Schwartz et al. Journal of Neurodevelopmental Disorders (2021) 13:25 https://doi.org/10.1186/s11689-021-09373-2 REVIEW Open Access Behavioral features in Prader-Willi syndrome (PWS): consensus paper from the International PWS Clinical Trial Consortium Lauren Schwartz1,2* , Assumpta Caixàs3,4, Anastasia Dimitropoulos5, Elisabeth Dykens6, Jessica Duis7, Stewart Einfeld8, Louise Gallagher9, Anthony Holland10, Lauren Rice11, Elizabeth Roof12, Parisa Salehi13, Theresa Strong1,14, Bonnie Taylor15 and Kate Woodcock16 Abstract Prader-Willi syndrome (PWS) is a rare neurodevelopmental genetic disorder associated with a characteristic behavioral phenotype that includes severe hyperphagia and a variety of other behavioral challenges such as temper outbursts and anxiety. These behaviors have a significant and dramatic impact on the daily functioning and quality of life for the person with PWS and their families. To date, effective therapies addressing these behavioral challenges have proven elusive, but several potential treatments are on the horizon. However, a limiting factor for treatment studies in PWS is the lack of consensus in the field regarding how to best define and measure the complex and interrelated behavioral features of this syndrome. The International PWS Clinical Trials Consortium (PWS-CTC, www.pwsctc.org) includes expert PWS scientists, clinicians, and patient advocacy organization representatives focused on facilitating clinical trials in this rare disease. To address the above gap in the field, members of the PWS-CTC “Behavior Outcomes Working Group” sought to develop a unified understanding of the key behavioral features in PWS and build a consensus regarding their definition and description. The primary focus of this paper is to present consensus definitions and descriptions of key phenotypic PWS behaviors including hyperphagia, temper outbursts, anxiety, obsessive–compulsive behaviors, rigidity, and social cognition deficits. Patient vignettes are provided to illustrate the interrelatedness and impact of these behaviors. We also review some available assessment tools as well as new instruments in development which may be useful in measuring these behavioral features in PWS. Keywords: Prader-Willi syndrome, Behavior, Hyperphagia, Temper outbursts, Anxiety, Obsessive–compulsive, Rigidity, Social cognition, Patient vignettes * Correspondence: lauren.roth@fpwr.org; lschwrtz@uw.edu 1 Foundation for Prader-Willi Research, Walnut, CA, USA 2 Department of Rehabilitation Medicine, University of Washington School of Medicine, Seattle, WA, USA Full list of author information is available at the end of the article © The Author(s). 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Schwartz et al. Journal of Neurodevelopmental Disorders (2021) 13:25 Page 2 of 13 Background psychiatric illness, including psychosis, anxiety disorders, Prader-Willi syndrome (PWS) is a rare genetic neurode- and major depression [19]. The PWS neuropsychiatric velopmental disorder that occurs in approximately 1 in phenotype is further complicated by impaired cognition, 15,000 to 30,000 births, caused by a loss of paternally including intellectual disability, academic difficulties, and expressed imprinted genes on chromosome 15q11.2– specific deficits in social cognition such as perspective q13 [1]. Genetic subtypes of PWS include paternal taking and reading social/emotional cues [20–22]. deletion (del) of the 15q11.2-13 region, which occurs in Although some clinical trials and intervention studies approximately 65% of individuals; maternal uniparental are occurring, there are distinct challenges to conducting disomy (UPD), which occurs in ~30%; and less com- studies in PWS due to the complex interrelated behav- monly, an imprinting center defect diagnosed in 3–5% ioral features. One limitation for the field is the lack of of cases [2]. PWS affects multiple systems, with clinical consensus on how to best define or measure many of features that include hypotonia, growth hormone the complex behaviors associated with PWS. PWS-CTC deficiency, hypogonadotropic hypogonadism, sleep distur- “Behavior Outcomes Working Group” includes PWS bances, reduced pain sensitivity, decreased gastrointestinal scientists, clinicians, and patient advocacy organization motility, and scoliosis. A defining feature of PWS, which is representatives with expertise in the behavioral aspects rare among neurodevelopmental disorders, is the signifi- of PWS. This group sought to address the lack of con- cant change in eating behavior over time. Whereas infants sensus definitions and descriptions of PWS-associated with PWS have difficulty feeding and may exhibit failure behavioral features. Using literature review, clinical pa- to thrive, a persistent and unregulated desire to eat tient experience, and parent focus groups, the Working (hyperphagia) develops during childhood. Unless access to Group developed a unified understanding of the key be- food is strictly controlled, an overwhelming drive to eat havioral features in PWS which is presented here. Devel- coupled with decreased energy expenditure in individuals oping a consensus understanding of the behavioral with PWS leads to morbid obesity. The