Inheritance in idiopathic premature ovarian failure: analysis of 71 cases.

Human Reproduction, Jul 1998

Premature ovarian failure is defined as cessation of ovarian function under the age of 40 years and affects approximately 1% of women in the general population. The aetiology of this disorder is still unknown in most cases. Although there have been some reports of familial premature ovarian failure, very little is known about the incidence and inheritance pattern of its idiopathic form. The aims of this study were to investigate the incidence and inheritance pattern of familial premature ovarian failure in a homogeneous group of patients with premature idiopathic menopause and to identify possible clinical differences between patients with the familial and the sporadic form of premature ovarian failure. A total of 71 women were recruited into the study. Clinical assessments and genetic counselling showed that 22 (31%) patients had familial premature ovarian failure, this high incidence strongly suggesting that the disorder is a recognizable heritable entity. There was a statistically significant (P < 0.05) difference in the median age of precocious menopause in patients with sporadic and familial premature ovarian failure (31.0 and 37.5 years of age in the two groups, respectively). Pedigree analysis strongly suggests the existence of a familial pattern of premature ovarian failure with a dominant maternal and/or paternal transmission and incomplete penetrance. In the presence of familial history of premature ovarian failure, reproductive counselling is recommended.

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Inheritance in idiopathic premature ovarian failure: analysis of 71 cases.

April Inheritance in idiopathic premature ovarian failure: analysis of 71 cases* Walter Vegetti 2 Maria Grazia Tibiletti 1 Giovanna Testa 0 Luciana De Lauretis Yankowski 2 Federica Alagna 2 Elena Castoldi 0 Monica Taborelli 1 Tiziano Motta 2 Pier Francesco Bolis 0 Leda Dalpr a` 3 Pier Giorgio Crosignani 2 0 Obstetrics and Gynaecology Unit, Department of Clinical and Biological Sciences, University of Pavia , Varese 1 Laboratory of Pathology, Department of Clinical and Biological Sciences, Ospedale di Circolo , Varese 2 First Department of Obstetrics and Gynaecology, University of Milan 3 Department of Biology and Genetics for Medical Sciences, University of Milan , Italy 4 Presented in part at the 13th Annual Meeting of ESHRE , Edinburgh, UK, June 22-25, 1997 5To whom correspondence should be addressed European Society for Human Reproduction and Embryology - Premature ovarian failure is defined as cessation of ovarian function under the age of 40 years and affects ~1% of women in the general population. The aetiology of this disorder is still unknown in most cases. Although there have been some reports of familial premature ovarian failure, very little is known about the incidence and inheritance pattern of its idiopathic form. The aims of this study were to investigate the incidence and inheritance pattern of familial premature ovarian failure in a homogeneous group of patients with premature idiopathic menopause and to identify possible clinical differences between patients with the familial and the sporadic form of premature ovarian failure. A total of 71 women were recruited into the study. Clinical assessments and genetic counselling showed that 22 (31%) patients had familial premature ovarian failure, this high incidence strongly suggesting that the disorder is a recognizable heritable entity. There was a statistically significant (P , 0.05) difference in the median age of precocious menopause in patients with sporadic and familial premature ovarian failure (31.0 and 37.5 years of age in the two groups, respectively). Pedigree analysis strongly suggests the existence of a familial pattern of premature ovarian failure with a dominant maternal and/ or paternal transmission and incomplete penetrance. In the presence of familial history of premature ovarian failure, reproductive counselling is recommended. Key words: familial/idiopathic/premature ovarian failure/reproductive risk Cessation of ovarian function under the age of 40 years has been defined as premature ovarian failure and affects ~1% of women in the general population (Coulam et al., 1986). The condition can be associated to autoimmune (Aiman et al., 1985; Blumenfeld et al., 1993; Wheatcroft et al., 1997) or genetic (Mattison et al., 1984) disorders, ovarian surgery and iatrogenic causes. Thus this disorder is highly heterogeneous, but in most cases the aetiology of premature ovarian failure is still unknown. A familial pattern of premature ovarian failure, suggesting autosomal dominant or X-linked inheritance, has been described in the past (Mattison et al., 1984; Coulam et al., 1998). In addition, several authors have reported the correlation between premature ovarian failure and different chromosome X abnormalities (Schmidt and Du Sart, 1992; Beck et al., 1995; Seller et al., 1995). So far, two critical regions