OBJECTIVE: To determine recent trends in the diagnosis of children with fragile X syndrome (FXS) and identify factors associated with the timing of diagnosis.
METHODS: More than 1000 families of children with FXS participated in a national survey. Of these, 249 had their first child (213 boys, 36 girls) diagnosed between 2001 and 2007 and did not know about FXS in their family before diagnosis. These parents answered questions about the average age of first concerns, developmental delays, early intervention, and the FXS diagnosis. They also provided other information about their child and family, reported who made the diagnosis, and described ramifications for other children and extended family members.
RESULTS: The average age of FXS diagnosis of boys remained relatively stable across the 7-year period at ∼35 to 37 months. The 36 girls with full mutation were given the diagnosis at an average age of 41.6 months. A trend was noted in earlier diagnosis of developmental delay for boys in more recent years. Approximately 25% of the families of male children had a second child with the full mutation before the diagnosis was given to the first child; 14 (39%) of the 36 families of female children had a second child with the full mutation before the diagnosis.
CONCLUSIONS: Despite patient advocacy, professional recommendations regarding prompt referral for genetic testing, and increased exposure to information about FXS in the pediatric literature, no changes were detected in the age of diagnosis of FXS during the time period studied. Earlier identification in the absence of systematic screening will likely continue to be a challenge.
Fragile X syndrome (FXS), the most common inherited form of intellectual disability, results from >200 CGG repeats in the FMR1 gene, affecting production of the fragile X mental retardation protein. FXS is associated with intellectual disability, attention problems, hyperactivity, autism, and behavior problems.1 Premutation carriers are at risk for primary ovarian insufficiency, fragile X–associated tremor ataxia syndrome, and other physical and emotional consequences.1–6
FXS leads to overactivation of MGluR5, a metabotropic glutamate receptor that affects synaptic plasticity.7–9 Compounds that reduce excess glutamate signaling can improve the behavioral phenotype and morphologic consequences of FXS in both mice10 and Drosophila,11 leading to hope for medications that could improve human functioning.
Meanwhile, children with FXS continue to be identified, although not without difficulty.12 FXS has no obvious phenotype at birth and must be “discovered” as delays become evident. Authors of an article in 2003 reported that for boys born in 1990–1999, the average age of diagnosis was 32 months.13 An average of 18 months lapsed between first concerns and a diagnosis. Parents reported frustration with the length of time needed to obtain a diagnosis, which delays access to services and often leads to the birth of a second child with FXS.
In recent years there has been increased emphasis in pediatrics on early identification of children with disabilities. In 2001 the American Academy of Pediatrics urged pediatricians to begin routine developmental screening.14 However, full implementation has been challenging.15 A 2006 amendment recommended developmental surveillance at well-child visits, followed by screening if there are any concerns.16 Standardized screening is recommended at 9, 18, and 30 months.
Awareness of FXS should have grown as a result of research, statements by professional organizations, and advocacy. Infants and toddlers with FXS show developmental and behavioral problems during the first 2 years of life.17,18 One study suggested that delays could be detected in boys with FXS through developmental screening by 9 to 12 months of age.19 The American College of Medical Genetics20 and a joint statement by the Child Neurology Society and the American Academy of Neurology21 recommend testing any child with unexplained delays for FXS. The American Academy of Pediatrics Committee on Genetics urged pediatricians to consult with clinical geneticists to reduce the time between presenting signs and a genetic diagnosis.22 In 2004 the National Fragile X Foundation mailed a card entitled “What Do Pediatricians Need to Know About Fragile X?” to every pediatrician in the United States, providing information about presenting signs, diagnosis, and links to the foundation's Web site (www.fragilex.org/html/home.shtml).
Whether such initiatives have affected the timing of FXS diagnosis is unknown. For this article we drew on a survey of >1000 families to identify a subset whose first child with FXS was given the diagnosis between 2001 and 2007. We report trends in the timing of first concerns, verification of problems, and diagnosis of FXS. We report whether families had additional children with FXS before a diagnosis and the effect of a diagnosis on reproductive decisions. One child factor (number of co-occurring conditions) and 2 family factors (income and maternal education) were examined to determine associations with age of diagnosis.
