation.

No conflicting variants or alternative disease associations have been reported. Together, genetic and experimental data establish a robust link between biallelic ESR1 loss-of-function variants and estrogen resistance syndrome, enabling molecular diagnosis and guiding management. Key Take-home: ESR1 sequencing should be implemented in patients with primary amenorrhea, hormonal hypergonadism, and multicystic ovaries to confirm estrogen resistance syndrome and inform clinical care.

References

• The Journal of clinical endocrinology and metabolism • 2022 • Estrogen Receptor α Inactivation in 2 Sisters: Different Phenotypic Severities for the Same Pathogenic Variant PMID:35134944
• The Journal of clinical endocrinology and metabolism • 2017 • Familial Multiplicity of Estrogen Insensitivity Associated With a Loss-of-Function ESR1 Mutation. PMID:27754803
• Bone • 2025 • Novel estrogen receptor-α gene inactivating missense variant in a woman: Therapeutic challenge and long-term follow-up data PMID:40032016

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