physiological basis manifestations in PWS provides an important founda- of hyperphagia in PWS remains unclear, and currently, tion upon which treatment studies targeting those be- there are no approved medications that effectively treat haviors can be developed and pursued. hyperphagia or other symptoms commonly seen in the syndrome. However, clinical trials testing the Hyperphagia in PWS effectiveness of novel agents against hyperphagia and Definition related PWS symptoms are currently underway or Hyperphagia in PWS manifests as an intense persistent recently completed [3–11]. sensation of hunger accompanied by food preoccupa- In addition to hyperphagia, other behavioral challenges tions, an extreme drive to consume food, food-related also prominent in PWS include temper outbursts, anx- behavior problems, and a lack of normal satiety. Hyper- iety, obsessive–compulsive behaviors, rigidity, and social phagia falls at the far end of a continuum of overeating skills (Table 1) [12–18]. These behaviors may or may behaviors and is considered the most extreme form of not be food related. In addition, as individuals with PWS overeating [23]. reach adulthood, they are also at high risk for developing Description Table 1 PWS behavioral features definitions A complex progression characterizes the development of hyperphagia, a hallmark feature of PWS [24]. Infants Hyperphagia: intense persistent sensation of hunger accompanied by food preoccupations, an extreme drive to consume food, food-related with PWS present with hypotonia, excessive sleepiness, behavior problems, and a lack of normal satiety decreased activity, poor suck, and may show little inter- Temper outbursts: highly explosive episodes in which the person with est in food. This stage is typically followed by a period of PWS becomes very angry or upset in a way that seems excessive for the relatively normal growth and weight gain. Subsequently, situation and also beyond the person’s control young children with PWS begin to gain weight easily Anxiety: excessive worry and tension often related to schedules/ and show an increasingly strong interest in food. Most routines, food planning or food security, persons/items of special interest and excessive concerns about the possibility of change individuals go on to develop hyperphagia marked by a lack of normal satiety and an overwhelming drive to eat. Obsessive compulsive behaviors: repetitive, ritualistic behaviors, collecting and hoarding items, insistence on “sameness,” need to know, The onset of hyperphagia is variable and can occur in ask, or tell early childhood, but the average age of onset is 8 years Rigidity: ardent inflexibility with certain routines, concepts, or ways of old [24, 25]. This strong drive to consume food is likely thinking; vigorous resistance to change; black and white thinking underpinned by persistent feelings of hunger with sati- Social cognition: difficulties relating to others, challenges with ation only developing after excessive calorie intake. Even reciprocal social communication, recognizing others’ emotions, empathy then, satiety does not persist for any length of time com- and accurate interpretation of social cues. pared to a control group without PWS [26]. Individuals Schwartz et al. Journal of Neurodevelopmental Disorders (2021) 13:25 Page 3 of 13 with PWS can readily consume up to three times the they will eat, and persistently searching for food. The normal caloric intake at a given meal, may hoard food, drive to eat can lead to food sneaking/food theft, eating and may eat discarded food [26, 27]. The lack of normal food left on other people’s plates, eating food that is nor- satiety is notable, as exemplified by reported cases of mally considered unacceptable (e.g., food scraps, food in gastric necrosis or stomach rupture arising from extreme the trash, raw food) or non-food items (e.g., dirt, grass, overeating [28, 29]. Hyperphagia is life-long in most soap), getting up at night to look for food, taking very individuals with PWS, but eating and food interest can large bites of food, and eating very fast [40]. Additional wax and wane over time, especially in response to behaviors include becoming agitated or anxious in the changes in the environment, such as changes in food presence of food, bargaining for more food, trying to de- security or alterations of the food schedule. In general, ceive others or lying to obtain food, becoming upset or no consistent differences in hyperphagia have been exhibiting temper outbursts when food is denied, and found between gender or PWS genetic subtypes [30]. becoming aggressive to obtain food. However, one small study found that food-related behav- iors were more severe in PWS males with deletion [31]. Assessment of the behavior Overall, the severity of hyperphagia is not necessarily The assessment of hyperphagia in the typical population correlated with degree of obesity in PWS; access to food has employed food diaries, visual scales, and test meals is typically the biggest determinant of weight. in research settings [41]. These methods are considered PWS-associated hyperphagia has overlap with several not useful in PWS due to the individual with PWS’s other