Female sex preponderance for idiopathic familial premature ovarian failure suggests an X chromosome defect: Opinion

Colin J. Davis1,3, Rina M. Davison2, Nadia N. Payne2, Charles H. Rodeck1 and Gerard S. Conway2

1 Department of Obstetrics and Gynaecology, 2 Department of Endocrinology, University College Hospital London, The Cobbold Laboratories, Middlesex Hospital, London W1N 8AA, UK


    Abstract
 Top
 Abstract
 Premature ovarian failure is...
 Genetic associations with POF...
 A detailed family history...
 Pedigree analysis infers...
 POF pedigrees appear to...
 Amalgamated published pedigrees...
 Female predominance in POF...
 Occult X chromosome defects...
 Consanguinity is an unusual...
 Conclusions
 References
 
Premature ovarian failure (POF) is defined as ovarian failure occurring before the age of 40 years. A genetic aetiology is suggested by the occurrence of families with two or more affected females. We have characterised the pattern of inheritance of 41 cases of familial POF and compared them to published pedigrees. In eleven families a clear genetic association of POF could be identified. In the remaining 30 families the mechanism of inheritance was obscure. We found a female sex preponderance in the siblings of 30 families with idiopathic POF and in previously published series of idiopathic familial POF. In contrast, other known causes of POF, such as blepharophimosis ptosis epicanthus and inversus and autosomal recessive gonadal dysgenesis, had no altered sex ratio. One of our series of 30 pedigrees demonstrated transmission of POF susceptibility through fathers, which we believe is the first to be described in the literature. We present a group of five consanguineous families where we assume the mode of inheritance is autosomal recessive and where there was no female sex preponderance. Female sex preponderance for idiopathic familial POF suggests an X chromosome defect is inherited as a major cause of ovarian failure.

Key words: BPES/FRAXA premutation/premature ovarian failure/X chromosome


    Premature ovarian failure is familial in up to one-third of cases
 Top
 Abstract
 Premature ovarian failure is...
 Genetic associations with POF...
 A detailed family history...
 Pedigree analysis infers...
 POF pedigrees appear to...
 Amalgamated published pedigrees...
 Female predominance in POF...
 Occult X chromosome defects...
 Consanguinity is an unusual...
 Conclusions
 References
 
Menopause before the age of 40 years is defined as premature ovarian failure (POF) and its incidence is widely quoted as 1% (Coulam et al., 1986Go). The aetiology of this condition is heterogeneous with the majority being idiopathic (Conway et al., 1996Go). A genetic basis for ovarian failure is suggested in families with two or more women affected with POF (Coulam et al., 1983Go; Mattisson et al., 1984; Aittomaki, 1994Go; Vegetti et al., 1998Go; Van Kasteren et al., 1999Go). With careful analysis of the family history, the prevalence of familial POF has been reported to be 4, 12.7 and 31% in various series (Conway et al., 1996Go; Vegetti et al., 1998Go; Van Kasteren et al., 1999Go).

The mode of inheritance of idiopathic familial POF is usually impossible to define because of necessarily small pedigrees; autosomal dominant, X-linked dominant (Van Kasteren et al., 1999Go) and autosomal recessive (Aittomaki, 1994Go; Meyers et al., 1996Go) are each possible. POF, however, also presents as a part of the phenotype of rare syndromes for which the mode of inheritance is clear.


    Genetic associations with POF provide examples of inheritance patterns
 Top
 Abstract
 Premature ovarian failure is...
 Genetic associations with POF...
 A detailed family history...
 Pedigree analysis infers...
 POF pedigrees appear to...
 Amalgamated published pedigrees...
 Female predominance in POF...
 Occult X chromosome defects...
 Consanguinity is an unusual...
 Conclusions
 References
 
Blepharophimosis ptosis epicanthus and inversus (BPES) is transmitted in an autosomal dominant fashion. It has been divided into type I in which females experience ovarian failure and type II in which females have normal fertility (Zlotogora et al., 1983Go). Subsequently, both types have been mapped to the same locus in 3q22q23, suggesting that ovarian failure is part of a spectrum of phenotype rather than a distinct entity (Amati et al., 1996Go; Toomes et al., 1998).

The inactivating point mutations of the FSH receptor are responsible for POF inherited as an autosomal recessive trait first recognized in Finland (Aittomaki et al., 1995Go). This specific loss of function mutation has not been identified in other groups of women with ovarian failure (Layman et al., 1998Go; da Fonte Kohek et al., 1998Go; Conway et al., 1999Go). Recently, a woman presenting with secondary amenorrhoea has been reported to have FSH receptor mutations (Beau et al., 1998Go).

