Fragile-X Syndrome A fragile site on the X chromosome has been implicated in mental retardation and behavioral problems among both males and females. The fragile-X syndrome is second only to Down syndrome among causes of mental retardation associated with cytogenetic abnormalities. The clinical phenotype is extremely variable. During the early years, many affected children demonstrate normal or near-normal intellect and development. Folic acid may be of benefit before puberty. Because of the large number of males with mental retardation, the concept of an X-linked factor was proposed in the 1940s(1,2) and revitalized in the 1960s.(3,4) In 1969, Lubs(5) reported on a family with mental retardation and a specific "marker-X" chromosome in two brothers and their mother. This entity is now referred to as the fragile-X syndrome. It is responsible for approximately 40 percent of all X-linked mental retardation.
An evaluation of school-age children in England disclosed fragile-X-associated mental retardation in one out of 1,350 males and one out of 2,033 females, giving an overall prevalence of one per 1,634 in the children studied.(6) In Australia, the prevalence rates for intellectually handicapped persons with the fragile-X syndrome in the public school population were computed to be one in 2,610 males and one in 4,221 females.(7) The reported prevalence of this syndrome in various populations has ranged from 1.9 percent to 5.9 percent.(8,11) This makes fragile-X syndrome second only to Down syndrome among etiologies of mental retardation associated with cytogenic abnormalities.
Fragile-X syndrome primarily affects males, but unlike other X-linked diseases, it may also significantly affect females. Since this is an inherited disorder, the family physician is in a unique position to identify and counsel affected families and thus prevent recurrence of the syndrome.
The clinical data presented here are based on findings in members of 39 families affected with fragile-X syndrome. Within these families, there are 93 affected males and 33 affected females.
The adult male patient with this syndrome typically has a long face, large ears, prominent forehead, midfacial hypoplasia and a prominent jaw. The long face and the large ears are the two most common facial features.
Macro-orchidism is a significant diagnostic feature among the adult male population. This feature is not reported, however, in approximately half of the prepubertal males. This may represent a failure to recognize increased testicular volume in prepubertal males, either because of inadequate examination technique or because of unfamiliarity with the range of normal for this age group.
The phenotype of affected individuals is highly variable; adult males are more likely to exhibit the characteristic features than prepubertal males or females. Facial features among affected females are exceedingly variable and cannot be used to make the diagnosis. Table 1 presents the physical, findings and their frequency among males with fragile-X syndrome in our study.
Typical fragile-X syndrome pedigree. It demonstrates the pattern of X-linked inheritance. Carrier females pass the condition to their daughters (who may or may not have the fragile-X chromosome on laboratory testing), who may then pass it on to their sons. Females who have the fragile-X are frequently mentally retarded. An obligate carrier is negative for the fragile-X but, based on analysis of the family pedigree, she must carry the condition.
Within one family, 31 patients have had chromosome studies completed. There are six mentally retarded males with the fragile-X, one mentally retarded male without the fragile-X, one mentally retarded female and four nonretarded females with the fragile-X, four obligate carriers and 12 potential carriers ascertained by pedigree and laboratory analysis.
Fragile sites on chromosomes, identified as nonstaining gaps in the chromatin structure, were described in 1965.(12) It was not until 1976 and 1977 that the fragile site on the X chromosome was related to a common form of X-linked mental retardation.(13,14) The fragile site appears as a gap or break on the long arm of the X chromosome in the 27 or 28 region.
A standard chromosomal analysis will not demonstrate fragile-X. The cytogenetic expression is dependent on a culture medium deficient in folate and thymidine. The blood sample should be drawn into a sodium heparin tube, and the cell cultures can be grown from lymphocytes.
The fragile condition is not expressed in all cells. In our experience, the percentage of expression of fragile sites among males ranged from 3 to 56 percent (mean: 23 percent). Among females, the range was from 3 to 47 percent (mean: 16 percent). The percentage of cells with fragile sites (degree of expression) does not correlate with the intelligence level or the presence of characteristic craniofacial features.
