Autosomal translocation associated with premature ovarian failure.

EDITOR—Although the average age of menarche has decreased over the last century, the mean age of menopause appears to be invariant with time and race and occurs at approximately 50 years. The loss of functional follicles occurring in women under the age of 40 is defined as premature ovarian failure. It occurs in about 1-2% of women, in some as early as their teens. Before the onset of premature ovarian failure, most women appear to have a normal menstrual history, age of menarche, and fertility. Unexplained premature ovarian failure is clinically recognised as amenorrhoea with low levels of oestrogen and raised levels of luteinising hormone (LH) and follicle stimulating hormone (FSH) occurring before the age of 40. Premature ovarian failure may have a chromosomal, genetic, enzymatic, iatrogenic, autoimmune, or infectious aetiology. In approximately 5% of women with premature ovarian failure there is a significant family history of early menopause. However, in most cases, no known cause has been identified. Genetic causes have been suggested, and a range of candidate loci have been identified. These regions are currently under investigation to determine the underlying basis of ovarian failure. The proband (III.10), a 33 year old woman, presented for fertility care. She is the only woman in a sibship of three and her pedigree is shown in fig 1. Her brothers have fathered healthy children and each of their wives has had one early spontaneous miscarriage. Her mother (II.3) had an uncomplicated gynaecological history with no menstrual disturbances and underwent an easy menopause at the age of 55 years. She had an early miscarriage and three successful pregnancies, which were separated by four and nine years respectively. The proband’s paternal grandmother (I.2) had two healthy pregnancies two years apart and was described as having had a problematical menopause in her early sixth decade. There is no family history of ill health or disability. There is a suggestion that some of the males in the family could be subfertile, as they have had small families and the children have been widely spaced. The proband experienced menarche at the age of 14 and her menses were irregular. She suVered secondary amenorrhoea at the age of 16 years with markedly increased FSH and LH levels. She has been treated with hormone replacement therapy for the past 10 years, which has resulted in cyclical bleeding. She has remained anovulatory. The karyotype of the proband showed a translocation between chromosomes 2 and 15: 46,XX,t(2;15) (q32.3;q13.3). Fig 2 shows the breakpoints of the chromosomes. On further investigation of her family, her father was found to have the same translocation. Her brothers have declined cytogenetic testing at this time. In most cases of POF, no cause can be identified. Iatrogenic agents, such as chemotherapy or radiotherapy, are known to reduce follicle numbers. Chromosomal abnormalities have been described, especially those that involve the X chromosome. These include XO (Turner’s syndrome), 47,XXX, X chromosome mosaics (45,XO/ 46,XX, 46,XX/47,XXX, 45,XO/46,XX/47,XXX), X chromosome deletions and inversions, and X;autosome balanced translocations. A family history has been noted in some women with POF, approximately 5%, that would suggest an inherited defective gene. Several candidate genes have been suggested to cause both familial and sporadic POF. These include genes on the X chromosome