Gynecological Endocrinology, October 2010; 26(10): 717–724 REVIEW Chromosomal abnormalities in women with premature ovarian failure PAOLO GIOVANNI ARTINI, MARIA RUGGIERO, FRANCESCA PAPINI, VALERIA VALENTINO, ALESSIA UCCELLI, VITO CELA, & ANDREA RICCARDO GENAZZANI Gynecol Endocrinol Downloaded from informahealthcare.com by UNIVERSITA DEGLI STUDI DI PISA on 11/06/12 For personal use only. Division of Obstetrics and Gynecology, Department of Reproductive Medicine and Child Development, University of Pisa, Via Roma 56, 56126 Pisa, Italy (Received 18 May 2010; accepted 8 June 2010) Abstract Premature ovarian failure is a complex disorder that results in the early loss of ovarian function; however this disease must be separated from early menopause because these patients can sporadically ovulate and in literature are described pregnancies. The aetiology and the patho-physiology of premature ovarian failure are still matter of debate, but is commonly accepted that genetic factors play an important role. This review is aimed to present an overview of known inherited factor implied in the pathogenesis of this disorder to help physician in the counselling of affected pregnant women. Keywords: Assisted reproductive technology, infertility, premature ovarian failure, chromosomal abnormalities, pregnancy Introduction Premature ovarian failure (POF) is defined as a primary ovarian defect characterised by absent menarche (primary amenorrhea) or premature depletion of ovarian follicles/ arrested folliculogenisis before the age of 40 years (secondary amenorrhea) [1,2]. POF affects approximately one in 10,000 women by age 20; one in 1000 women by age 30; one in 100 women by age 40 [3]. The aetiology of this disorder is still unknown in the majority of cases. Even though a familial POF form represents 4–31% of all cases of POF [4–6]. POF represents the end stage of a variety of disorders that result in the loss of ovarian follicles. Nevertheless, POF is different from physiologic menopause, because the latter is an irreversible condition, whereas the former is characterised by intermittent ovarian function in half of these young women. These young women intermittently produce estrogen and sometimes even ovulate despite the presence of high gonadotropin levels. Indeed, pregnancy has occurred after a diagnosis of POF [7,8], both in spontaneous cycles and after the use of birth-control pills, Hormone Replacement Therapy (HRT) and ovarian stimulation [9]. The age of onset of ovarian failure may be variable and Kalantaridou et al. found that pregnancies have occurred in 5–10% of women after the diagnosis of POF, even in women with no follicles on ovarian biopsy [10]. However, possible causes of POF can be principally divided in two main group: chromosomic and nonchromosomic anomalies. Among genetic causes, X monosomy as in Turner syndrome or X deletions and translocations are known to be responsible for POF. The genes involved in ovarian function, located on the X chromosome are still unknown. On the other hand, autosomal abnormalities have been identified in patients with POF such as mutations of the Follicle Stimulating Hormone (FSH) gene, the luteinizing hormone (LH) and FSH receptor genes, chromosome 3q containing the blepharophimosis gene, the Ataxia-telangiectasia (ATM) gene. Mutations in AIRE gene (responsible for APECED syndrome), in FOXL2 (transcription factor involved in BPES), in growth derived factor 9 (GDF9) gene and in progesterone membrane receptor component 1 (PGRMC1) can involve ovarian insufficiency [12]. Non-chromosomic anomalies can be classified in three groups: iatrogenic origin (surgery, chemotherapy and radiations), autoimmunity (susceptibility mediated by AIRE gene mutation), infections (herpes virus, cytomegalovirus, mumps) and idiopatic form. The different causes of POF are summarised in the Table I. Chromosomic anomalies Pathogenesis of premature ovarian failure Chromosome X defects. The pathogenesis of POF is currently unknown and in the future, a better knowledge of the cellular and biochemical components involved in folliculogenesis and apoptosis should elucidate the involved mechanisms. Moreover, several data indicate that POF has a strong genetic component [11]. Turner’s syndrome. Ovarian failure and amenorrhea are the typical features in Turner’s syndrome resulting from an accelerated loss of oocytes from the ovaries after the 18th week of fetal life or over a few postnatal months or years. The cause and mechanism of this loss are unknown. About 5–10% of girls with Turner’s Syndrome have spontaneous Correspondence: P. G. Artini, M.V. Sc.B., PhD, Division of Obstetrics and Gynecology, Department of Reproductive Medicine and Child Development, University of Pisa, Via Roma 56, 56126 Pisa, Italy. Tel: