Body-Focused Repetitive Behaviors in Patients with FOXP1 Syndrome: An International Cross-Sectional Survey-Based Study

Abstract Introduction: FOXP1 syndrome is a rare neurodevelopmental disorder due to forkhead box protein 1 (FOXP1) gene mutations and is associated with intellectual disability, dysmorphic features, and autism spectrum disorder. We aimed to assess body-focused repetitive behavior (BFRB) prevalence in this patient population using a cross-sectional survey-based study. Methods: A validated survey assessing for BFRBs was administered to parents attending the International FOXP1 Foundation conference on June 21, 2023, and was sent to a FOXP1 syndrome listserv. Results: Excoriation disorder, onychophagia, onychotillomania, and trichotillomania were reported by 58.6%, 38.6%, 29.7%, and 10.0% of subjects, with 63.4%, 59.3%, 54.5%, and 14.3% having moderate to severe disease, respectively. Overall, 28.6%, 30.0%, and 10.0% had one, two, and three BFRBs, respectively. Conclusion: Prevalence of BFRBs is high among FOXP1 syndrome patients surveyed, affecting quality of life for patients and their families and causing significant sequelae.


Introduction
FOXP1 syndrome is a rare neurodevelopmental disorder due to forkhead box protein 1 (FOXP1) gene mutations and is associated with intellectual disability, dysmorphic features, and autism spectrum disorder (ASD) [1].Siper et al. [1] reported compulsive skin and nail picking in 56% of FOXP1 syndrome patients in a small prospective phenotype characterization study (n = 9).Therefore, we aimed to assess bodyfocused repetitive behavior (BFRB) prevalence in this patient population using a cross-sectional survey-based study.

Methods
A validated survey [2] assessing for BFRBs was administered to parents attending the International FOXP1 Foundation conference on June 21, 2023, with a 76.7% (33/43) response rate.A digital survey was sent to the International FOXP1 Foundation listserv, with 37 responses (unknown denominator).The International FOXP1 Foundation is a support group for FOXP1 syndrome patients and their families.Inclusion criteria were patients with a genetically confirmed diagnosis of FOXP1 syndrome as self-reported by parents.BFRB severity was calculated individually for each BFRB scale based on three domains (time spent, interference, and distress).
Overall, 77.1% and 81.3% of patients and patient families, respectively, reported BFRB-associated distress (online suppl.Table 3).On average, patients reported having BFRBs for 6.8 years, with 79.1% reporting stable or worsening disease course.Only 22.9%  Country not reported to protect anonymity of patients, many of whom are the only patient diagnosed with FOXP1 syndrome in their respective countries.Curtis/Lipner of patients saw a physician for their BFRB, and of those, 37.5% reported satisfaction with treatment (online suppl.Table 4).

Discussion
We demonstrate strikingly high BFRB prevalence in FOXP1 syndrome patients surveyed compared to the general population, which is estimated at 1.2-11.2%for excoriation disorder [3], 20-45% for onychophagia [4], 0.9% for onychotillomania [4], and 0.6-2.9% for trichotillomania [3].In a meta-analysis [5] of 14,379 patients with ASD, pooled prevalence of self-injurious behavior was 42%, with hair pulling and self-scratching associated with intellectual disability (p = 0.008, p = 0.002, respectively), which may explain why FOXP1 syndrome patients, many of whom have both ASD and intellectual disability, are at increased BFRB risk.Stimulus control (reducing BFRB cues such as idleness), aversion therapy (pairing BFRB with discomfort, such as applying unpleasant-tasting nail polish to discourage onychophagia), habit reversal training (teaching alternative behaviors such as fist clenching or sitting on hands), or pharmacotherapies (such as N-acetylcysteine or antidepressants) are potential BFRB treatments for FOXP1 syndrome patients [4,6].
Cutaneous infections were frequently self-reported with BFRBs in our survey-based study.Similarly, Siper et al. [1] reported a recurrent skin infection rate of 22% in FOXP1 syndrome patients.Cutaneous infections may be BRFB-associated complications, or FOXP1 patients may have higher infection risk, given the potential role of FOXP1 in immune regulation.
Estimated prevalence of FOXP1 syndrome is <1/1,000,000, with only ~200 patients identified to date.Therefore, while sample size is small, the study includes a large proportion of patients.Volunteering bias and survey design are limitations.
In conclusion, we show that prevalence of BFRBs is dramatically high among FOXP1 syndrome patients surveyed, affecting quality of life for patients and their families and causing significant sequelae.Dermatologists are well positioned to advocate for FOXP1 syndrome patients and to manage BFRBs as part of a multidisciplinary approach.

Statement of Ethics
This study was reviewed and approved by the Medical Ethical Review Committee of Weill Cornell Medicine (IRB #23-05026040).The study has been granted an exemption from requiring written informed consent by the medical ethical review committee of Weill Cornell Medicine.Informed consent was obtained for publication of accompanying figures.

Fig. 1 .
Fig. 1.Excoriation disorder in a patient with FOXP1 syndrome.The mode of injury was peeling skin from fingers with teeth.

Fig. 2 .
Fig. 2. Shortened nail beds secondary to long standing onychophagia in a patient with FOXP1 syndrome.

Table 1 .
Characteristics of FOXP1 syndrome patients