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Figure 1 shows that compared with his unaffected brother, the mentally retarded twin has a relatively long face, large ears, and a prominent jaw and forehead.

Fragile X syndrome is the most common form of inherited mental retardation, affecting approximately 1 in 1250 males and 1 in 2500 females. Because of the variable and often subtle nature of its physical manifestations, the syndrome may be difficult to diagnose clinically.¹ As young children, fragile X males tend to be taller than their age-matched controls.² On physical examination, other common findings include joint hyperextensibility, pectus excavatum, flat feet, mitral valve prolapse, and aortic root dilatation.^1- 2 Macroorchidism is rarely found before puberty, but it occurs in up to 90% of postpubertal males.¹ While the degree of mental retardation is variable, the mean IQ scores of the affected boys fall between 30 and 45.¹ Commonly seen behavioral abnormalities include autistic-like behaviors, such as hand flapping and gaze avoidance.³ Compared with affected males, females who are affected with fragile X syndrome usually show less severe mental retardation, fewer behavioral problems, and less obvious physical characteristics.²

Until recently, the laboratory diagnosis of fragile X syndrome relied on the finding of a fragile site on the long arm of the X chromosome, at band Xq27.³ This fragile site, called FRAXA is not seen under standard culture conditions, but it can be induced by various methods, such as growth in a medium containing low levels of folate and thymidine.² With the identification of the fragile X syndrome gene, called FMR1, testing for the disorder is now performed at the molecular level using Southern blotting or the polymerase chain reaction of the FMR1 gene directly.⁴ The FMR1 gene product is found in various tissues of the body, with especially high amounts in the brain.¹ The FMR1 mutation responsible for most cases of the fragile X syndrome involves the expansion of a segment of the gene that contains a series of CGG repeats. In normal individuals, the FMR1 gene contains up to approximately 60 CGG repeats. Repeats in the range of 60 to approximately 200 are found in normal transmitting males and have been designated premutations. Expansion repeats to greater than 200 repeats, which only occurs when a premutation is passed on to a child by a carrier female, leads to a full mutation.¹ Children with the full mutation manifest both the clinical and the cytogenetic phenotype of the fragile X syndrome. This expansion of CGG repeats leads to abnormal methylation of the FMR1 gene, causing decreased or absent levels of the FMR1 protein.¹

The discovery of the FMR1 gene also explained the Sherman paradox, the unusual pattern of inheritance that was seen in families with fragile X syndrome. The Sherman paradox refers to the observation that fragile X syndrome did not follow a conventional X-linked type of inheritance. Rather, the chance that an individual would be affected was found to depend on the position within the pedigree. For example, brothers of normal transmitting males are at low risk (≈9%), while grandsons have a much higher risk (≈40%) of having fragile X syndrome.⁵

Due to the prevalence of fragile X syndrome, most professionals believe that molecular testing should be performed in any individual, especially any male, with unexplained mental retardation. Although molecular testing has taken the place of cytogenetic testing for the fragile X syndrome, a constitutional karyotype should also be done in individuals with unexplained mental retardation because they are equally as likely (≈3%) to show a chromosomal abnormality other than FRAXA as they are to be positive for fragile X by molecular testing.⁴

Accepted for publication May 21, 1997.

Reprints: Nathaniel H. Robin, MD, Department of Genetics, Case Western Reserve University School of Medicine, Lakeside 1500, 11100 Euclid Ave, Cleveland, OH 44106.