þþ39-050-554104. Fax: þþ39-050-551293. E-mail: g.artini@obgyn.med.unipi.it ISSN 0951-3590 print/ISSN 1473-0766 online ª 2010 Informa UK, Ltd. DOI: 10.3109/09513590.2010.500427 718 P. G. Artini et al. Table I. Causes of POF. Chromosomic anomalies Chromosome X . Turner syndrome defects . Fragile X syndrome (FMR1gene premutation) [Xq27.3 and Xq28] . X aneuploidy . Bone morphogenetic protein 15 (BMP15) mutations [Xp11.2] Gynecol Endocrinol Downloaded from informahealthcare.com by UNIVERSITA DEGLI STUDI DI PISA on 11/06/12 For personal use only. Autosomic defects Syndromic defects: Galactosemia Blepharophimosis-ptosis-epicanthus inversus syndrome (FOXL2 mutations) [3q22–q23] Pseudohypoparathyroidism (PHP) type Ia Isolated defects: Follicle stimulating hormone (FSH) receptor mutations (FSHR) [2p21–p16] Luteinizing hormone (LH) receptor mutations (LHR) [2p21] Inhibin A mutations [2q33–q36] ATM gene mutations [11q22.3] PGRMC1 [Xq22–q24] Other minor genes Non-chromosomic anomalies Iatrogenic origin . surgery, . chemotherapy, . radiations. Autoimmune mutations in AIRE gene (polyglandular autoimmune syndrome) Infections . herpes zoster, . cytomegalovirus, . mumps. Idiopathic pubertal development and 5% having menstrual periods [13]. Spontaneous pregnancies are seen in 2–5% of these women, and up to 30% have at least some pubertal development, indicating the presence of follicles in their ovaries in adolescence. It has not been clear at which age the follicles disappear [14]. Only 2% of the women have natural pregnancies, with high rates of miscarriages, stillbirths and malformed babies [15]. Since ovarian failure occurs relatively early during adolescence, cryopreservation of ovarian tissue should be considered as soon as the girl or her parents are able to make the necessary decisions. On the other hand, beside risks for congenital anomalies in the newborn, the risks of pregnancies in Turner’s syndrome should not be neglected. Indeed, Waelkens reported the birth of a girl with Turner’s syndrome because of a 45,X mosaicism and a ring chromosome with a 29-year-old mother with a non-mosaic 45,X in her blood lymphocytes [16]. Fragile X syndrome (FRAXA). The molecular basis of the syndrome is usually an expansion of a repetitive CGG triplet sequence located in the 50 -untranslated region (50 UTR) of the FMR1 gene on the X chromosome (Xq27.3) [17]. Rarely, FRAXA results from point mutations or deletions within the FMR1 gene [18] The normal number of triplet repeats is polymorphic and varies from 6 to 50 [19]. The expansion of the number of repeats above a threshold of approximately 200 repeats results in hypermethylation and subsequent transcriptional silencing of FMR1 and the absence of its coding protein FMRP. The full mutation is associated with fragile X mental retardation syndrome. When the expanded repeat numbers range from 50 to 200 (premutation), the allele becomes unstable in the transmissions [20]. The frequency of premutation in the general population is *1 in 259 females and recent reports suggest that women with FRAXA premutations, but not full mutations, have an increased likelihood of having POF [21,22] .The expansion of trinucleotide repeats to a full mutation is not well understood and remains an area of intense investigation; anyhow the process is exclusively on females transmission and the instability of premutation alleles in females is correlated with the repeat size [23]. Few years ago, Hundscheid et al. opened an active debate on the influence of parental imprinting of transmission; the German study underline the pivotal role of paternally inherited fragile X premutations in POF transmission [24], while subsequent statistics do not support the hypothesis of a parent-of-origin effect of the FMR1 premutation on ovarian function [25–27]. The mechanism of the association between FRAXA premutations and POF is unknown but as a genetic marker, FRAXA screening will be particularly valuable in predicting POF in some pedigrees and in the identification of families at risk of transmitting fragile X syndrome [28]. When counselling pregnant females with premutation and intermediate alleles, clinicians must consider the risks of repeat instability in allele transmission from mother to child. For premutation alleles, there is a clear risk for expansion to a full mutation. This is not only a hypothetical risk, because Corrigan et al. recently described a woman affected with POF who conceived a child with mental retardation because of fragile X syndrome [29]. Finally, recent studies underline the importance of screening for fragile X premutations for the routine work-up for any woman presenting with POF. The reason is that women with POF have an *5% chance of conceiving and as written above, this possibility may