Fragile X syndrome is a common cause of moderate learning difficulties in males. It is due to an expansion of >200 trinucleotide repeats in exon 1 of the FMR1 gene resulting in failure of gene transcription and protein synthesis which occurs most notably in the brain and ovary (Hinds et al., 1993Go). The FRAXA premutation occurs when there are between 50 and 200 trinucleotide repeat sequences. FRAXA premutations are associated with POF (Conway et al., 1995Go; Partington et al., 1996Go; Uzielli et al., 1999Go), accounting for 16% of kindreds with familial POF (Conway et al., 1998Go). While the mechanism of ovarian failure remains obscure in women with the FRAXA premutation, this association provides an example of X dominant inheritance (Allingham-Hawkins et al., 1999Go).

In Turner's syndrome (karyotype 45XO) ovarian dysgenesis occurs in ~84% of cases (Pasquino et al., 1997Go). One major X chromosome locus for POF is on the short arm Xp 11.2–22.1 (Zinn et al., 1998Go). Lesser defects of the X chromosome are often associated with POF. On the long arm of the X chromosome a POF1 locus has been assigned to Xq26-q28 (Fitch et al., 1982Go; Krauss et al., 1987Go; Davison et al., 1998Go) and POF2 locus at Xq13-q21 (Powell et al., 1994Go). Families transmitting stable deletions of the X chromosome provide another example of X dominant POF. (Fitch et al., 1982Go; Krauss et al., 1987Go; Veneman et al., 1991Go; Powell et al., 1994Go; Davison et al., 1998Go). We noted that pedigrees transmitting X chromosome defects have a predominance of females presumably because the males inheriting an abnormal X are not viable. We postulated that if occult defects of the X chromosome were responsible for the inheritance of cytogenetically normal POF then pedigrees might also show female selection.


    A detailed family history can reveal occult inheritance of POF
 Top
 Abstract
 Premature ovarian failure is...
 Genetic associations with POF...
 A detailed family history...
 Pedigree analysis infers...
 POF pedigrees appear to...
 Amalgamated published pedigrees...
 Female predominance in POF...
 Occult X chromosome defects...
 Consanguinity is an unusual...
 Conclusions
 References
 
Forty-one families with more than one female affected with POF were identified from our reproductive medicine and endocrinology clinics at University College Hospital London. The definition of POF was a cessation of menses for a duration of 6 months or longer before the age of 40 years in the presence of raised FSH >40 IU/l. We noted that five families comprised affected females with both primary and secondary amenorrhoea, three families with primary amenorrhoea only and 22 families with secondary amenorrhoea only. Because of this variable penetrance of ovarian failure, we have chosen to include subjects who might have been labelled as `ovarian dysgenesis'.

A total of 35 families was identified by detailed family history taken from each of 184 women with POF. The prevalence of familial POF in our series has risen from 4% quoted in an earlier paper (Conway et al., 1996Go) to 19% by the process of detailed interview in a similar fashion to that described (Van Kasteren et al., 1999Go). A further six families have been referred to our clinic because of our research interest. Families were categorized according to physical stigmata of BPES, FRAXA premutation screening and FSH receptor mutation screening. Cytogenetic analysis was performed on all probands.

A detailed family history was obtained from each proband and in a total of 80% of families parents were interviewed. Family histories included medical information about parental and grandparent siblings where possible. In four of the 11 `sibling only' pedigrees it was impossible to obtain detailed information of paternal siblings. For these families the number of affected females may have been underestimated. From each family tree the following was recorded: the age of onset of amenorrhoea, and the total number of male and female siblings. In this exercise, there is a particular problem with ascertainment bias. All familial forms of POF were identified on the basis of at least one affected female. For statistical analysis therefore, one female from each family was removed from consideration. For the six families referred to us because of a familial tendency, two females were removed for statistical analysis on the premise that our ascertainment was on the basis of at least two affected members with POF. We have compared inheritance patterns in all known forms of familial POF and applied ascertainment correction uniformly.

Results are expressed as means and percentages. The significance of the distribution of primary amenorrhoea or sex ratio between groups was tested using {chi}2 distribution and Fisher's exact tests, as appropriate.


