Fragile X-associated primary ovarian insufficiency (FXPOI)

Women with FXPOI present with hypergonadotropic hypogonadism before age 40 years. Ovarian insufficiency has been documented as early as age 11 years and may present with primary amenorrhoea and delayed puberty. Affected individuals have high rates of infertility together with menopausal-type symptoms, including vasomotor symptoms, mood changes, and vaginal dryness. In contrast to physiological menopause, ovarian function in FXPOI is erratic and unpredictable; irregular ovulation and menses may continue for years after diagnosis, and up to 12.6% of women conceive following a FXPOI diagnosis. Some women are completely amenorrhoeic. Women with full-mutation FMR1 alleles, by contrast, are not at increased risk for FXPOI and do not show signs of diminished ovarian reserve. Affected women are at risk of long-term health sequelae arising from a hypoestrogenic environment, including osteoporosis and increased cardiovascular risk. The clinical presentation is highly variable in both age of onset and disease course.

The prevalence of a premutation allele in FMR1 is estimated to be 345:100,000 in males and 677:100,000 in females.

FXPOI is caused by a germline CGG repeat expansion in FMR1. The premutation allele carries approximately 55-200 repeats within the 5’UTR of FMR1, which is located at Xq27.3 and is the single gene implicated in FXPOI. The pathomechanism of FXPOI is not fully understood but is linked to toxicity through elevated FMR1 mRNA levels.

FXPOI is inherited in an X-linked manner. A female premutation carrier has a 50% chance per pregnancy of transmitting the allele. CGG repeats may expand on maternal transmission: an offspring may inherit a full-mutation allele and present with rather than carrier risk for FXPOI. Prenatal molecular testing is technically possible once the familial pathogenic variant has been identified.

FXPOI is diagnosed in premutation carriers who fulfil clinical POI criteria. The premutation range comprises approximately 55-200 CGG repeats in FMR1. POI is defined as hypergonadotropic hypogonadism before age 40 years: at least 4-6 months of amenorrhoea with two menopausal-range seru FSH values obtained at least one month apart.

Main differential diagnoses include:

• Turner syndrome: 45,X karyotype with short stature and primary amenorrhoea; diagnosed by karyotype rather than FMR1 testing.
• Autoimmune primary ovarian insufficiency: anti-ovarian or steroid-cell antibodies with associated autoimmune endocrinopathies; acquired aetiology, not FMR1-related.

• Establishing the diagnosis enables confirmation of the clinical impression and provides a definitive aetiology for affected individuals and their families.
• Specific and individualised surveillance and clinical management: identification of the underlying pathogenic variant enables targeted long-term monitoring tailored to the molecular diagnosis and is a prerequisite for targeted medical care; decisions on its implementation rest with the treating physicians in consultation with the affected individual.
• Identification of the familial pathogenic variant enables predictive testing of at-risk relatives within the framework of genetic counselling.

Hunter JE, Berry-Kravis E, Hipp H, Todd PK. FMR1 disorders. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews^® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. PMID: .