be increased further in the FRAXA premutation subgroup. Moreover, the identification of a family in which the fragile X repeat site is expanded can lead to the identification of other female family members at risk of transmitting fragile X syndrome. The identification of an index case should, therefore, trigger genetic counselling throughout the pedigree according to the wishes of the family [30]. X aneuploidy. X trisomy is the most frequent aneuploidy which affects 1 in 900 women in general population. The 47,XXX genotype usually has no significant effect on fertility; however, association with hypergonadotrophic POF has been reported. The real incidence of the association between X aneuploidy and POF is not known, because these form are only exceptionally described [31–35]. Recently, Goswami et al. reported a 3.8% of triple X syndrome among patients with POF; furthermore found an association with autoimmune thyroid disorders [36]. Literature also reported different X alterations in patients with POF, as a case of 48XXXX [37] and two cases of dicentric isochromosome X, dic (Xp7) [38]. In the most recent literature, some authors realised cytogenetic analyses of POF using karyotypyng and interphase fluorescence in situ hybridisation (FISH) , and they showed as in POF patients with 46,XX normal karyotype, the percentage of cells with X-chromosome monosomy was significantly higher as compared with controls in the same age. This cytogenetic study of patients with POF showed a high prevalence of chromosome anomalies either in primary or in secondary amenorrhoea. Moreover, they showed that mosaic X-chromosome’s Genetic mutations in POF women Gynecol Endocrinol Downloaded from informahealthcare.com by UNIVERSITA DEGLI STUDI DI PISA on 11/06/12 For personal use only. aneuploidy was the most frequent abnormality and some patients with POF may be attributable to low-level 45,X/ 46,XX mosaicism detectable using FISH analysis [39]. Growth differentiation factor-9 and bone morphogenetic protein 15-mutations. Growth differentiation factor-9 (GDF9) and GDF-9B/bone morphogenetic protein-15 (BMP15), which is closely related homolog, are expressed in the human ovary from the primary follicular stage onward [40,41]. GDF-9 and BMP-15 genes are involved in the maintenance of folliculogenesis and granulosa cell proliferation and its mutation seems to be related to female infertility [42,43]. Di Pasquale et al. firstly reported heterozygous mutation in BMP15 in two sisters with POF presenting with primary amenorrhoea and infertility [44], and they afterwards identified the same mutation in a large cohort of women [45]. Furthermore, a study observed that one alteration in GDF9 (S186Y) and one in BMP15 (L148P) may have led to amenorrhea and high FSH levels as both positions are conserved in a large number of POF affected patients [46]. Also recent studies show how various missense variants of the BMP15 gene are identified among patients with POF. For most variants, the impact of the amino-acid substitution on the protein structure and function is predicted to be low. The two variants predicted as potentially deleterious are also identified among controls and could be considered as rare polymorphisms [47]. 719 Pseudohypoparathyroidism type Ia. Pseudohypoparathyroidism types Ia (PHP-Ia) results from heterozygous inactivating mutations of Gs a, the a-subunit of the heterotrimeric stimulatory G-protein (Gs), caused by mutations of the GNAS1 gene. More than 100 mutations have been characterised in patients with PHP-Ia and these maternally inherited mutations lead to an end-organ resistance to multiple hormones [55]. In particular, The McCune–Albright syndrome is clinically characterised by cafe-au-lait spots, precocious puberty and fibrous dysplasia. Endocrinologists and gynecologists are confronted with new issues when these children reach adulthood. Gonadal function and fertility are often abnormal in women in whom puberty was precocious, owing to the persistence of a variable degree of ovarian autonomy that hinders adequate follicular development and ovulation [56]. Reproductive dysfunction is common in affected women and probably represents partial resistance of the theca and granulosa cells of the ovary to gonadotropins because of deficient Gs a activity [57,58]. Isolated defects. Galactosemia. Classical galactosaemia is an autosomal recessive disorder of galactose assimilation pathway, caused by a deficiency of the enzyme galactose-1-phosphate uridyltransferase (GALT). Long-term complications also include hypergonadotrophic hypogonadism in 60–70% of these patients [48]; however the mechanism of galactoseinduced ovarian toxicity remains unclear. Possible mechanisms of ovarian damage include direct toxicity of galactose and