Classic clinical features of FXS include an elongated face, broad forehead, prominent ears, and flat feet. Hyper flexibility of joints and connective tissue problems are also common. New evidence suggests that as adults, individuals with FXS may be at increased risk for a number of other medical problems, such as obesity, hypertension, and gastrointestinal disorders. Additionally, seizures are a common co-morbid feature. Females with FXS have a less severe presentation given the presence of a second unaffected X-chromosome.⁴ A review of neuroanatomical studies of individuals with FXS have shown dendritic spine abnormalities and changes in brain structure and EEG studies show alterations in gamma waves which correlate with clinical symptomology.⁵

Our earlier paper¹ provides a detailed overview of the cognitive development of individuals with FXS. A recent review furthers this work by summarizing what is known about executive function in FXS.⁶ Verbal and non-verbal working memory is impaired in individuals with FXS across the lifespan, although performance on tasks was dependent on cognitive load. Challenges with inhibitory control, cognitive flexibility, and processing speed emerge early in childhood and persist into adulthood. Attention is one of the core deficits in FXS, with impairments in both auditory and visual sustained attention when compared with chronologically age-matched and mental age-matched peers. In a study of infants with FXS, delays in overall development were seen as early as 6 months when compared with typically developing peers.⁷

Language development in FXS is well studied. Recent work adds to the knowledge base in receptive, expressive, and pragmatic development. Children with FXS show signs of receptive and expressive language delays as early as 12 months.⁸ Early use of consonants during babbling and intentional communication, including the use of gestures, is predictive of later expressive language.⁹ By the time of preschool, though, children with FXS have the ability to repair a breakdown in communication (e.g., when there is a miscommunication with a conversational partner), indicating well-developed language and social skills. In addition, maternal language plays a role in language development. Maternal commenting is associated with receptive but not expressive vocabulary from early childhood into adolescence.¹⁰ Maternal pragmatic language is associated with receptive and expressive vocabulary in adolescents and young adults.¹¹ Although receptive language ability is lower in children and adolescents with FXS than those who are typically developing, it is a relative strength when compared with ability levels of those with autism spectrum disorder (ASD) or Down syndrome.^12,13

Children with FXS continue to make improvements in their functional skills into middle childhood, at which point cognitive development begins to slow. However, those with lower nonverbal developmental scores or more ASD symptoms had different growth patterns and less overall skill attainment when examining raw scores.¹⁴ Over time, males with higher adaptive behavior age-equivalent scores in early childhood had fewer aberrant behaviors at age 10.¹⁵ When compared with typically developing children, those with FXS show plateaus or declines in their adaptive behavior over time suggesting that those with FXS overall have a lower rate of skill attainment.¹⁶ Cross-sectional studies have found similar patterns when comparing young children with FXS to their same-aged peers.¹⁷ Another study, though, showed adaptive skills, in particular standard scores for communication and social ability, improved over time.¹⁸

In a recent review of behavioral concerns, prevalence estimates across studies for individuals with FXS were 48.8% for self-injury, 35.8% for aggression, and 24.5% for destruction, with males significantly more likely than females to engage in any type of challenging behavior.¹⁹ When compared with males with mixed-etiology intellectual disability, males with FXS had higher rates of self-injury and specific forms of aggression, such as scratching or biting other.^20,21 Functional analysis of these behaviors has shown that social or environmental factors, including gaining attention or access to preferred objects or escaping from social demands, reinforce and maintain these challenging behaviors.²²

Other behavior problems include restrictive and repetitive behaviors and sensory issues. Cross-sectional studies across the lifespan show peaks in sensory-motor behaviors between 2 and 12 years of age, and in restricted and repetitive behaviors between 7 and 12 years of age.²³ Restricted interests, such as being strongly attached to one specific object and fascination with one subject or activity, were rated as moderate to severe.²⁴ Studies differ, however, on whether restricted and repetitive behaviors are related to IQ.^23,24 Recent work exploring sensory processing indicate that hypersensitivity to visual, auditory, or tactile stimuli may be the underlying issue in behavioral challenges in individuals with FXS.^25,26