on Xq, which are essential for normal ovarian function, have been identified: Xq13.3-q21.1 (Powell et al., 1994; Sala et al., 1997) and Xq26-28 (Skibsted et al., 1984; Delon et al., 1997). The postulated X-linked inheritance was demonstrated in another premature ovarian failure pedigree and was associated with interstitial deletion of the long arm of the X chromosome (Krauss et al., 1987). More recently a correlation between premature menopause and fragile X carriers has been suggested (Partington et al., 1996; Vianna-Morgante et al., 1996). Cytogenetic data and the correlation between premature ovarian failure and fragile X carriers again suggest a possible X localization of the premature ovarian failure gene or genes. Some forms of ovarian failure associated with other gene defects have been reported. In 1994 and 1995 Aittomaki et al. described cases of primary amenorrhoea with FSH receptor gene mutation in the Finnish population. Amati et al. (1996) reported two families with premature ovarian failure-related eyelid malformations and localized this disease to chromosome 3q22-q23. Although there have been some reports of the familial form of the disorder (Coulam et al., 1983; Mattison et al., 1984) and recent epidemiological evidence that supports the familial association between menopausal age of mothers and daughters (Cramer et al., 1995; Torgerson et al., 1997), very little is known about the incidence and inheritance pattern of the so called idiopathic premature ovarian failure. The aims of this study were to investigate the incidence and inheritance pattern of familial premature ovarian failure in a homogeneous group of patients with idiopathic premature ovarian failure and to identify possible clinical differences between patients with the familial and the sporadic form of premature ovarian failure. Materials and methods ductive Endocrinology Services, Department of Obstetrics and Gynaecology in Milan and Varese. Both centres followed a pre-established protocol for patient selection. For the purpose of this study, secondary hypergonadotrophic amenorrhoea was defined as cessation of menses for a duration of 6 months or longer before the age of 40 years and follicle stimulating hormone (FSH) concentrations .40 IU/l. Patients with amenorrhoea due to known causes or associated with autoimmune diseases were excluded from the study. Clinical assessments All patients underwent the following clinical assessments: complete medical history; complete gynaecological history including age at menarche and previous menses; complete obstetrics history, with previous pregnancy outcome; history of cigarette-smoking, alcohol consumption and diet; clinical gynaecological examination; ultrasound pelvic evaluation using a 56.5 MHz vaginal probe (Ansaldo 538); serum gonadotrophin assessment; non-organ specific autoantibody (against nucleus, mitochondria, ribosomes, DNA) by the standard indirect immunofluorescence on cryostat tissue sections as reported by Preziati et al. (1995) and organ-specific serum autoantibody assessments on sections of human pancreas, monkeys ovary, testis and adrenal gland and rat stomach. Genetic assessments Peripheral blood lymphocyte cultures were set up conventionally and incubated for 72 h and, in order to obtain high resolution chromosomal spreads (.550 bands), 103 M methotrexate (MTX) supplied by Sigma, Italy, was added in cultures for 17.3 h and replaced, after washing, with 1.2 104 M thymidine (Sigma, St Louis, MO, USA) for an additional 4 h. Colcemid (Boehringer Mannheim, Germany) at a final concentration of 0.1 g/ml was added for 10 min to the culture. Chromosome spreads and QFQ banding were prepared according to the standard methods. The karyotype reconstructed followed the guidelines expressed in International System for Chromosome Nomenclature 95 (ISCN, 1995). For each karyotype a minimum of 20 cells were analysed and an additional 50 cells were assessed to exclude sex chromosome mosaicism. A family history was reviewed during genetic counselling and family members were traced back three generations. Patient population Eighty-one patients with secondary hypergonadotrophic amenorrhoea were initially considered eligible for study entry. No-one presented clinical evidence of autoimmune disorders. After screening 10 patients were excluded from the study due to premature ovarian failure phenotype-related clinical conditions. Of the 10 excluded patients, three were withdrawn due to previous ovarian surgery, one due to galactosaemia, one due to previous chemotherapy for the treatment of Hodgkins disease and five because they presented abnormal karyotypes. Two of the five patients with abnormal karyotypes had a previous diagnosis of trisomy 21 and trisomy 18 at mosaic, respectively, while X chromosome abnormalities were found in the remaining three at premature ovarian failure screening. In particular, the following karyotypes were identified: 46,XX,del(X) (q22.3; q26.3); 46,XX,del(X) (q22qter); 45,X/46,Xisodic(X) (q23qter). Seven patients reported a