The present study is the first published report on BPES in the Polish population. PBES is usually suspected based on the patient’s phenotypic characteristics. Although our proband displayed ophthalmic signs typical of the syndrome, and had undergone several corrective ophthalmologic surgeries, PBES had not previously been diagnosed.
Several types of rearrangements in the 3q23 region affecting the FOXL2 gene have been described in the literature. It has been suggested that FOXL2 mutations truncating the protein before polyalanine tract are associated with POI, while those causing polyalanine expansion tend to lead to BPES type 2 [14, 15]. However, in cases where other mutations are described (such as missense mutations or microdeletions), the genotype-phenotype correlation was not apparent [14, 16].
The c.223C > T p.(Leu75Phe) mutation in the FOXL2 gene was previously found by Xue et al. in a study of three women from two Chinese families [17]. In that study, two women in family A and one woman in family B had typical eyelid malformations, which were the same as those found in our patient and her affected family members. The first of the Chinese subjects was 63 years old, following menopausal onset at age 52y. The second and the third subjects were of reproductive age and with regular menstrual cycles. None of the subjects had fertility problems. However, none of those subject’s hormone status is known as the investigators did not carry out any hormonal tests. Careful interpretation of the genetic tests, in order to predict the risk of POI, is advisable [14].
Hormonal results in our study suggest there is a correlation between the type 1 specific genotype and hormonal disturbances. Although they are not typical, they may still indicate a poor ovarian reserve.
There are several tests which evaluate a subject’s remaining reproductive potential and which may be early signs of approaching menopause [10, 18]. Elevated FSH serum concentrations (21.9 IU/L) and very low estradiol levels (5.3 [pg/ml]) in patients, may point to the possibility of POI. Small atrial follicles (2–8 mm in diameter) are also an indicator of the remaining ovarian reserve. An AFC count of less than 4, suggests the subject will likely have problems with becoming pregnant, even after IVF [11]. In our study, the AFC counts were 5 and 9, in the right and left ovaries, respectively. AMH produced by pre-antral and small antral ovarian follicles are acknowledged markers of the ovarian reserve and the remaining reproductive capacity of the subject. Current guidelines of the American College of Obstetricians and Gynecologists recommend that AMH serum concentrations should be evaluated as one of the best tools for measuring the remaining ovarian reserve [12]. Both AFC counts and AMH concentrations have good predictive value, however the latter is preferred for ovarian reserve measurement, especially if the findings obtained from both tests persist [19, 20]. Our study demonstrated that consistently low AMH serum levels, below 0.52 ng/ml in the proband with the c.223C > T p.(Leu75Phe) mutation, allowed the detection of the subject’s decreased ovarian reserve.
Genetic testing in patients affected with POI is highly recommended, especially if iatrogenic causes are excluded [21]. Molecular tests should also be conducted in relatives, especially in adolescent females and in women at a reproductive age, as early diagnosis helps women retain their future fertility. For the women described in our study, fertility preservation methods (cryopreservation of the oocytes, or ovarian tissue) were offered.
The young ago for the patients and their decreased estradiol levels were indications for replacement therapy. II:3 preferred an oral substitutive hormonal therapy of 2 mg of estradiol daily, and 10 mg of dydrogesterone in the second phase.
Hormone testing of our patient did not unambiguously indicate preterm menopause, and it is difficult to assess whether the patient’s current hormonal disorders are transient or will indeed lead to menopause. The patient remains under constant observation. It is worth emphasizing that this paper is the first published description of the menopausal transition in a patient with the FOXL2 gene mutation that has been linked to BPES type 2.
We found mutations in the c.223C > T p.(Leu75Phe) FOXL2 gene in young women with hormonal alternations typical of POI. These results indicate the possibility that different phenotypes should be considered in patients with similar genetic mutations.