The study was part of a larger survey of families of children with FXS. Three foundations (National Fragile X Foundation, FRAXA Research Foundation, and Conquer Fragile X Foundation), researchers, and clinicians sent letters inviting families to enroll. Approximately 8000 letters were distributed. Because we did not have access to names, the families affiliated with more than 1 foundation and/or clinic received multiple letters; thus, we were not able to determine response rate or sample representativeness.
A total of 1250 families enrolled. For this article we focused on 249 families: (1) those who received the first diagnosis of full-mutation FXS in 1 of their children between 2001 and 2007; (2) those who before the diagnosis were not aware of parental carrier status; (3) those who learned about FXS through the diagnosis of this child, not through an extended family member; and (4) those whose child had the full mutation. Eighty-five percent were white, 7% were Hispanic/Latino, 2% were African American/black, 2% were Asian, and 5% were Native Hawaiian or Pacific Islander, American Indian, Alaska Native or other races or ethnicities. Among the respondents were 89% mothers, 8% fathers, and 3% other family members. The majority had a 4-year college or graduate degree (60%) and an annual income of at least $75000 (58%).
The 249 families had 563 children at the time of the survey. Of these children, 333 had full-mutation FXS, 16 had the premutation, 81 had been tested and did not have FXS, and 133 had not been tested. We focused on the first child diagnosed with the full mutation of FXS. This group consisted of 213 boys and 36 girls. Because of the small number of girls, the study focused primarily on boys. Seven boys first identified between 10 and 26 years of age were excluded as outliers (Fig 1) when computing means and regressions.
Instrumentation and Procedure
Families enrolled on-line (88%) or by calling a toll-free number (12%), providing family (marital status, ethnicity, maternal education, income) and child (gender, birth date, genetic status) demographics. Families also indicated if their children had been treated or diagnosed with any of 8 co-occurring conditions (attention problems, hyperactivity, aggressiveness, self-injury, autism, seizures, anxiety, depression). Approximately 6 months after enrollment, families completed the full survey, including questions about first concerns, the diagnostic process, and whether other family members were tested.
In the first analysis we examined the diagnostic process, and from the second analysis we describe how the diagnosis led to testing other family members. With the final analysis we investigated whether learning problems, co-occurring conditions, family income, or maternal education predicted age of diagnosis or the time between first concern and diagnosis.
Table 1 displays the mean, SD, and median for each step toward diagnosis for boys. On average, someone first became concerned at 11.6 months. A professional confirmed a delay 8 months later. Soon thereafter, children began early intervention. The diagnosis of FXS was confirmed 12 to 14 months later. The average length of time between first concern and diagnosis was 24 months.
Figure 2 displays these data according to year of diagnosis. The average age of first concern, confirmation of delay, and start of early intervention seem to decrease over time. However, the average age at FXS diagnosis remained relatively stable (39.5 months in 2001, 37.9 months in 2008). A simple regression analysis (null hypothesis: slope = 0) confirmed significant trends toward a lower age in the confirmation of a delay (P = .04) and onset of early intervention (P = .001) but no significant trend in age of first concern or diagnosis of FXS.
Only 36 girls were the first to be identified in this sample, and so their data were aggregated across the time period. For them, the average age of first concern was ∼16 months, a delay was confirmed at 26 months, and diagnosis occurred at 42 months.
Parents (73%) or another family member (8%) were typically the first to express concern about the child. For 14%, a health care professional was the first concerned. The remainder indicated that a teacher or someone else was the first person concerned. The percentage of cases in which a health care professional was the first concerned increased somewhat across the 7 years (from 10% in 2001–2004 to 21% in 2005–2007).
When a family member was the first concerned, most (81%) thought the child was behind in development. Others reported behavior problems (3%) or lack of eye contact and difficulty interacting with others (5%). Other concerns included poor eating habits or that the child did not like to snuggle or be touched.
When someone other than a health care professional expressed the first concern (81% of the sample), 22% were told on their first visit to a health professional about their concerns that their child was normal, and 47% were told to “wait and see.” Another 14% were referred to a specialist. Approximately 9% received a diagnosis other than FXS on their first visit, and 4% were referred for FXS testing.
