A cryptic full mutation in a male with a classical fragile X phenotype

Fragile X syndrome (FRX) is the most common inherited cause of mental retardation affecting approximately 1/4000 males and half as many females. Mosaicism has been reported in 12-41% of male cases. We present a 47-year-old male with the typical FRX phenotype referred for an evaluation of mental retardation and a psychiatric disorder. Analysis of the FMR-1 CGG repeat size was performed on peripheral blood by PCR and Southern blot analysis. The proband was shown to carry a premutation allele of 58 CGG repeats. Because of the compelling clinical phenotype, further testing was performed on DNA extracted from skin fibroblasts, which yielded a 500 CGG repeat allele. Mosaic cases of FRX have been reported but rarely without detectable mosaicism in peripheral blood. Therefore, this case is atypical because of the striking differences in the results obtained for the two different cell types. We concur with others that testing of ectodermally derived tissues may provide improved diagnosis and perhaps better insight into the overall prognosis of the affected individual. This case demonstrates the need to consider further study on other tissues when there is a strong clinical suspicion of FRX.