dysthyroidism (six in the sporadic and one in the familial group): four of the seven had thyroid disease some years after premature ovarian failure, two showed hypothyroidism 1 and 7 years before the onset of premature ovarian failure, respectively, and the patient with familial premature ovarian failure was diagnosed with hyperthyroidism 14 years before the onset of premature ovarian 48 (2555) 49 (4155) 40 (2555) aMannWhitney test. failure. Since thyroid assessment at study entry was normal, all these patients were considered eligible. In summary a total of 71 (Milan, n 5 41; Varese, n 5 30) phenotypically and chromosomally normal women with a diagnosis of idiopathic premature ovarian failure were entered into the study. The mean value of serum FSH levels was 77.33 6 23.68 UI/l. No serum autoantibodies were found in the first 20 patients specifically tested. The median age at menarche in both groups was similar (13 years in the sporadic group and 12 years in the familial group). Menstrual history showed that 44 patients had eumenorrhoea before the onset of premature ovarian failure (30 patients in the sporadic group and 14 in the familial group); 24 patients had episodes of eumenorrhoea/oligomenorrhoea before the onset of premature ovarian failure (19 and five in the sporadic and familial groups, respectively), while eight patients had oligomenorrhoea since menarche (six in the sporadic and two in the familial premature ovarian failure group). Twenty-two (44.9%) pregnancies were recorded in the sporadic group compared to 18 (81.8%) in the familial group (P , 0.05, Fishers exact test). On ultrasound examination, all ovaries showed an afollicular pattern with no sign of ovarian activity and an endometrial thickness 5 mm. Table I reports the age at menopause for the patients and their mothers. Thirteen patients (26.5 %) in the sporadic group and four (18.2 %) in the familial group were habitual smokers. Results obtained from genetic counselling showed that 22 of the 71 index cases (31.0%) had familial premature ovarian failure, while the remaining 49 had the sporadic form of the disorder. In the familial premature ovarian failure group, pedigree analysis showed another 37 cases of premature ovarian failure, for a total of 59 affected females. All patients included in this study appeared to be phenotypically normal on physical examination (normal height, weight and habitus). No family showing blepharophimosis or Figure 1. Pedigree of four premature ovarian failure families. A black circle indicates premature ovarian failure features and the Arabic numbers in bold type the age at menopause. with conditions related to cancer cluster nor families presenting cases showing fragile X syndrome or other forms of mental retardation were found. Figure 1 shows four of the most significant familial premature ovarian failure pedigrees. Pedigree analysis showed a vertical transmission of premature ovarian failure in both centres, suggesting a dominant pattern of inheritance. No families sharing only affected sibship were observed. Transmission was through either maternal (13 families) (see family 1 in Figure 1 as example) or paternal (four families) (see family 2 in Figure 1 as example) relatives. In addition, five families (see family 3 in Figure 1) had both maternal and paternal transmission. All transmitting males were phenotypically normal and no consanguineous matings were reported. Our pedigree analysis suggests either an autosomal or Xlinked dominant sex-limited pattern of inheritance, irrespective of maternal or paternal transmission. It is known that in cases with an X-linked inheritance, all transmitting males will have affected females. However, we recorded two families in which the transmitting males had unaffected daughters over the age of 45 years. This may be explained by incomplete penetrance (see family 4 in Figure 1). In another family the transmitting male had two daughters: one showing the premature ovarian failure phenotype and the other undergoing menopause at the age of 41 years. Not all probands had premature ovarian failure mothers, therefore the penetrance in our study was not complete (79.1%) considering only female subjects. Interestingly, among the non-penetrant group, two females from two different families underwent early menopause at 44 and 45 years of age, respectively. In addition, in the sporadic premature ovarian failure group, we found eight index cases with mothers showing early menopause between the ages of 41 and 45 years. Similar genetic characteristics (percentage of familial cases and pattern of inheritance) were recorded in both centres. A clinical and genetic investigation was conducted in 71 patients with a diagnosis of idiopathic premature ovarian failure. All patients were phenotypically and chromosomally normal. Although other authors (Coulam et al., 1983, 1986; Krauss et al., 1987; Riva et al., 1996; Sala et al., 1997) report genetic information on premature ovarian failure patients, the populations considered were not homogeneous. As far