metabolites, deficient galactosylation of glycoproteins and glycolipids, oxidative stress and activation of apoptosis [49]. Nevertheless, Menezo et al. suggest that infertility could rather be related to alterated FSH recognition by its receptor and not to a toxic alteration of the ovary. This hypothesis is supported by a pregnancy obtained in a galactosemiaaffected woman after stimulation with rFSH [50]. Follicle stimulating hormone receptor mutations. Follicle stimulating hormone and it receptor (FSHR) play a crucial role for the initiation of follicular growth only after the primary stage [59,60]. The gene encoding FSHR is located on the short arm of chromosome 2 in humans and consists of 10 exons spanning 54 kB of genomic DNA. FSHR mutation associated with phenotype of POF was first described in the Finnish population [61]. Subsequent studies show a large variety of FSH receptor mutations related to different clinical severity of fertility dysfunctions [62–65]. Some mutations as the Ala189Val one results in a functionally inactive FSHR, consistent with the severe phenotype as poorly developed secondary sexual characteristics, primary amenorrhoea and recessively inherited hypergonadotrophic ovarian failure. However, other mutations had a milder phenotype consisting of normal secondary sexual development and secondary amenorrhoea, compatible with a pregnancy. FSHR mutations are transmitted with a recessive mode and although appear to be rare in most populations [66,67]. Recent studies investigating the presence of mutations/ polymorphisms in the FSH receptor (FSHR) gene and their association with phenotype in women with POF showed that the presence of the Ala307Thr polymorphism may be associated with a more precocious onset of clinical disease [68]. Blepharophimosis-ptosis-epicanthus inversus syndrome. FOXL2 (Forkhead box L2 ) is a transcription factor essential for proper reproductive function in females. Human patients carrying mutations in the FOXL2 gene (chromosome 3q23) display blepharophimosis/ptosis/epicanthus inversus syndrome (BPES), an autosomal dominant disease associated with eyelid defects and POF in females. In BPES type I, craniofacial abnormalities are associated with POF in female patients. The defect can lie in either the oocyte itself or in the surrounding follicle cells [51]. The clinical spectrum of infertility associated with BPES ranges from primary amenorrhea to erratic menses followed by POF. Ovarian appearance can vary from seemingly normal to streak gonads [52,53]. Moreover, more than one hundred mutations of FOXL2 have been described to date. In agreement with the BPES phenotype, FOXL2 is expressed (though not exclusively) in the developing eyelids and in fetal and adult ovaries [54]. Luteinizing hormone receptor mutations. The luteinizing hormone receptor (LHR) plays a critical role in reproductive physiology. A large number of LH receptor mutations were described as the cause of female infertility, and in particular amenorrhoea and ovarian resistance to LH. The most important part of the receptor implied in infertility seems to be the b-subunit, because an increased prevalence of different silent polymorphisms of LH-b subunit variant in women with POF as compared to controls [69,70]. Takahashi et al. reported successful pregnancies after a stimulation protocol with gonadotrophin-releasing hormone analogue and estrogen–progesterone replacement in a women carrying a variant LH b-subunit with severe ovarian dysfunction and infertility associated [71,72]. However, some authors have recently published how the elevation of LH was more pronounced than that of FSH, so their studies could hint towards possible LH receptor mutation, which is generally found in POF, but diagnosis of cases in this region may need a new cut-off level for Autosomal defects Syndromic defects. 720 P. G. Artini et al. POF, as the elevation of FSH itself was not as pronounced as reported by other workers [73]. Inhibin a-subunit. Inhibin a-subunit (INHa) has a role in regulating the pituitary secretion of FSH, acting in negative feedback control of FSH; furthermore it has a pivotal role in the recruitment and development of follicles during follicologenesis. A decline in serum INHa concentration occurs when ovarian follicular pool begins to subside [74] and a defect of this glycoprotein has been reported also in women with PCO [75]. Consequently, INHa has recently been indicated as a potential candidate gene POF pathogenesis. An alteration of INHa gene decreases the bioactive amount of protein and increase of FSH levels, leading to a premature depletion of follicle, typical feature of POF ovaries. The INHa gene mutation candidate in POF pathogenesis is the missense mutation (769G–4A transition) in the exon 2; the