conditions, including binge eating disorder, reluctance to report on their food intake related to addiction, and obsessive-compulsive features (preoccupa- concerns about “getting in trouble” and worries about tion with food) [32, 33]. However, it is distinguished from dietary repercussions [42, 43]. Self-report of degree of these conditions by its presence in early childhood as well hunger in individuals with PWS may also be limited as physiological studies suggesting that the hyperphagia in by cognitive and communication challenges [44]. In PWS likely is related to a pathological defect of satiety [26, addition, many people with PWS are on calorie- 34–36]. Additionally, a recent study indicated that individ- restricted diets; thus, food diaries would not accurately uals with PWS display abnormal patterns of neural activity reflect their hunger or hyperphagia. Finally, there are in response to food representations [37]. ethical problems of test meals [23] in PWS. And given For families and caregivers, PWS-related hyperphagia the physiological impairments in satiety mechanisms is incessant in that once hyperphagia starts, individuals in PWS, individuals may not fully experience the con- with PWS are constantly in search of food. Thus, for the trast between hunger and satiety. Thus, PWS patient- safety of the person with PWS, restricting access to food reported hunger scales are considered to be unreliable and controlling food intake “food security” are para- in this population. mount and a 24/7 concern for families. Food security Given the challenges of self-reporting in this popu- may include restricting access to food with locks on re- lation, the field has focused on the use of observer frigerators and pantries, keeping food out of sight and (i.e., caregiver) reported assessment of hyperphagia in constant supervision, i.e., “eyes on” the person with PWS PWS. The most frequently used measure of hyperpha- at all times to ensure they are not seeking/eating food gia in PWS is the Hyperphagia Questionnaire for they should not be consuming. This food security must Clinical Trials (HQ-CT) [45]. The HQ-CT is a 9-item be implemented across all settings, i.e., home, school, scale that assesses the severity of specific hyperphagic work, and social; families must educate all who interact behaviors including food seeking and food-related with the person with PWS. Food security also includes preoccupations by assessing distress and adaptive im- schedules and plans for all meals and food consumption. pairment related to hyperphagia. This instrument is Changes to those plans can lead to significant behavioral modified from a questionnaire developed specifically challenges for the person with PWS. Families, caregivers, to quantify hyperphagia in PWS [42], and adapted for and clinicians have described hyperphagia in PWS as an use in clinical trials [45]. This observer-reported out- overwhelming, life-threatening force, which sentences come measure, which aims to measure more objective people with PWS to a lifetime of environmental control food-related behavior, is based on behaviors over the and restricted lifestyle [23, 38]. Treating hyperphagia is past 2 weeks reported by a caregiver who is familiar the highest priority for caregivers [39]. with the daily activities of the person with PWS. Beyond self- or observer-reported assessment of Observable behaviors hyperphagia in PWS, there is interest in the field for Hyperphagic behaviors in PWS include intense focus on developing assessment tools that employ objective, food, which can manifest as excessive talking/asking direct measures of food interest, such as eye gaze or about food, especially details regarding what and when evoked response potentials [46, 47]. Schwartz et al. Journal of Neurodevelopmental Disorders (2021) 13:25 Page 4 of 13 Temper outbursts in PWS in PWS. A small pilot study [58] indicated that stimula- Definition tion of the vagus nerve decreased temper outbursts for Temper outbursts in PWS are defined as highly emo- some individuals with PWS, suggesting the role of the tional or explosive episodes in which the person with autonomic nervous system in this behavioral feature. PWS becomes “very angry or upset in a way that seems excessive for the situation and also beyond the person’s Observable behaviors control” [48]. Temper outbursts often manifest with the following behaviors: repetitive questioning that may escalate in Description volume, angry facial expression, increased salivation, Temper outbursts, sometimes described as emotional talking very loudly, crying, yelling, stomping the feet, outbursts, “tantrums,” or “meltdowns,” are one of the slamming doors, kicking, hitting, laying on the ground, most common maladaptive behaviors reported by and throwing objects/destroying things. Temper out- parents of children, adolescents, and adults with PWS bursts often follow a particular sequence of behaviors [5, 6, 37], with a significant impact on quality of life, in starting with emotional behaviors, such as crying and some instances equal to or greater than hyperphagia. A emotional vocalizations. This is rapidly followed by small study of PWS families showed a high percentage rising anger and