Developmental, Intellectual and Behavioral Characteristics
Characteristics of behavior and intellect are far more significant for lifetime functioning and are more consistent diagnostic tools than are the physical findings associated with fragile-X syndrome. Early diagnosis enables the physician to provide management, intervention and preventive services for the affected individual and the family.
Because of the lack of significant dysmorphic features, deviations from normal growth and development provide the earliest postnatal clues to the diagnosis of fragile-X syndrome. These milestones are easily and routinely monitored by family physicians and parents.
Initial reports indicated that males with fragile-X had generalized overgrowth during the prenatal period and that this extended into early childhood.(15-18) We reviewed growth data on 33 affected males and reported that "excessive prenatal growth in fragile-X males may reflect, in part, differences in commonly used newborn growth references."(19) We were able to evaluate the patient's head circumference, length and weight, retrospectively, from the time of birth.
Data on postnatal growth from the age of one month to 18 years were available for 32 males. No deviation in weight was reported, but height (length) was accelerated for the first five years of life; thereafter, stature of the males with fragile-X did not differ from that of normal children.(20)
Head circumference was measured in an institutionalized population of 34 white and 26 black postpubertal males with the syndrome, who ranged in age from 18 to 67 years. The mean head circumference was 56.96 cm. While this approximated the mean for normal adult males, it was significantly above the mean of 55.77 cm for a sample of 100 institutionalized, mentally retarded adult males without the clinical features of fragile-X. Anthropometric data probably remain too variable to be a significant aid in making the diagnosis of fragile-X syndrome.
Milestones of early development may be moderately or severely delayed.(16,21,22) Children with fragile-X syndrome may not be brought to the attention of a physician and may do quite well until difficulties with speech and language develop. Boys with the syndrome have demonstrated normal intellectual ability when assessed at an early age,(23,24) and many remain undetected until the first few years of formal education.
Mental retardation is the most significant clinical finding in the fragile-X syndrome. Table 2 presents the mean and standard deviation of intellectual abilities and percentage of expression of fragile-X sites seen on chromosomal analysis among 126 tested individuals with fragile-X syndrome. As one might expect, intellectual functioning is more severely affected in male hemizygotes than in female heterozygotes. The concept of a slowly progressive neurologic degeneration underlying the decline in IQ cannot be excluded.
One of our patients was tested with the revised Wechsler Intelligence Scale for Children when he was seven years and eight months of age. He earned a full scale IQ of 93. He was given the same test at ten years and ten months of age and earned a full scale IQ of 64. Retrospective analysis of longitudinal intellectual data among 21 males with fragile-X syndrome demonstrated a significant decrease in IQ during childhood, thereby lending support to the concept of either a progressive neurologic deterioration or an arrest in development.(24,25)
Hagerman and colleagues(23) studied four young male patients who were referred for evaluation because of mild learning disabilities and attention difficulties. These patients, ranging in age from four to seven years, had demonstrated intellectual abilities in the low-normal to mildly retarded range. It is significant that, first, these four boys had fragile-X syndrome and were not considered retarded by either their parents or their teachers and, second, that mental retardation was not the presenting complaint. The family physician should be aware that absence of frank mental retardation does not rule out fragile-X syndrome.
Autism and autistic-like behaviors have been observed in a number of males with fragile-X, especially during early childhood.(14,26-30) One investigator(31) studied 76 autistic males and found four patients (5.3 percent) who demonstrated fragile-X. Results of a study of 183 autistic males, when combined with data from 11 other investigators, showed that the fragile-X syndrome was present in 7.7 percent of autistic males, while 21.2 percent of the males with the syndrome exhibited autistic behaviors.(32)
Hyperactivity was observed in many of our patients and also has been reported by other authors.(15,23,30,33,34) Other behaviors seen among affected patients include aggressive, self-mutilating, psychotic and schizoid behaviors.(30) Retardation and behavioral difficulties are generally less severe in female patients with fragile-X. Our experience, however, has shown that some affected females fall into the severely retarded range in terms of general intellectual functioning. Other investigators have reported similar observations.(35-38)
Evaluations of nonretarded females with the fragile-X have demonstrated unsuspected learning disabilities, with the possibility of mild, neuropsychologic dysfunction of the right cerebral hemisphere.(37,39,40) In a series of 23 females with fragile-X, 41 percent had some physical signs of the syndrome and 65 percent had one or more behavioral or emotional problems. Furthermore, five of the ten girls who were of school age had been identified by the school psychologist as "learning-disabled."(41) The data suggest that identifiable chromosomal abnormalities can be seen in patients without significant deficits or dysmorphology, and that such abnormalities should be included in the differential diagnosis among patients with learning disabilities or attention disorders.