functional Gynecol Endocrinol Downloaded from informahealthcare.com by UNIVERSITA DEGLI STUDI DI PISA on 11/06/12 For personal use only. Table II. Minor genes potentially candidates to be involved in POF onset. Gene Gene-name Locus Experimental evidences HSD3B2 Hydroxy-delta-5-steroid dehydrogenase, 3 b- and steroid delta-isomerase 2 LIM homebox 8 1p13.1 Autoantibodies to 3betaHSD in POF patients are rare and are also found in patients with autoimmune polyendocrinopathy syndromes type 1 (APS1) [90]. Mutations in the LHX8 exons are uncommon in Caucasian women with POF [91]. Mutational report of the TGFBR3 gene in correlation with ovarian failure. Significant diversity of genotype distribution and haplotype analysis suggested susceptibility of the TGFBR3 gene for ovarian failure aetiology [92]. Mutations in GPR3 are not a common cause of POF [93]. Subset of women with sporadic, premature ovarian failure harbor mutations in FIGLA [94]. The correlation between the age at onset of the neurological deterioration and the severity of POF suggests a common pathophysiological pathway [95]. DAZL polymorphisms and deletions may be associated with age at menopause and/or sperm count [96]. Patients with a heterozygous substitution in exon 2 of the MSH5 gene and DMC1 homozygote mutation, provide indirect evidence of the role of genes involved in meiotic recombination in the regulation of ovarian function [97]. Potentially causal mutations in FOXO3A and FOXO1A were identified in POF patients [98]. ESR1 gene including PvuII and XbaI polymorphisms may modify the risk of idiopathic premature ovarian failure (POF) but not idiopathic early menopause (EM) risk [99]. Mutations in the homeobox domain of NOBOX are not common explanations for POF [100]. POLG mutations can segregate with POF and demonstrates for the first time that the Y955C mutation can lead to mtDNA depletion [101]. Not a common cause of nonsyndromic premature ovarian failure [102]. Mutations in NANOS3 exons are rare in both Chinese and Caucasian women with premature ovarian failure [103]. Variant LH may contribute to female reproductive disorders, including infertility and premature ovarian failure [104]. The mutations of AIRE gene are responsible for polyendocrinopathies (APS I-III) [105]. LHX8 1p31.1 TGFBR3 Transforming Growth Factor Beta teceptor III 1p33-p32 Gpr3 FIGLA G protein coupled receptor 3 Folliculogenesis specific basic helix-loop-helix Eukaryotic Translation Initiation Factor 2B 1p36.1-p35 2p13.3 DAZL Deleted in Azoospermia-like 3p24 MSH5- DMC1 MutS Homolog5- Disrupted Meiotic cDNA 1 Homolog 6p21.3-22q13.1 Foxo 3a-1a Foxo subfamily 3a-Forkhead box 01 Estrogen receptor a 6q21-13q14.1 eIF2B ESR1 NOBOX 2q11.2 6q25.1 POLG Newborn Ovary Homebox gene Polymerase, Dna, Gamma 15q25 NOG Noggin 17q22 NANOS3 Nanos Homolog 3 19p13.12 LHB 19q13.32 DACH2 Luteinizing Hormone Beta Polypeptide Autoimmune RegulatorAutoimmune Polyendocrinopathy Candidiasis Ectodermal Dystrophy Dachshund homolog 2 POF1B Premature Ovarian Failure Xq21.1-1q21.2 DIAPH2 Diaphanous Homolog 2 POF1 Premature Ovarian Failure 1 AMH Anti-Mullerian hormone AIRE 7q35 21Q22.3 Xq21 Xq21.33 Xq26-q28 19p13.3 Rare mutations in the DACH2 gene may have a role in the POF phenotype [106]. Homozygous point mutation in POF1B influences the pathogenesis of POF by altering POF1B binding to nonmuscle actin filaments [107]. Human DIA gene affects the cell divisions that lead to ovarian follicle formation[108]. Distal X-breakpoint involving POF1 locus is able to cause POF without virilization during adolescence [109]. AMH can inhibit the basal and stimulated development of primordial follicles [110]. Gynecol Endocrinol Downloaded from informahealthcare.com by UNIVERSITA DEGLI STUDI DI PISA on 11/06/12 For personal use only. Genetic mutations in POF women significance of this aminoacid variant is not well understood, but probably it could interfere with receptor binding [76,77]. The prevalence of the G769A variant differs in various population between 0 and 11% [78,79]. However, incomplete penetrance spawn the diatribe on the real action of INHa gene variants, because some researchers suggest that this could explain the disease heterogeneity [77], but other groups very recently suggested that it may not be associated to POF disease [80]. A recent meta-analysis of published studies showed that a decline in inhibin bioactivity caused by a mutation could increase FSH levels; and in a susceptible individual, the heightened sensitivity to gonadotrophins causes POF. Moreover, impaired paracrine effects of inhibin could impact folliculogenesis because of reduced antagonism of activin, bone morphogenetic protein 15 and growth differentiation factor 9. Lots of functional studies of this mutation indicate normal production