more overt behaviors such as verbal of siblings experienced PTSD symptoms, and families and sometimes physical aggression. Early on, it may be reported lower overall quality of life compared with possible to distract the individual and avert the full out- normative samples [49]. Additionally, for the individual burst, but there is a point at which the person is unable with PWS, temper outbursts often result in reduced op- to bring themselves under control. Temper outbursts portunities to socialize in the community, limit living may last from minutes to hours before resolving, and options, and undermine employment. Approximately there is often a distinct period of “tuning out” or shut 80% of individuals with PWS exhibit severe temper out- down after an outburst and a need for sleep. The bursts beginning in childhood and persisting throughout sequence may often end with expressions of regret and adult life [50]. There may be some decrease in frequency distress [54]. of outbursts in adults compared to children with PWS, but adolescents and adults often have outbursts of lon- Assessment of the behavior ger duration than children with PWS [48]. There are no Currently, there are no measures that are validated consistent differences in the characteristics of temper specifically for the assessment of temper outbursts in outbursts across genders or PWS genetic subtypes [48]. PWS; however, several measures have been developed to The sequence of behaviors and emotions within tem- assess severe behavior challenges in individuals with in- per outbursts in PWS are similar to those seen in typic- tellectual disability, which may be applicable to assessing ally developing young children, yet the onset begins temper outbursts in PWS studies. Among these, the slightly later in life, and they continue throughout adult- Developmental Behavior Checklist–Monitoring Version hood [48]. These outbursts may be related to “arrested (DBC-M) is a caregiver-reported daily diary using items emotional development” in PWS as well to the conflu- from the Developmental Behavior Checklist [59]. It has ence of hyperphagia, diminished coping skills, poor emo- been used in a previous clinical trial examining the tional control/regulation, and limited executive function potential utility of oxytocin for treating behavioral skills [51–54]. Triggers for temper outbursts in PWS challenges in PWS [53]. Alternatively, the Challenging generally fall into the following categories: blocking of a Behavior Interview has shown utility in a small study desired goal, a violation of social expectations, perceived assessing the impact of vagus nerve stimulation on tem- injustice, or difficulty dealing with a change in routine per outbursts in PWS [58]. Finally, the Aberrant Behav- [48, 54, 55]. It has been hypothesized that PWS out- ior Checklist (ABC-2 [60]; irritability scale) which has bursts might be related to hyperphagia. However, Rice been used widely in studies on those with intellectual et al. [48] found that most parents of young children disability may provide a useful validated measure of with PWS reported temper outbursts occurring before temper outbursts in PWS. Bespoke informant diary mea- the onset of hyperphagia, suggesting outbursts may be sures [61] and structured interviews [54] have also been developing independent of hyperphagia. One possible used with some preliminary evidence of validity in PWS. mechanism driving the temper outbursts triggered by changes in routine may be a deficit in task-switching Anxiety symptoms and behaviors in PWS ability, a cognitive-related executive function that is an Definition area of particular difficulty in individuals with PWS [56, Anxiety is common in PWS and is characterized by ex- 57]. Dysregulation of the autonomic nervous system may cessive worry, and tension often related, but not limited be another key mechanism underlying temper outbursts to, schedules/routines, food planning or food security, or Schwartz et al. Journal of Neurodevelopmental Disorders (2021) 13:25 Page 5 of 13 persons or items of special interest (e.g., teachers, care- individuals with PWS, there is a constellation of explicit givers, pets). Concerns about the possibility of change in behaviors that appear to represent anxiety symptoms these areas are often a trigger for anxiety in PWS. commonly expressed in individuals with PWS. These Anxiety symptoms in PWS can overlap with Generalized include repetitive questioning especially related to Anxiety Disorder (GAD) but also have unique features (e.g., schedules, food and people, pacing, loud and/or fast talk- significant worry about food planning/security and items/ ing, excessive body and hand movements, trembling, people of special interest) that are not fully captured using and checking behaviors (e.g., checking on people of par- definitions based on the Diagnostic and Statistical Manual ticular interest and schedules). In addition, individuals of Mental Disorders (DSM-5) [62]. with PWS who are more verbal will frequently express many different worries and feelings of being “stressed” Description or overwhelmed. It should be noted that there is overlap Parents and clinicians have observed that individuals between