The first case described: monozygotic twin sisters with the fragile X premutation but with a different phenotype for premature ovarian failure.

Objective To describe the first case of monozygotic twin sisters with fragile X premutation and discordance for premature ovarian failure (POF). Design A descriptive case study. Setting Academic center. Patient(s) Monozygotic twin sisters with fragile X premutation and discordance for POF. Intervention(s) Serum laboratory testing, fragile X premutation screening, zygosity testing, X-inactivation ratio and Southern blot studies. Main Outcome Measure(s) Incidence of POF in this twin cohort. Result(s) Zygosity analysis using polymerase chain reaction of 15 polymorphic markers via capillary gel electrophoresis in these patients confirmed their monozygosity. X-inactivation studies were performed using the human androgen receptor ( HUMARA ) gene and revealed similar X-inactivation ratios for both the patient and her sister (11:89 and 12:88, respectively) from peripheral serum samples. Southern blot evaluation of the proband and her sister revealed a similar methylation pattern in which the premutation allele was unmethylated much more than the normal allele. The contribution of the premutation on the active allele as determined by Southern blot analysis was consistent between sisters. Conclusion(s) The inactivation ratio studies and subsequent Southern blot analysis do not show differences between the patients; therefore, we are unable to identify a causative mechanism for the identical sisters' discordant phenotypes. It is possible that the inactivation ratios observed from the peripheral blood specimens obtained from the sisters do not represent the allele expression and skewing present at the level of the ovary.