    Pedigree analysis infers variable modes of inheritance of POF
 Top
 Abstract
 Premature ovarian failure is...
 Genetic associations with POF...
 A detailed family history...
 Pedigree analysis infers...
 POF pedigrees appear to...
 Amalgamated published pedigrees...
 Female predominance in POF...
 Occult X chromosome defects...
 Consanguinity is an unusual...
 Conclusions
 References
 
We identified 41 families with POF comprising the following: 30 with idiopathic POF, six of which were referred to us on the basis of our research interest, seven FRAXA premutation families, three families with BPES and one with an X chromosome deletion. Apart from this latter instance all other families were cytogenetically normal. The family trees of affected generations for our series of 30 families with idiopathic POF are shown in Figure 1Go. Five consanguineous pedigrees and one pedigree with transmission of susceptibility through fathers were identified and the inheritance pattern of these was assumed to be autosomal recessive and autosomal dominant respectively. The remaining 24 pedigrees were grouped into `sibling only' pedigrees and `multiple generation' pedigrees (Figure 1Go and Table IGo).



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Figure 1. Patterns of inheritance in 30 families with idiopathic premature ovarian failure (POF). • Female with POF occurring before the age of 40 years. {circ} Female not affected with POF or not yet reached 40 years. {square} Male.

 

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Table I. Analysis of a series of 30 families with idiopathic premature ovarian failure
 

    POF pedigrees appear to contain an excess of female siblings
 Top
 Abstract
 Premature ovarian failure is...
 Genetic associations with POF...
 A detailed family history...
 Pedigree analysis infers...
 POF pedigrees appear to...
 Amalgamated published pedigrees...
 Female predominance in POF...
 Occult X chromosome defects...
 Consanguinity is an unusual...
 Conclusions
 References
 
When all 30 idiopathic families were considered together there was a preponderance of female siblings of women with POF (ratio 2.6:1, corrected for ascertainment bias to 1.7:1, P = 0.036). This altered sex ratio was especially apparent in `sibling only' pedigrees and was not evident in consanguineous families or the family with transmission of susceptibility through fathers (Table IGo). Affected females of `sibling only' pedigrees were more likely to present with primary amenorrhoea and had a trend to earlier onset of secondary amenorrhoea compared with other inheritance patterns (Table IGo). Interestingly, a similar reduction in male siblings of affected females was found in a paper examining the families of women with early (as opposed to premature) menopause (Cramer et al., 1995Go).


    Amalgamated published pedigrees of idiopathic POF also show predominance of female siblings
 Top
 Abstract
 Premature ovarian failure is...
 Genetic associations with POF...
 A detailed family history...
 Pedigree analysis infers...
 POF pedigrees appear to...
 Amalgamated published pedigrees...
 Female predominance in POF...
 Occult X chromosome defects...
 Consanguinity is an unusual...
 Conclusions
 References
 
For comparison, we assessed the inheritance patterns of all published forms of inherited POF. These included BPES, autosomal recessive gonadal dysgenesis families, FRAXA premutation and X chromosome deletions. In some instances only families with accurate data were included (Vegetti et al., 1998Go). The following pedigrees with POF were identified: 91 families with autosomal recessive gonadal dysgenesis, 13 with idiopathic POF, one with FRAXA premutation, seven with BPES and four with X chromosome deletions. Our families with POF associated with BPES (n = 3), FRAXA premutation (n = 7) and X chromosome defect (n = 1) were combined with the published families to assess the female/male sex ratio (Table IIGo). No FSH receptor mutations were found in our families. A similar excess of female siblings was found in the combined published idiopathic POF group but not in other forms of POF, although a trend to an altered sex ratio appeared to occur in the X chromosome defect group (Table IIGo), but this was not statistically significant.


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Table II. Comparison of a series of 30 families with idiopathic premature ovarian failure (POF) with published series
 

    Female predominance in POF pedigrees may arise from ascertainment bias
 Top
 Abstract
 Premature ovarian failure is...
 Genetic associations with POF...
 A detailed family history...
 Pedigree analysis infers...
 POF pedigrees appear to...
 Amalgamated published pedigrees...
 Female predominance in POF...
 Occult X chromosome defects...
 Consanguinity is an unusual...
 Conclusions
 References
 
One explanation for altered sex ratio in POF pedigrees is ascertainment bias. Most of our familial cases were ascertained when family history of POF became evident from interview with an apparent sporadic case. In these cases a correction for bias was made by removal of the proband in the sex ratio analysis. When families were referred `intact', two females were removed from consideration. Some women may have been aware of a family history of early menopause and despite the correction it is still possible that ascertainment bias has distorted the figures. In a second strategy, we have compared sex ratios across different causes of POF maintaining correction for ascertainment through females. This comparison demonstrates that the combined idiopathic series and the X chromosome defects group share a female preponderance suggesting that a common mechanism is in play.