Social avoidance is a key characteristic which emerges in males as early as infancy, with increases into middle childhood, but steadying in later years.²⁷ During observational assessments, eye contact avoidance, in particular, was evident in adolescent and young adult males, especially in those with more ASD symptoms. Alternate measurement techniques of social avoidance have been developed, including caregiver-completed assessment scales,²⁸ other observational rating scales,²⁹ and eye-tracking techniques.³⁰

One of the gaps we identified in our earlier paper was lack of information regarding subtypes of the FXS phenotype. Since then, our understanding of the FXS phenotype has continued to grow, with increased focus on genotype-phenotype associations and neuroanatomical correlates of clinical features. Mosaicism (i.e., variation in CGG repeats across different cell types) and methylation status (i.e., variation in FMRP levels across different cell types) are now well-known molecular indicators of phenotypic impact.^31,32 Research uncovering novel mutations and mosaic genetic presentations on the FMR1 gene have helped to identify disruptions on specific exons and untranslated regional variations, which have implications for the function of FMRP and the variable phenotypic expression seen in FXS.^33,34 Studies have explored how FMRP acts as a regulator and impacts clinical features in individuals with FXS.^35,36 In one, as FMRP levels decreased below 70% of the mean for unaffected individuals, individuals with FXS had declining IQ scores. An average FMRP level of 35% below the mean was needed for individuals with FXS to reach an IQ of 85, or one standard deviation below average.³⁷ Given the role FMRP plays in cognitive functioning, studies have suggested it as a therapeutic target.³⁸ However, challenges remain in accurately measuring FMRP in different sample types (e.g., blood versus buccal cells).³⁵

Work on identifying phenotypic subgroups in FXS has continued to emerge. One study examined how best to diagnose ASD in individuals with FXS using FX-specific versions of the Social Communication Questionnaire and the Social Responsiveness Scale.³⁹ Additional studies have examined behavioral differences in those with FXS only compared with those with FXS and ASD. In keeping with earlier work, individuals with FXS and ASD show more severe behavioral problems, challenges with receptive and expressive language and social interaction, and greater cognitive impairment.^40-42 A second subgroup, those with both the FXS and Prader-Willi phenotype, is marked by obesity, hyperphagia, and delayed puberty, with about half also diagnosed with ASD.⁴³

Traditionally, diagnosis of FXS is done clinically after the onset of symptoms.⁵¹ However, this process can be long and arduous for families, with a mean age of diagnosis around 32 months and fewer than 20% of children receiving a diagnosis within the first year of seeking medical attention.⁵² There have been efforts to decrease the diagnostic odyssey and improve the process for receiving a clinical diagnosis, including carrier screening of women prior to or during pregnancy^53-55 preimplantation genetic testing, ^56,57 and newborn screening.

Newborn screening for FXS in both males and females is supported by the majority of developmental and behavioral pediatricians. However, voluntary screening is preferred over mandatory.⁵⁸ Voluntary screening in hospitals shortly after birth is possible, but challenging. In a multi-site U.S. study of 28,000 newborns, two-thirds of parents were willing to have their child screened, but educational materials were essential in supporting informed decision-making.⁵⁹ A smaller-scale study in Australia found higher rates of consent, with 94% agreeing to screening.⁶⁰ More recently, a statewide, voluntary newborn screening study conducted in North Carolina was implemented as a partnership between public health staff and researchers. One of the main considerations was how to best recruit families.^61-63 Barriers to full-scale newborn screening for FXS include public health burden to conduct the screening; the need for inexpensive, high-throughput screening methodologies; lack of demonstrated treatment for asymptomatic children; and insufficient capacity for long-term follow-up.^64,65

