Prader-Willi syndrome (PWS; OMIM #176270) is a genetic neurodevelopmental disorder, caused by an anomaly in the paternally derived long arm of chromosome 15. PWS is characterized by multiple physical, cognitive, behavioral, and psychiatric symptoms. Hypotonia and pituitary hormone deficiencies, particularly hypogonadism occur most frequently (1–3). After birth, patients suffer from feeding difficulties, often necessitating tube feeding. Later in childhood, patients typically develop hyperphagia. In the absence of external control, this can result in excessive eating behaviors including pica, and consequent risks of developing obesity, diabetes mellitus, cardiopulmonary disease, and other serious somatic comorbidities (1, 4, 5). While PWS requires lifelong medical treatment and behavioral management, overall mortality rate is estimated at 3% per year and the average age at time of death is 40–50 years (6, 7).

As to cognitive and behavioral characteristics, PWS presents with mild to moderate intellectual disabilities, executive and social cognitive impairments and symptoms from the autism spectrum such as general cognitive inflexibility with perseverations, repetitive and ritualistic behaviors, temper tantrums, and self-injury (e.g., skin-picking). Challenging behaviors typically increase from teenage years up to their thirties, and affective disorders, mood instability or psychosis may frequently occur from adolescence onwards, albeit with varying severity (8–10).

PWS also has a major impact on PWS relatives. Lower levels of quality of life, increased burden of care and family problems have been reported in primary caregivers of young children with PWS (11–13). Furthermore, there is evidence of increased levels of distress and mood disturbances in family members (mostly mothers), as well as symptoms of posttraumatic stress disorder (PTSD) in siblings of young PWS patients (12, 14, 15).

So far, no information is available on trauma related distress and quality of life regarding wider family members related to PWS individuals in all chronological ages. This study aims to identify possible psychopathology and any underexposure of the issue in the group of family members. To this end, in those PWS relatives, we studied (a) traumatic life events and symptoms of PTSD, (b) trauma symptom severity and PWS-related stressors, (c) trauma symptom severity and Quality of Life, (d) age of PWS individuals and PWS symptom severity, the amount of PTSD symptoms, and Quality of Life respectively, and (e) living situation in relation to the occurrence of trauma symptoms, and content of reported trauma (see Table 1 for the specific hypotheses).

Lifetime prevalence of traumatic events in family members of PWS patients was 92.9% (n = 91 out of 98). Seven participants (7.1%) reported no occurrence of any traumatic experience. Of those who reported traumatic events, 46.2% (n = 42) reported a PWS related experience as a traumatic event and 53.8% (n = 49) reported a traumatic experience of a different nature. Of the participants who reported a PWS-related traumatic event, 73.8% (n = 31) considered the PWS related event as currently the worst (currently bothering them the most). Furthermore, 11 of the 91 participants (12.1%) who reported traumatic events scored at or above the cut-off point of 33 on the PCL-5-NL, implicating that the severity of their current trauma symptoms probably indicates PTSD.

Participants who reported a PWS-related trauma scored significantly higher on both the total symptoms of PTSD of the PCL-5-NL, as well as on the four distinct clusters of PTSD symptoms of the PCL-5-NL compared to participants who experienced different, non PWS-related traumatic events. Results are displayed in Table 3.

There was a significant and substantial negative correlation between total PCL-5-NL score of trauma symptoms and the total WHOQOL-BREF-NL score of quality of life (r₍₉₄₎ = −0.57, p<0.001, R^{2 =} 0.33). There were significant differences in PTSD symptom clusters “cognition and mood” (F_{(4, 86)} = 5.589, p < 0.001, ηp2 = 0.206), and “hyperarousal and reactivity” (F _{(4, 86)} = 4.124, p = 0.004, ηp2 = 0.161). These two symptom clusters were further examined. Negative alterations in cognition and mood appeared to be inversely related with all four domains of quality of life (physical health, psychological, social relationships, and environment). Further, negative alterations in arousal and reactivity were negatively related to the quality of life domain physical health. These significant results are presented in Table 4.

Family members of PWS individuals reported more severe PWS symptoms in the PWS age groups “10–30 years” and “≥ 31 years,” compared to PWS individuals aged 0–9 years. PTSD symptom scores among family members of patients aged 10–30 years were significantly higher than in the youngest age group, for the Total PTSD-score of the PCL-5-NL, as well as on its four trauma clusters (intrusion symptoms, avoidance symptoms, negative alterations in cognition and mood, and negative alterations in arousal and reactivity). The Total PTSD score and the level of arousal and reactivity symptoms were significantly lower in PWS individuals over 30 years than in those aged 10–30 years. The results are presented in Table 5. Quality of life did not differ between age groups.

A significant interaction was found between the occurrence of trauma symptoms in family members with PWS patients living in a care facility or not (χ² (1) = 6.02, p = 0.021). More often the absence of trauma symptoms (73%) than the presence (34%) was reported among relatives of PWS patients living in a care facility. Another significant interaction was found between the content of the experienced trauma (LEC-5-NL) and living setting of the family member (χ² (1) = 4.99, p = 0.035). Family members who reported a PWS-related traumatic event (64%) more often lived with their relative with PWS than family members who reported other traumatic events (41%).