of dimeric inhibin A and B and impaired bioactivity of inhibin B. So in conclusion the identification of an autosomal mutation in the inhibin a-subunit gene that is significantly linked to POF in certain ethnic populations highlights the role of inhibin in the regulation of ovarian biology and fertility. Although the reduction of inhibin B bioactivity by the INHA G769A mutation is clearly not the only cause, evidence suggests that this change may serve as a susceptibility factor, increasing the likelihood of POF [81]. Ataxia-telangiectasia gene. Ataxia telangiectasia (AT) is an autosomal recessive disorder with an incidence estimated at 1 in 40,000 to 1 in 100,000 live births. AT principal features are oculocutaneous telangiectasia, progressive cerebellar ataxia, B- and T-cell immunodeficiency with recurrent sinopulmonary infections, sensitivity to ionising radiation and cancer predisposition. Infertility is also a common feature of the inherited human disease ataxia telangectasia [82]. ATM, the mutated gene maps to chromosome 11q 22.3 and is known as a member of phosphatidylinositol 3-kinase family [83] and it directly phosphorylates p53 which is involved in response to a critical DNA damage cell-cycle checkpoint control [84–86]. ATM gene mutation causes the complete absence of mature gametes in adult gonads [87,88]; probably due to meiotic arrest at the prophase I as a result of abnormal chromosomal arrangement and subsequent chromosome fragmentation. PGRMC1 gene mutation. Recent studies worked by some authors, analysing mutation of females with idiopathic POF, identified a third patient with a missense mutation (H165R) located in the cytochrome b5 domain of PGRMC1. PGRMC1 mediates the anti-apoptotic action of progesterone in ovarian cells and it acts as a positive regulator of several cytochrome P450 (CYP)-catalysed reactions. The CYPs are critical for intracellular sterol metabolism, including biosynthesis of steroid hormones. H165R mutation associated with POF abolishes the binding of cytochrome P450 7A1 (CYP7A1) to PGRMC1. In addition to this, the missense mutation attenuates PGRMC1s ability to mediate the anti-apoptotic action of progesterone in ovarian cells. So, in conclusion these findings suggested that mutant or reduced levels of PGMRC1 may cause POF through impaired activation of the microsomal cytochrome P450 and increased apoptosis of ovarian cells [89]. Other minor genes potentially candidates to be involved in POF oneset. See Table II. 721 Conclusion POF is transmitted as a familiar inheritance in 4–31% of cases. Infertility is a characteristic feature of POF, nevertheless women with POF have a 5–10% chance of conceiving after diagnosis and pregnancy lost rate is the same as that of general population. This data suggest the importance of a proper genetic counselling to families with POF recurrence. In this review, we analyse the most important genes involved in POF pathogenesis, but the large variety and heterogeneity of genes implicated determine a big variability in transmission modality. Firstly, incomplete penetrance makes difficult to distinguish an autosomal pattern of inheritance from an X-linked one. In addition, it is not well known whether parental imprinting have a role in POF transmission, but hypothetically, there is a similar genetic risk involved in the recurrence of the disorder with both autosomal and X-linked patterns of inheritance [111]. Presently, the most useful genetic investigation is the analysis of FMR1 premutation because the fragile X syndrome is available for the testing and mothers with premutation alleles have the possibility of transmitting a full mutation to her offspring, as well as POF [27,112]. The genetic counselling regarding the other gene involved in POF is today advisable only in families with recurrence for a specific disease. In conclusions, POF is a rare disease which the main feature is infertility, therefore the possibility of pregnancy is not theoretical. The high familiar recurrence underline the importance of an adequate genetic counselling, however the huge heterogeneity of the genetic aspect make difficult at the present a full counselling. Future studies are needed to elucidate the complex pool of gene involved in POF pathogenesis with the intent that gives an adequate advice to women with hidden disease. Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper. References 1. Santoro N. Mechanisms of premature ovarian failure. Ann Endocrinol 2003;64:87–92. 2. Timmreck LS, Reindollar RH. Contemporary issues in primary amenorrhea. Obstet Gynecol Clin North Am 2003; 30:287–302. 3. Coulam CB, Adamson SC, Annegers JF. Incidence of premature ovarian failure. Obstet Gynecol 1986;67:604–606. 4. 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