For the 29 families for which a health care professional first expressed concern, 28% referred them to a specialist after the concern, 24% recommended screening or genetic testing, and 24% recommended testing for FXS. The remaining families either were told to “wait and see” (7%) or given a range of other recommendations (17%).
Many families (36%) reported that it took 3 to 5 visits before the FXS test was ordered, but this varied; 19% needed only 1 to 2 visits, and 27% required >10 visits. The test was most commonly ordered by a neurologist (27%), family doctor or pediatrician (23%), or geneticist (18%). For 10% a developmental pediatrician requested the test; 7% reported that a psychologist or therapist (eg, speech-language therapist) ordered it. Approximately 4% of the families requested the FXS test themselves. The remainder indicated that a variety of other professionals (eg, ear, nose, and throat doctor) recommended testing.
Families reported that the most difficult part of the process was the number of professionals they had to see (39%), followed by waiting for the diagnosis (31%), and getting a professional to agree that something was wrong (24%). Most said that getting to the doctor's office (70%) and paying for the test (86%) were not at all difficult. Most of the FXS testing was covered by health insurance (87%) or a source such as Medicaid (6%).
Approximately half (47%) first received information about FXS from a genetic counselor or geneticist, and 33% received it from a physician (17% pediatrician, 6% other physician). Most families were very (42%) or somewhat (39%) satisfied with how the information was delivered, but 19% were not at all satisfied.
Approximately 19% never received genetic counseling. Of those who did, 19% received it at the time of diagnosis, 11% within 1 week, 33% within 1 month, and 32% after >1 month. Three percent received counseling before the diagnosis. When asked about the helpfulness of information from a genetic counselor, most said that it was very (33%) or somewhat (34%) helpful. However, 17% said that counseling was not very helpful, and 8% indicated that it was not at all helpful.
Impact on Family
Most (95%) respondents told at least 1 extended family member that they might be carriers. Usually the mother (78%) told the extended family. Others were told by the father (7%) or another family member (9%). In a few instances a doctor, geneticist, or someone else talked with extended family members. Almost all families acknowledged that talking with relatives about FXS was very (46%) or somewhat stressful (36%). Of the respondents who told an extended family member, 70% reported that at least 1 extended family member was subsequently tested for FXS.
Reproductive Decisions and Testing Family Members
The majority of respondents (76%) said that the diagnosis affected reproductive decisions. Most of these parents decided not to have additional children; some tried techniques such as preimplantation genetics, and 4 reported terminating an affected fetus detected prenatally. Almost all parents who said the diagnosis did not affect reproductive decisions reported that by the time they had received the diagnosis, they had already decided not to have additional children. Only 5 reported that they would continue to have children regardless of the diagnosis or risks.
Most (69%) had tested all of their children for FXS. Of those who had not, 52% did not because they did not have any symptoms. Another 5% indicated that they could not genetically inherit FXS, and 8% said they did not want to know the status yet. The remainder gave a wide range of other reasons.
Forty-six families had only 1 child. The rest had 306 siblings, of which 261 were born before the first child was given the diagnosis. Of these, 120 had not been tested for FXS, 58 did not have FXS, 15 had the premutation (4 boys, 11 girls), and 68 had the full mutation (31 boys, 37 girls). Twenty-seven percent of families whose first child diagnosed was male and 39% of those whose first child diagnosed was female had a second child with the full mutation before the diagnosis of the first child. Forty-one children were born after the first child was diagnosed. Of these, 17 had not been tested for FXS. For the remaining, 15 did not have FXS, 1 had the premutation (male), and 8 had the full mutation (4 boys, 4 girls).
Predictors of the Diagnostic Process
In the final analysis we examined whether child (co-occurring conditions) or family (income; maternal education) factors influenced the diagnostic process (Table 2). Two regression models were developed. The first included age at diagnosis as the outcome variable, and the second included the time between age of first concern and diagnosis. Each model contained all 3 predictor variables. Although the overall model was not statistically significant, the total number of co-occurring conditions was associated with age of diagnosis and time between first concern and diagnosis. Children with more co-occurring conditions were given the diagnosis earlier (B = 1.64; SE = 0.76; P = .03) and had shorter delays between first concern and diagnosis (B = 1.81; SE = 0.73; P = .01).