    Occult X chromosome defects provide an alternative mechanism for female predominance in POF pedigrees
 Top
 Abstract
 Premature ovarian failure is...
 Genetic associations with POF...
 A detailed family history...
 Pedigree analysis infers...
 POF pedigrees appear to...
 Amalgamated published pedigrees...
 Female predominance in POF...
 Occult X chromosome defects...
 Consanguinity is an unusual...
 Conclusions
 References
 
One biological explanation for an excess of females is through occult defects of the X chromosome. The series of families with X chromosome defects showed a similar degree of female preponderance but did not achieve significance because of small numbers. It has been postulated that ovary-determining genes on the X chromosome must escape X inactivation (Davis et al., 1998Go; Davison et al., 1999Go) and do not have homologues on the Y chromosome (Page et al., 1987Go). Thus males would be haplo-insufficient for these genes, some of which might have a vital extra-ovarian function. Males inheriting mutations of genes on the X chromosome would have to be non-viable. No male subject with a terminal deletion of the long arm of the X chromosome has been described. It has been postulated that essential genes necessary for life, such as glucose-6-phosphate dehydrogenase are located on the long arm of the X chromosome and therefore haplo-insufficient males would be non-viable (Fitch et al., 1982Go). In the process of our interviews no other suggestion of male lethality such as miscarriage emerged.

We would expect that `multiple generation' pedigrees would have a dominant mode of inheritance whereas `sibling only' pedigrees could reflect either recessive or dominant modes. Interestingly, the altered sex ratio was present in both `multiple generation' and `sibling only' pedigrees, again, suggesting a common mechanism. If this is so, then the determinant of `sibling only' pattern must be the phenotype of primary amenorrhoea preventing vertical transmission rather than through a recessive pattern of inheritance. The fact that a female preponderance is still evident in the `sibling only' group (Table IIGo) would suggest an X-linked inheritance. As previously mentioned, some of the `sibling only' pedigrees may have had occult paternal inheritance as details of paternal aunts were occasionally missing.


    Consanguinity is an unusual feature in familial POF
 Top
 Abstract
 Premature ovarian failure is...
 Genetic associations with POF...
 A detailed family history...
 Pedigree analysis infers...
 POF pedigrees appear to...
 Amalgamated published pedigrees...
 Female predominance in POF...
 Occult X chromosome defects...
 Consanguinity is an unusual...
 Conclusions
 References
 
The five consanguineous families are the first to be described for POF and all arise from a wide region of the Indian subcontinent. We presume that POF is inherited in an autosomal recessive manner in these families. The gene(s) responsible for POF do not appear to have an influence on sex ratio in these families. Also, our pedigree demonstrating transmission of susceptibility through fathers is the first definite proof of autosomal dominant inheritance of POF.


    Conclusions
 Top
 Abstract
 Premature ovarian failure is...
 Genetic associations with POF...
 A detailed family history...
 Pedigree analysis infers...
 POF pedigrees appear to...
 Amalgamated published pedigrees...
 Female predominance in POF...
 Occult X chromosome defects...
 Consanguinity is an unusual...
 Conclusions
 References
 
The concept of POF as a heterogeneous disease is well established; however, a definable genetic cause is strongly suggestive in certain families. A detailed, precise family history of POF is essential for defining a subgroup of familial POF. The aim of identifying mutations causing familial POF is daunting because many genes may be involved. If this observation of an altered sex ratio in POF families is substantiated then focusing on the X chromosome may bring early rewards.


    Notes
 
3 To whom correspondence should be addressed at: Department of Obstetrics and Gynaecology, University College Hospital London, London, UK. E-mail: c8davis{at}aol.com Back


    References
 Top
 Abstract
 Premature ovarian failure is...
 Genetic associations with POF...
 A detailed family history...
 Pedigree analysis infers...
 POF pedigrees appear to...
 Amalgamated published pedigrees...
 Female predominance in POF...
 Occult X chromosome defects...
 Consanguinity is an unusual...
 Conclusions
 References
 
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Submitted on May 12, 2000; accepted on July 11, 2000.