This first study on trauma and distress in adult relatives of individuals with PWS shows an increased risk for traumatic experiences and greater vulnerability to PTSD. As expected, we have found higher life time prevalence of traumatic events in adult family members than in the general Dutch population (92.9 vs. 80.7%) (30). Of those who reported any traumatic event, almost half reported PWS-related events. Furthermore, the prevalence of probable PTSD in this study (12.1%) exceeded the general lifetime prevalence of PTSD (worldwide between 1.3 and 8.8%; (31)) and in the Netherlands (7.4%; (30)). These findings are in line with previous research which showed that a severe or chronic illness of a relative can be experienced as a traumatic stressor and has been associated with manifestations of PTSD symptomatology (32–34). In addition, as hypothesized, family members who reported PWS-related trauma scored higher on PTSD symptoms than participants who experienced a different, non PWS-related traumatic event. These findings should increase clinical awareness of signs of psychopathology, and result in a recommendation to systematically monitor the experience of traumatic events in relatives of patients with PWS.

As expected, there was a negative relation between trauma symptoms and quality of life; particularly with respect to negative alterations in arousal and reactivity (cluster E), and in negative alterations in cognition and mood (cluster D). Cluster E symptoms were specifically negatively correlated to physical quality of life. The physical aspects of (acute and chronic) stress (high adrenaline and/or cortisol levels, sleep issues) could contribute to this relationship. Cluster D symptoms were negatively and fairly evenly related to all quality of life domains, affecting the experienced physical health, psychological health, social relationships, and living environment simultaneously. These results encourage awareness of clinicians regarding reciprocal influences of quality of life and the forementioned particular trauma symptoms in family members of PWS individuals. Cure of PTSD symptoms in family members might be supported by care in different life domains.

Further, results showed that higher chronological age of the PWS individual was related to increased PWS symptom severity evaluated by the family members. Both the total trauma score as well as the respective scores in all different trauma symptom clusters (B-E) were significantly higher in family members of the PWS patient age group 10 to 30 years (adolescents and young adults), compared to the age group 0 to 9 years (childhood). These findings regarding chronological age, PWS symptom severity and PTSD symptom severity did not fully demonstrate the expected quadratic relationship, since the expected PWS- and trauma severity differences between the age groups 2 and 3 did not reach significance. A possible explanation could be admittedly lower degree of challenging behaviors in PWS patients in group 3 (35), but higher levels of physical problems in this PWS patient age group (36), which may also cause stress and psychological complaints in caregivers (37). Nevertheless, as expected, increasing age of the PWS patient (from 10 years and up) was related to both PWS symptom severity and PTSD symptom severity negatively. This finding endorses the importance of clinical attention to both advanced care planning for the individual PWS patient, and timely support for their family members.

Finally, living together with their PWS relatives increased the risk of trauma symptoms, also of PWS-related trauma. Follow up research could explore trauma related symptoms in family members in relation to the intensity of their involvement in daily care of an individual with PWS, and the experienced caregiver burden.

Several limitations can be identified in the current study that may limit the generalizability of the results. At least the following two have to be mentioned here. Firstly, while selection-bias is difficult to avoid in research on genetic developmental disorders, due to participant recruitment by volunteer sampling, an over-representation of family members who felt attracted to the research topic may have occurred. Secondly, the sampling period was during the COVID-19 pandemic, which may have had a pre-existent negative impact on the experienced quality of life and health (38). Nevertheless, this applies to all participants who participated and leaves aside the differences we have found within our study population. Notwithstanding these limitations, the strengths of the study concern the considerable sample size, and the wide age range of related PWS individuals (from infancy to late adulthood), enabling cross sectional analyses. Furthermore, participation concerned all adult family members, instead of parents only. Demographic data regarding participants' educational levels indicate a fairly distributed representation, but a tendency to the higher end. At the same time, a majority of female relatives (~2/3) was involved in this study. Both aspects could both under- and over-estimate the results, since distress can be considered a product of a dynamic transaction between individuals (including cognitive, physiological, affective, psychological, neurological systems) and their complex environment; consistent with the transactional model of stress and coping (39).

The results presented in this study warrant further, preferably longitudinal, research. When compared to other rare genetic developmental disorders, such as Williams syndrome, Fragile X syndrome, or Smith-Magenis syndrome, parents of patients with PWS have shown higher levels of stress (40, 41). Future research could compare our results with those on trauma and quality of life in relatives of patients with other genetic developmental disorders.

Having a relative with PWS is associated with higher prevalence of experienced traumatic events, and of PTSD, affecting the wider family system. Raising awareness in health care professionals of the typical presentation of trauma symptoms in PWS relatives may contribute to effective treatment of their psychosocial stress. In addition, timely, transdisciplinary (medical-psycho-social) attention to all relatives might prevent them from developing psychopathology like PTSD.

The raw data supporting the conclusions of this article will be available from the corresponding author on reasonable request.

The studies involving human participants were reviewed and approved by the Vincent van Gogh Institutional Review Board (Decision letter references: JE/hr/2020.012/; JE/hr/2021.004). The participants provided their written informed consent to participate in this study.

AB-R, EW, LG, and JE designed and planned the study. AB-R and AB performed data collection and executed statistical analyses. AB-R drafted the manuscript. EW, LG, and JE revised and critically reviewed the manuscript for important content. All authors read and authorized the final version of the manuscript.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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