Study Design and Limitations
Three limitations should be noted. First, the data depend on the recall of survey respondents with regard to the timing of events, and some error in reporting is likely. Second, the results of genetic testing and other child variables were reported by parents but were not verified by other sources. Finally, the sample, although large, is not nationally representative (we had a low response rate from low-income families and from members of ethnic minority groups). Also, the sample likely does not include higher-functioning children with FXS. Nonetheless, the study provides more current data with a larger sample than previous studies.13
Summary of Findings and Discussion
We found a decrease in the average age of initial concerns (13–15 months in 2001–2004 compared with 7–10 months in 2005–2007). The reasons cannot be fully determined from this study. One possibility is that parents are becoming more knowledgeable about development and more proactive in bringing concerns to the attention of their physician, a theory we cannot test from our data. A second possibility is that physicians are becoming more attentive to developmental issues and more likely to discuss them earlier with families. This hypothesis is partially supported by the increase over time in the proportion of cases in which a health care professional was the first to have concerns about development and behavior (from 10% in 2001–2004 to 21% in 2005–2007).
Paralleling this trend is an apparent decrease in the average age that a delay is confirmed and the length of time between first concern and diagnosis of a delay. This occurred despite the fact that two thirds of the families were told when they first expressed a concern that their child was normal or that they should wait and see. Earlier confirmation of delay seemed to lead to earlier enrollment in early intervention. Children with diagnosed delays are eligible for early intervention in the United States even without a diagnosed medical condition.23
We found no changes in the age of FXS diagnosis, which ranged between 35 and 39 months for boys and somewhat later for girls. The only positive change noted was in cases of extremely late identification. One family reported a first diagnosis at 26 years in 2001; in 2002, 1 child was diagnosed at age 17 years and another at 21 years. In subsequent years no child was identified older than 13 years and most occurred under 6 years. Age at diagnosis was not associated with severity of delay, family income, or maternal education. The number of co-occurring conditions, however, was associated with age at diagnosis and suggests that if children have developmental delay and at least 1 of these co-occurring conditions, genetic testing may have a greater probability of being positive for FXS.
In general, however, the trend toward earlier identification of delays in children with FXS does not seem to be leading to an earlier diagnosis, despite recommendations for closer links between pediatricians and geneticists and for any child with unexplained delays to be tested for FXS.20–22 Most families reported that it took at least 3 to 5 visits to a health care professional before a test for FXS was ordered, and 27% needed >10 visits. Getting a health care provider to agree that something was wrong and waiting for the diagnosis were the most stressful aspects of the diagnostic process. General physicians rarely ordered the FXS test, relying instead on neurologists, geneticists, or developmental pediatricians. Research shows that pediatricians are aware of FXS and support diagnostic testing for children at high risk24 but would refer to a specialist instead of ordering a diagnostic test even if they suspected FXS.25 The lag is probably due in part to delayed referral to specialists and in part to the time lag between referral and actual appointment.
For almost all families the diagnosis of FXS led to testing other children and relatives. Most families had additional children before the diagnosis, and a substantial proportion (25% of the families with male children first diagnosed) had a second child with the full mutation before the diagnosis, with a much higher rate (39%) in families whose first child diagnosed was female. Most respondents had to tell at least 1 extended family member about FXS, which is a stressful experience. And, for the majority of families, learning about FXS led them to decide not to have additional children.
It seems that delays in children with FXS are identified earlier and children enter intervention at younger ages. However, no changes are evident in the average age at which FXS is diagnosed, despite concerted efforts by professional organizations and advocacy groups. Delayed identification has important ramifications for families, many of whom have 2 affected children. In the absence of genetic screening, changing the age at diagnosis will be difficult to achieve without broader and more systemic changes in pediatric practice. Routine genetic screening for FXS has the potential for significant benefits to children and families26 and would be accelerated by the development of a cheap and accurate screening test. However, important ethical and practical concerns remain, including the best time to offer screening (eg, preconception, prenatal, newborn, well-child visits) and need to be studied systematically.27
Preparation of this article was supported in part by Centers for Disease Control and Prevention and Association for Prevention Teaching and Research cooperative agreement U50/CCU300860, project TS-1380.
