1 Department of Obstetrics and Gynaecology, 2 Department of Endocrinology, University College Hospital London, The Cobbold Laboratories, Middlesex Hospital, London W1N 8AA, UK
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Abstract |
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Key words: BPES/FRAXA premutation/premature ovarian failure/X chromosome
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Premature ovarian failure is familial in up to one-third of cases |
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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., 1999) and autosomal recessive (Aittomaki, 1994
; Meyers et al., 1996
) are each possible. POF, however, also presents as a part of the phenotype of rare syndromes for which the mode of inheritance is clear.
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Genetic associations with POF provide examples of inheritance patterns |
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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., 1995). This specific loss of function mutation has not been identified in other groups of women with ovarian failure (Layman et al., 1998
; da Fonte Kohek et al., 1998
; Conway et al., 1999
). Recently, a woman presenting with secondary amenorrhoea has been reported to have FSH receptor mutations (Beau et al., 1998
).
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., 1993). The FRAXA premutation occurs when there are between 50 and 200 trinucleotide repeat sequences. FRAXA premutations are associated with POF (Conway et al., 1995
; Partington et al., 1996
; Uzielli et al., 1999
), accounting for 16% of kindreds with familial POF (Conway et al., 1998
). 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., 1999
).
In Turner's syndrome (karyotype 45XO) ovarian dysgenesis occurs in ~84% of cases (Pasquino et al., 1997). One major X chromosome locus for POF is on the short arm Xp 11.222.1 (Zinn et al., 1998
). 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., 1982
; Krauss et al., 1987
; Davison et al., 1998
) and POF2 locus at Xq13-q21 (Powell et al., 1994
). Families transmitting stable deletions of the X chromosome provide another example of X dominant POF. (Fitch et al., 1982
; Krauss et al., 1987
; Veneman et al., 1991
; Powell et al., 1994
; Davison et al., 1998
). 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.
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A detailed family history can reveal occult inheritance of POF |
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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., 1996) to 19% by the process of detailed interview in a similar fashion to that described (Van Kasteren et al., 1999
). 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 2 distribution and Fisher's exact tests, as appropriate.
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Pedigree analysis infers variable modes of inheritance of POF |
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POF pedigrees appear to contain an excess of female siblings |
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Amalgamated published pedigrees of idiopathic POF also show predominance of female siblings |
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Female predominance in POF pedigrees may arise from ascertainment bias |
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Occult X chromosome defects provide an alternative mechanism for female predominance in POF pedigrees |
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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 II) 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.
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Consanguinity is an unusual feature in familial POF |
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Conclusions |
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Notes |
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References |
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Submitted on May 12, 2000; accepted on July 11, 2000.