Indirect and direct healthcare costs are sizable for individuals with FXS. Using Medicare/Medicaid administrative claims data, annual all-cause healthcare costs ranged from $2222 to $9702, with higher costs in the Medicaid cohort. Main cost drivers included medical procedures, both routine (e.g., office visits, immunizations) and non-routine (e.g., lab tests, therapies, anesthesia), followed by hospitalizations in a subset of individuals, and finally medications.⁶⁶ Studies in Europe also have found high healthcare and caregiver burden costs, with non-healthcare costs (e.g., informal care) being the main contributor.^67,68 Direct and indirect healthcare costs are higher for those with FXS and their families than those without FXS. ^69,70

In a survey study of over 600 caregivers of individuals with FXS, 20% reported having difficulty accessing specialty services and nearly 40% indicated their child’s primary care provider was not knowledgeable about FXS.⁷¹ Parent-reported data of preventive care services have shown that 92% of individuals with FXS met immunization guidelines and 75% met dental care guidelines, but only 55% met influenza vaccination guidelines, and just 24% met physical activity guidelines.⁷²

Stakeholder involvement from the beginning of treatment development is considered best practice.⁷³ As such, understanding the perspectives of parents and individuals with FXS has been a key goal over the last few years. In a study of treatment targets, 439 family members of at least one individual with FXS indicated medications to address anxiety, learning, and behaviors such as tantrums and aggression were their top priorities.⁷⁴ Similarly, Cross and colleagues⁷⁵ found behavior and self-care to be the most important targets for treatment for caregivers across age groups. Parents are generally supportive of pharmacological clinical trials, yet there may be concerns about safety and long-term implications for their child in the decision process.⁷⁶ Concerns about side effects, swallowing tablets, blood tests, financial costs and travel can be barriers to participation in clinical trials,⁷⁷ as are misunderstanding of the objectives of pharmacological clinical trials,⁷⁶ and the likelihood that their child will experience a direct benefit.⁷⁸

Psychotropic medications are used by more than two-thirds of adolescents and adults with FXS, while a quarter are likely to use non-psychotropic medications.⁷⁹ Once on a medication, individuals with FXS were more likely to stay on medication over a 3-year period. Those with more autism symptoms, behavioral challenges, and greater family incomes were more likely to use psychotropic medications. In a review of psychopharmacologic management in FXS, Eckert and colleagues⁸⁰ analyzed the use of medications to address irritability, aggression, agitation, and self-injury in 415 individuals with FXS. The most commonly utilized medications identified were the antipsychotics aripiprazole and risperidone (used by 37% and 27% respectively), with the majority of users experiencing no side effects from these medications. Psychopharmacological management tended to be accessed more often by older males who had more significant impairments. A retrospective analysis of the use of risperidone in conjunction with other non-antipsychotic medications to target irritability in 32 male patients with FXS found a 33% responder rate,⁸¹ leading to a conclusion that monoantipsychotic treatment with risperidone is limited in FXS.

Clinical trials of gamma-aminobutyric acid (GABA) modulators, including ganaxolone (a GABA_A receptor agonist) and arbaclofen (a GABA_B receptor agonist), and amino-terminal tripeptide of insulin-like growth factor 1 (i.e., trofinetide), have been used to target the core pathophysiology of FXS. A randomized, double-blind, placebo-controlled trial of ganaxolone ⁸² in children with FXS did not meet primary (i.e., Clinical Global Impression-Improvement scale) or secondary (e.g., Pediatric Anxiety Rating Scale-Revised) study end points. However, post hoc analyses showed a trend in reducing anxiety, hyperactivity, and social avoidance for a subset of participants who entered the study with higher anxiety or lower IQ scores. A Phase 3 trial of arbaclofen ⁸³ demonstrated positive change in children who were on the highest dose (10 TID), with lower irritability and parenting stress scores; scores for social avoidance and hyperactivity trended towards statistical significance. More recently, a Phase 2 trial of trofinetide demonstrated benefit, with individuals in the treatment group having lower clinician- and parent-reported symptom scores on three core efficacy measures ⁸⁴.

