Clinical Report—Health Supervision for Children With Fragile X Syndrome

Fragile X syndrome (an FMR1–related disorder) is the most commonly inherited form of mental retardation. Early physical recognition is difficult, so boys with developmental delay should be strongly considered for molecular testing. The characteristic adult phenotype usually does not develop until the second decade of life. Girls can also be affected with developmental delay. Because multiple family members can be affected with mental retardation and other conditions (premature ovarian failure and tremor/ataxia), family history information is of critical importance for the diagnosis and management of affected patients and their families. This report summarizes issues for fragile X syndrome regarding clinical diagnosis, laboratory diagnosis, genetic counseling, related health problems, behavior management, and agerelated health supervision guidelines. The diagnosis of fragile X syndrome not only involves the affected children but also potentially has significant health consequences for multiple generations in each family. Pediatrics 2011;127:994–1006 INTRODUCTION This set of guidelines was designed to assist pediatricians in caring for children with fragile X syndrome after a diagnosis has been confirmed by DNA analysis. Fragile X syndrome (secondary to an abnormality in the fragile X mental retardation 1 [FMR1] gene) is the most commonly inherited formofmental retardation. The disorder affects the child and potentially the mother and other family members. These guidelines, therefore, discuss issues pertinent to the clinical manifestations of this disorder in younger and older people. The multiple manifestations in different age groups have led to fragile X syndrome being designated as one in the spectrum of FMR1-related disorders.1 Awareness that mental retardation has a sex-linked component, with an excess of males affected, has existed for more than a century.2 This observation led to the suggestion that genes affecting cognition were located on the X chromosome. In 1943, Martin and Bell3 reported that mental retardation segregated as an X-linked gene in a family in which both males and females were affected. Twenty-six years later, in 1969, Lubs4 reported a distinctive fragile site on the X chromosome, which required culture media deficient in folic acid to be induced on a chromosome analysis, that segregated with mental retardation in 3 generations of a family. This is now known as the fragile X chromosome. In 1977, the relationship of this fragile site at band q27.3 on the long arm of the X chromosome (Xq27.3) to X-linked mental retardation was confirmed, and fragile X syndrome, as a clinical entity, was defined. Since Joseph H. Hersh, MD, Robert A. Saul, MD, and COMMITTEE ON GENETICS