Attention and Anxiety Top the List of Behavioral Problems in Children With Fragile X Syndrome

Fragile X syndrome, the most common inherited form of intellectual disability, has long been known to bring with it a heavy burden of behavioral and psychiatric difficulties. Yet for all the individual studies that have examined anxiety, hyperactivity, irritability, or autism in this population, no one had systematically mapped how the most common behavioral conditions cluster together, how severe they are, and which combinations drive the greatest functional impairment. A new analysis of the largest clinic-based natural history study of fragile X syndrome now fills that gap, offering clinicians one of the most detailed portraits to date of the behavioral comorbidities that shape daily life for children with the condition.

The study, led by Walter E. Kaufmann of the Department of Human Genetics at Emory University School of Medicine and Paul S. Horn of the Division of Neurology at Cincinnati Children’s Hospital Medical Center, together with the FORWARD Consortium, drew on the pediatric FORWARD database, a multi-site registry and longitudinal clinical database established to study fragile X syndrome across specialty clinics in the United States. The analytical sample comprised 1,072 males and 338 females, an unusually large cohort for a rare genetic disorder, allowing the researchers to examine patterns of co-occurrence with a statistical power that smaller, single-center studies could not achieve.

The team focused on the eight most common behavioral comorbidities identified by clinicians in these specialty fragile X clinics: attention problems, anxiety, hyperactivity, autism spectrum disorder, mood disturbances, irritability and aggression, self-injurious behavior, and sleep problems. Importantly, the researchers treated these as clinician-identified behavioral concerns rather than formal diagnoses, with one exception. Autism spectrum disorder was the only comorbidity defined using explicit DSM-5 criteria, reflecting the particular diagnostic challenges that autism presents in fragile X syndrome, where the social and repetitive features of the syndrome itself can blur the boundary between behavioral phenotype and co-occurring condition.

Across the cohort, attention problems and anxiety emerged as the two most frequent behavioral comorbidities, and, notably, also as the mildest in terms of functional impact. By contrast, the cluster of disruptive behaviors captured under the umbrella of irritability, aggression, agitation, and self-injurious behavior, while less universally present, carried substantially greater weight in terms of impairment. Roughly half of the children affected by any given behavioral comorbidity showed functional impairment from that condition, a proportion that underscores how often these difficulties cross the threshold from trait to clinically meaningful problem in fragile X syndrome.

The most striking finding concerned co-occurrence. Among children with fragile X syndrome, 69 percent were reported to have impairing behavioral comorbidities occurring together, and 39 percent of those children presented with more than two comorbidities simultaneously. Children with multiple co-occurring conditions showed the greatest overall impairment, a dose-response-like pattern suggesting that the cumulative behavioral load, rather than any single diagnosis, is what most powerfully determines how much a child’s daily functioning is compromised. For families and clinicians, this finding reframes fragile X syndrome not as a condition with one dominant behavioral complication but as one in which multiple behavioral challenges frequently compound one another.

To dissect these patterns, the researchers deployed an unusually rich statistical toolkit. Chi-square analyses quantified how frequently pairs of comorbidities appeared together. Polychoric and polyserial correlations, methods designed to estimate the association between ordinal and continuous variables that underlie observed categorical ratings, allowed the team to measure the strength of association between comorbidities while correcting for the fact that co-occurrence is partly driven by simple frequency. Mann-Whitney tests compared behavioral scale scores between groups. This distinction between frequency-driven co-occurrence and genuine statistical association proved crucial: the researchers found that while which comorbidities co-occur is influenced by how common each one is, the strength of the association between any pair was relatively independent of frequency, implying that some pairings reflect shared underlying mechanisms rather than mere arithmetic.

Two of those strong associations stood out because they replicate well-documented patterns in the general, non-fragile X population. The first was the pairing of attention problems with hyperactivity, a combination familiar from attention deficit-hyperactivity disorder in typical development. The second was the coupling of anxiety with mood disturbances, echoing the extensive literature on comorbidity between anxiety and mood disorders in the general psychiatric population. That these canonical pairings also hold in fragile X syndrome suggests that at least some of the architecture of behavioral comorbidity in this genetic condition mirrors the structure seen in the broader population, even though the underlying biology is profoundly different.

The team also examined how standardized behavioral scale scores related to the clinician-identified comorbidities. Scale scores broadly aligned with other severity parameters, lending convergent validity to the clinician-based classification. However, correlations between comorbidities and specific scales tracked the relevance of the behaviors each scale evaluates, rather than behaving as simple proxies for severity. In other words, a given scale correlated most strongly with the comorbidities whose symptom content it directly captures, a finding that helps clinicians interpret behavioral checklist data in fragile X syndrome with appropriate nuance.

Perhaps the most unexpected result of the entire analysis was the discovery that all eight behavioral comorbidities were strongly correlated with the Sensory problems scale. Sensory difficulties, including hyperarousal to sound, touch, and visual stimuli, have been increasingly recognized as central features of fragile X syndrome, with prior work from the FORWARD registry documenting their prevalence and their links to hyperarousal. But the uniformity of the association across such clinically distinct comorbidities, from attention deficits to aggression to sleep disturbance, was not anticipated. The finding raises the possibility that sensory dysregulation functions as a transdiagnostic factor in fragile X syndrome, a common physiological substrate that feeds into or amplifies virtually every major behavioral problem the condition produces. If confirmed by future longitudinal work, this would carry direct therapeutic implications: interventions targeting sensory hypersensitivity and hyperarousal might yield benefits across a wide swath of behavioral comorbidities simultaneously, rather than requiring separate treatments for each condition.

The authors caution that their data are cross-sectional and clinic-based, drawn from children evaluated at specialty fragile X clinics and therefore not necessarily representative of the full population spectrum of the disorder, which includes individuals with milder presentations never referred to specialty care. Even so, the scale of the FORWARD database and the consistency of the findings give the profiles considerable weight. The research team suggests that the reported profiles of impairing behavioral comorbidities could assist clinicians in the early identification of behavioral symptoms in children with fragile X syndrome and in refining the management of those symptoms, and, they add, perhaps in other neurodevelopmental disorders as well, where multi-comorbidity burdens are similarly common and similarly under-characterized. The study was supported by cooperative agreements and a contract funded by the Centers for Disease Control and Prevention, and de-identified data from the FORWARD project are available under the project’s data sharing plan and CDC policies, opening the door for further analyses of how these behavioral trajectories unfold over time.

Subject of Research: Behavioral comorbidities and their co-occurrence patterns in children with fragile X syndrome

Article Title: Profile of Behavioral Comorbidities in Children With Fragile X Syndrome

Article References: Kaufmann, W. E., Horn, P. S., FORWARD Consortium, Berry-Kravis, E., Velinov, M., Talboy, A. L., Sherman, S. L., Kaufmann, W. E., Schuster, M., Tartaglia, N., Filipink, R. A., Budimirovic, D. B., Barbouth, D., Lightbody, A., Reiss, A., Delahunty, C. M., Hagerman, R. J., Hessl, D., Erickson, C. A., … Morris, S. M. (2026). Profile of Behavioral Comorbidities in Children With Fragile X Syndrome. Journal of Autism and Developmental Disorders. https://doi.org/10.1007/s10803-026-07525-8

Image Credits: AI Generated

DOI: 10.1007/s10803-026-07525-8

Keywords: fragile X syndrome, behavioral comorbidities, anxiety, attention problems, autism spectrum disorder, sensory problems, FORWARD registry, intellectual disability, hyperactivity, self-injurious behavior, neurodevelopmental disorders, FMR1