Other trials targeting cognition and/or behavior have found moderate success. A small study of individuals with FXS who received between 2.5 and 10.0 mg of donepezil, an acetylcholinesterase inhibitor, did not demonstrate change on cognitive or behavioral outcomes ⁸⁵. However, after 12 weeks of treatment, improvements were seen on direct versus averted gaze as measured by functional magnetic resonance imaging. In a randomized, double-blind, placebo-controlled trial of sertraline ⁸⁶, a selective serotonin reuptake inhibiter (SSRI), children with FXS made improvements in secondary endpoints, including improved motor and visual perception skills and social participation. Two case series of individuals with FXS examined the use of metformin, typically used to treat to treat type 2 diabetes, obesity, or glucose intolerance ^87,88. Results showed improvements in behavior and language development. Finally, cannabinoids have been used to reduce anxiety and aberrant behavior, and improve language skills and overall quality of life.^89,90.

In 2015, Moskowitz and Jones⁹¹ published a systematic review of 31 behavioral intervention studies. Findings suggest behavioral approaches are promising for addressing a variety of disruptive behaviors or functional outcomes in individuals with FXS. In a 12-week trial of a telehealth delivered function-based behavior analytic intervention, rates of problem behavior decreased significantly in 8 out of 10 children with FXS ages 2 to 10 years.⁹² In another intervention study, 20 boys with FXS, ages 8-18 years, were randomized to receive discrete trial instruction plus relaxation training administered at one of two prescribed doses over a 2-day period.⁹³ Levels of social gaze behavior increased significantly across blocks of training trials for six boys (60%) who received the high-dose behavioral treatment and for three boys (30%) who received the low-dose behavioral treatment. Therapeutic physical exercise⁹⁴ and specific diet⁹⁵ have also been used to address behavioral or socio-emotional challenges in FXS. Both of these studies suggest diet and exercise may be helpful for individuals with FXS but each approach requires further study.

A series of studies evaluated the use of Cogmed, a validated computer-based training designed to improve working memory and executive functioning in children with FXS. Results from the first study demonstrated the feasibility of a 5-week Cogmed training. ⁹⁶ A follow up study indicated significant improvement in working memory, some domains of executive function, as well as parent and teacher reported behaviors during the treatment period, with many changes maintained at follow-up after 3 months without training.⁹⁷ In a subsequent “deep dive” into the data, those with a higher IQ or mental age at baseline showed greater gains.⁹⁸

Communication is a significant challenge for many individuals with FXS and frustration with communication failures is likely a major contributor to problematic behaviors. In 2015, a multiple baseline study of a delayed video feedback intervention for a mother and her 31-month-old son showed that the behavior support strategies used increased appropriate requesting and reduced the frequency of the child’s self-injurious behavior.⁹⁹ Two pilot studies of a parent-mediated language intervention found that mothers were able to increase their use of strategies to help focus their child’s attention and communicative acts.^100,101 A follow-up randomized trial found that mothers in the treatment group used these strategies at post-treatment significantly more often than mothers of children in the comparison group. When compared with those in the control group, children in the treatment group were more likely to show increased duration of engagement, use more utterances that maintained the topic of the story, and use prompted inferential language.¹⁰² Similar results were found in sample of younger boys and their mothers.¹⁰³ A combined pharmacologic and language treatment study used a randomized, double-blind trial design and assigned families to the same parent-mediated language intervention plus lovastatin (10-40 mg/day) or an intervention group plus placebo.¹⁰⁴ Both groups demonstrated improvements in all primary outcome measures, including direct assessment and parent report measures, further supporting the efficacy of the language intervention but not providing evidence for the benefit of the addition of medication.

For a subsample of individuals with FXS, verbal expressive language does not develop with enough capacity for efficient communication. For these individuals, augmentative or alternative communication (AAC) techniques may be beneficial to provide an avenue for communicating their wants and needs. Schladant and Dowling recently conducted a qualitative study to explore parental acceptance, use, and engagement of AAC in four FXS affected mother-child dyads. The investigation exposed three main systemic gaps that may limit the successful integration of AAC in the home including (a) failure to consider unique aspects of the family context, (b) limitations of AAC technologies, and (c) inadequate knowledge of FXS and AAC among practitioners.¹⁰⁵