Fragile X premutation: A known under-diagnosed aetiology for premature ovarian insufficiency


Raya Almazrouei, Tawam Hospital/Al Ain/UAE


Background: Premature ovarian insufficiency (POI) is defined by loss of ovarian activity before the age of 40.  Chromosomal analysis, Fragile-X premutation testing and screening for 21OH-Ab are the basic recommended investigations for patients with non-iatrogenic POI. Two cases of POI with Fragile- X premutation are presented.


Case 1: 34 years old woman with past medical history of secondary amenorrhea and infertility from age 26. Prior to that, she had normal menarche at age 12 and regular periods with 1 child born while she was 23 years of age. Work up by her physician in obstetrics and gynecology division revealed POI. Further investigations revealed female karyotyping (46, XX) and absence of 21 hydroxylase antibodies (21OH-Abs). For sake of completion of POI investigation, Fragile X premutation testing was performed. It showed that she is a carrier of a premutated allele with presence of 78 CGG repeats in one of the allele (the second allele was normal with 30 CGG).


Case 2: 33 years old woman was seen for subacute thyroiditis.  Further history revealed primary infertility for 10 years with oligomenorrhea and several failed IVF attempts. Previous work up showed POI with female karyotyping (46, XX). 21OH-Ab screening was negative. Fragile X premutation testing confirmed the carrier state for premutated allele with 85 CGG repeats (the second allele was normal with 30 CGG). Further history revealed that the two patients are second-degree relatives.


Discussion: Fragile-X syndrome is an X-linked inherited condition caused by a mutation of the fragile-X mental-retardation 1 (FMR1) gene. The full mutation (> 200 CGG repeats) can result in mental retardation but primarily in men who carry the mutation. Women who carry the premutation (55-200 repeats) do not have an increased risk of intellectual disability, but have an increased risk of 13-26% to develop POI.  Studies on the Fragile-X premutation in women with POI have found a prevalence of 0.8 to 7.5% in women with sporadic POI (i.e. women without other family members with POI) and up to 13% in women with a positive family history of POI.  Many women with non-iatrogenic POI are not screened for Fragile X premutation due to lack of awareness. In fact with the high rate of consanguinity marriage in our region, Fragile-X premutation in women with POI may have a higher prevalence than reported in other parts of the world.


Conclusion: The earlier diagnosis of premutaion has several implications on patient and their families. Consequences such as risk for other associated features (ataxia), infertility options (early ovum preservation) and offering genetic counseling and testing to relatives of women with fragile-X permutation need to be discussed in advance.