There are reports of positive behavioral changes in males with fragile-X syndrome who were treated with folic acid.(27,42) A later study of this treatment in affected males(43) employed a double-blind crossover method of investigation. The patients were given psychologic, language and behavioral evaluations. Subjective behavioral reports from parents and caretakers were also obtained. These subjective evaluations indicated that prepubertal males showed increased attention spans and decreased levels of hyperactivity, aggressiveness, hand flapping and other abnormal movements while they were receiving folic acid. The psychologic assessment demonstrated statistically significant improvement in these patients during folic acid therapy.
We have treated a number of prepubertal males with folic acid, 10 mg daily. Parents and teachers reported improved behavior, intellectual performance and attention to tasks. Unfortunately, adult males treated with folic acid have exhibited minimal or no improvement.(43-46) Some patients demonstrated subjective behavioral improvement, while others became more hyperactive and more aggressive.(43)
Pharmacologic treatment of the attention deficit disorder in children with fragile-X syndrome has been reported to be effective. One child development unit found certain medications, including methylphenidate (Ritalin), dextroamphetamine (Dexedrine) and pemoline (Cylert), beneficial in 38 percent of the patients.(46)
As with other conditions that result in mental retardation or significant learning disabilities, the primary treatment is education. The patients should have special education and may benefit from speech and language therapy. Mildly retarded children may function effectively in resource rooms with some integration into regular educational programs. Patients with moderate to severe retardation may require placement in self-contained classes for educable or trainable mentally retarded children.
Behavioral management techniques utilizing positive reinforcement can be helpful in eliminating negative behaviors. For example, "time out" (eliminating the opportunity for positive reinforcement) is more effective than corporal punishment, which may lead to further aggression. The family physician may find school psychologic services to be both an excellent resource for materials dealing with a positive approach to changing behavior and a useful tool in appropriate class placement.
Many of the adult patients function very well in group homes and sheltered workshop situations. The goal for all handicapped patients, including those with fragile-X syndrome, is to find placement in the least restrictive environment. A valuable resource is the Fragile-X Foundation (P.O. Box 300233, Denver, CO 80203). The function of the foundation is to educate professionals, parents and the public in all aspects of fragile-X syndrome, as well as other forms of X-linked mental retardation. Information on support groups and conferences can be obtained from the foundation.
Prenatal diagnosis is available for couples at risk for fragile-X. Positive cytogenetic studies are significant, but negative results do not rule out the possibility of an affected offspring. DNA studies are more accurate but are expensive and time-consuming because samples from the extended family, including siblings, parents and grandparents, are required.
Genetic counseling is recommended for all couples seeking prenatal diagnosis. The limitations of prenatal testing must be thoroughly explained. The couple's options in the event that results are positive also must be discussed. These couples will need ongoing support from the genetic counselor and the family physician.
Fragile-X syndrome is an identifiable X-linked disorder that ranks second only to Down syndrome among causes of mental retardation associated with cytogenetic abnormalities. There is extreme variability in the appearance of affected males, although a characteristic phenotype has been developed. A suspected diagnosis can be confirmed with cytogenetic testing when cell cultures are grown in special media.
Folic acid may be useful in the treatment of prepubertal patients. Long-term treatment requires an appropriate educational program that may lead to a more independent lifestyle and may defer or prevent institutionalization.
Adult Males with Fragile-X Syndrome
IQ(*) and Percentage of Expression of Fragile-X Sites
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