We appreciate the research collaborators and organizations who supported the recruitment of study participants, the families who completed the survey, and RTI staff who assisted in survey development (Murrey Olmsted), programming (Venkat Yetukuri), data management (Anne Kenyon and Kirstin Miller), data analysis (David Holiday), and call center services (Ellen Fay).
- Accepted January 30, 2009.
- Address correspondence to Donald B. Bailey Jr, PhD, RTI International, 3040 Cornwallis Rd, Research Triangle Park, NC 27709-2194. E-mail:
The findings and conclusions in this publication are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention or Association for Prevention Teaching and Research.
Financial Disclosure: The authors have indicated they have no financial relationships relevant to this article to disclose.
What's Known on This Subject:
To date, only a few articles have been published on this topic, the last of which was a 2003 Pediatrics article.
What This Study Adds:
The study provides current data on trends (and lack of trends) in the diagnosis of FXS since 2001.
- ↵Bailey DB, Raspa M, Olmsted M, Holiday DB. Co-occurring conditions associated with FMR1 gene variations: findings from a national parent survey. Am J Med Genet A.2008;146A (16):2060– 2069
- Leehey MA, Berry-Kravis E, Goetz CG, et al. FMR1 CGG repeat length predicts motor dysfunction in premutation carriers. Neurology.2008;70 (16 pt 2):1397– 1402
- ↵Hessl D, Rivera S, Koldewyn K, et al. Amygdala dysfunction in men with the fragile X premutation. Brain.2007;130 (pt 2):404– 416
- ↵Ronesi JA, Huber KM. Metabotropic glutamate receptors and fragile X mental retardation protein: partners in translational regulation at the synapse. Sci Signal.2008;1 (5):pe6
- ↵Bailey DB, Skinner S, Sparkman KL. Discovering fragile X syndrome: family experiences and perceptions. Pediatrics.2003;111 (2):407– 416
- ↵American Academy of Pediatrics, Committee on Children With Disabilities. Developmental surveillance and screening of infants and young children. Pediatrics.2001;108 (1):192– 195
- ↵Sand N, Silverstein M, Glascoe FP, Gupta VB, Tonniges TP, O'Connor KG. Pediatricians' reported practices regarding developmental screening: do guidelines work? Do they help? Pediatrics.2005;116 (1):174– 179
- ↵American Academy of Pediatrics, Council on Children With Disabilities, Section on Developmental Behavioral Pediatrics, Bright Futures Steering Committee, Medical Home Initiatives for Children With Special Needs Project Advisory Committee. Identifying infants and young children with developmental disorders in the medical home: an algorithm for developmental surveillance and screening [published correction appears in Pediatrics. 2006;118(4):1808–1809]. Pediatrics.2006;118 (1):405– 420
- ↵Shevell M, Ashwal S, Donley D, et al. Practice parameter: evaluation of the child with global developmental delay—report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology.2003;60 (3):367– 380
- ↵Moeschler JB, Shevell MD; American Academy of Pediatrics, Committee on Genetics. Clinical genetic evaluation of the child with mental retardation or developmental delays. Pediatrics.2006;117 (6):2304– 2316
- ↵Spiker D, Hebbeler K. Early intervention services. In: Levine MD, Carey WB, Crocker AC, eds. Developmental-Behavioral Pediatrics. Philadelphia, PA: WB Saunders Company; 1999:793–802
- ↵Acharya K, Ackerman PD, Ross LF. Pediatricians' attitudes toward expanding newborn screening. Pediatrics.2005;116 (4). Available at: www.pediatrics.org/cgi/content/full/116/4/e476
- ↵Bailey DB, Skinner D, Davis A, Whitmarsh I, Powell C. Ethical, legal, and social concerns about expanded newborn screening: fragile X syndrome as a prototype for emerging issues. Pediatrics.2008;121 (3). Available at: www.pediatrics.org/cgi/content/full/121/3/e693
- Copyright © 2009 by the American Academy of Pediatrics