as we know this is the first study performed in a homogeneous group of patients with idiopathic premature ovarian failure. Premature ovarian failure has been often considered as an immunological disorder (Hoek et al., 1997), associated with Addison or autoimmune thyroid diseases (Alper et al., 1985). Moreover, premature ovarian failure patients with serological evidence of autoimmunity and no sign of autoimmune disease are frequently described (Wheatcroft, 1994). In a recent report, Wheatcroft et al. (1997) showed the different results obtained by the use of two different methods of antibody detection (indirect immunofluorescence versus enzyme-linked immunosorbent assay). Their results call into question the specificity of ovarian antibodies as a marker for autoimmune premature ovarian failure. Fenichel et al. (1997) also indicated the poor prognostic value of the antibodies found in patients without autoimmune disease. In our study no patient showed clinical evidence of autoimmune diseases. The screening test performed with the indirect immunofluorescence method in the first 20 subjects studied indicated uniformly negative results. Genetic counselling performed in our study showed that 31% of the patients had familial premature ovarian failure and this confirms that premature ovarian failure is a recognizable heritable entity. A vertical transmission of the disease through either maternal or paternal relatives was observed in this population, suggesting either an autosomal or X-linked, sexlimited dominant pattern of inheritance. Incomplete penetrance may interfere with inheritance pattern assessments. In fact, families having transmitting males with both normal and affected daughters may be compatible either with an autosomal dominant pattern or an X-linked pattern. Interestingly, two non-penetrant females underwent menopause at 44 and 45 years of age, respectively. The age of onset of ovarian failure may be variable, suggesting a different pattern of expression of the same disease. Moreover, the anticipation phenomenon should also be taken into consideration. Anticipation is defined as a phenomenon in which the age of onset of a disorder is reduced and/or the severity of the phenotype is increased in successive generations (Strachan and Read, 1996). The occurrence of anticipation may be masked by expression variability. A recent study (Conway et al., 1995) showed a correlation between anticipation and FRAXA amplification, detected in a family showing the premature ovarian failure phenotype. In our study no family presenting cases showing fragile X syndrome or other forms of mental retardation were found. The pedigrees reported in this study strongly suggest the existence of a familial pattern of premature ovarian failure showing a dominant transmission in all cases. Nevertheless, incomplete penetrance makes it difficult to distinguish an autosomal pattern of inheritance from an X-linked one. Both patterns share an obvious sex-limited transmission of the disorder. Contrary to the study conducted by Aittomaki et al. (1995) no pedigrees showing an autosomal recessive pattern of inheritance were reported in our series. Nevertheless, the gene mutation reported in the selected Finnish population with primary amenorrhoea is a very rare condition. Our findings on pedigrees sharing maternal and/or paternal inheritance indicate the need for proper genetic counselling. Theoretically, there is a similar genetic risk involved in the recurrence of the disorder with both autosomal and X-linked patterns of inheritance. In families with maternal transmission, the risk of recurring premature ovarian failure is 50% (39.5% corrected by penetrance), regardless of whether the pattern of inheritance is X-linked or autosomal. On the contrary, in families with paternal transmission, the risk is 100% (79.1% corrected by penetrance) when the disorder has an X-linked pattern of inheritance, but decreases to 50% (39.5% corrected by penetrance) when the dominant pattern of inheritance is autosomal. On this basis, pedigree analysis seems important in assessing the reproductive risk. Ovarian failure started later and the fertile period was longer in the familial compared with the sporadic group. These data show that patients with familial premature ovarian failure have a better reproductive chance as compared to patients with sporadic premature ovarian failure and strongly suggest the need for a specific reproductive counselling. The authors are indebted to Professor Pier Luigi Meroni and Doctor Luisa Guidali for performing autoantibody assays. We would also Aiman , J. and Smentek , C. ( 1985 ) Premature ovarian failure . Obstet. Gynecol., 66 , 9 - 14 . Aittomaki, K. 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W Vegetti, M Grazia Tibiletti, G Testa, de Lauretis Yankowski, F Alagna, E Castoldi, M Taborelli, T Motta, P F Bolis, L Dalprà, P G Crosignani. Inheritance in idiopathic premature ovarian failure: analysis of 71 cases., Human Reproduction, 1998, 1796-1800, DOI: 10.1093/humrep/13.7.1796