anxiety behaviors and compulsive behaviors in with PWS may exhibit significant anxiety in both food PWS as described in the section below. and non-food-related situations as well as during times of transition and change of routine [57, 63]. However, Assessment of the behavior some studies do not appear to capture the extent of anx- There is no validated standard for measuring anxiety in iety in the PWS population [64, 65], likely due to chal- PWS. Previous research has reviewed tools for measuring lenges of defining and measuring anxiety. Other studies anxiety in individuals with intellectual disability via self- have found moderate to high levels of anxiety in PWS report and observer-reported methods [71]. Although samples [18, 39, 40]. Einfeld et al. [40] found that 43% of some of these measures could be useful in describing anx- individuals with PWS assessed with the Developmental iety symptoms in PWS, for example, Glasgow Anxiety Behavior Checklist (DBC) had significant levels of anx- Scale (GAS-ID) [72] and Anxiety, Depression and Mood iety. A recent study, Feighan et al. [18], found that 37% Scale (ADAMS) [73], available measures do not appear to of participants with PWS were diagnosed with anxiety fully capture the unique and important manifestations of (29% of adolescents, 43% of adults), and that anxiety was anxiety in PWS, such as excessive worry about food plan- the most common psychiatric diagnosis in adolescents ning/food security and items/people of special interest. and adults. Another recent publication examining care- Additionally, given challenges with insight and cognitive giver preferences for PWS treatment revealed that care- difficulties in PWS (e.g., concrete thinking, short term/ givers rated anxiety as one of their top 2 targets for working memory difficulties), it can be difficult to accur- PWS treatment [39], underscoring the negative impact ately assess anxiety in this population especially using self- of anxiety in this population. Finally, a 2018 review of report assessment tools. As noted in the DM-ID2, anxiety data from the PWS Global Patient Registry [66] found symptoms in those with intellectual disability can go that anxiety symptoms are reported by caregivers to be a undetected by others, and individuals with intellectual significant problem for 48% of the sample of individuals disability often do not report symptoms of anxiety [70]. with PWS ages 10 and above [67]. Given these reporting difficulties, caregiver/observer-re- The prevalence of anxiety symptoms in PWS appears ported assessments of anxiety are recommended. Previous to be similar between males and females but higher in research and clinical trials have employed the (C)YBOCS individuals with the UPD genetic subtype of PWS [4] to assess anxiety in PWS. Although useful, this meas- compared to the deletion subtype (73% vs. 32%) accord- ure does not appear to fully capture the range of anxiety ing to reports of those caring for individuals with PWS symptoms in PWS as it focuses almost exclusively on ob- [67, 68]. Studies assessing age of onset of anxiety in sessive thoughts and compulsive behaviors. In response to PWS have not been conducted to date; however, clinical the lack of effective tools to measure the unique anxiety observations suggest that many individuals with PWS symptoms and behaviors in PWS, a new measure specific struggle with anxiety starting around preschool to school to assessing anxiety and distress in PWS is currently being age (3–6 years) with peak anxiety symptoms generally piloted. The Prader-Willi Syndrome Anxiety and Distress occurring during adolescence/early adulthood [66, 69]. Questionnaire (PADQ) is a 20-item caregiver-rated meas- ure that assesses common indices of anxiety and distress Observable behaviors in PWS. The PADQ is currently being used as a secondary The Diagnostic Manual–Intellectual Disablity-2 (DM- outcome measure in phase 3 clinical trial in PWS. ID-2) [70] speaks to the importance of highlighting the behavioral equivalents of anxiety in the assessment of in- Obsessive compulsive behaviors in PWS dividuals with intellectual disability and limiting reliance Definition on cognitive and more subjective criteria. Although Obsessive-compulsive behaviors (OCB) in PWS are overt behaviors of anxiety may vary in intensity among defined as repetitive, ritualistic behaviors that include Schwartz et al. Journal of Neurodevelopmental Disorders (2021) 13:25 Page 6 of 13 collecting, storing/hoarding items, insistence on rou- that many individuals with PWS struggle with OC symp- tines, and “sameness”. Other OCB that are common in toms starting around age 3 [15]. Higher rates of compul- PWS are “needing to know, ask or tell” about certain in- sive behavior have also been reported among 2–3 year formation and distress when this behavior is prevented olds with PWS compared to typically developing chil- [12, 13, 74–77]. dren and young children with Down syndrome [15]. The research on differences in OC symptoms among PWS Description genetic subtypes is inconclusive, with one study finding Anxiety in PWS is often discussed within the context of that overall OC behaviors were higher in the PWS obsessive compulsive behaviors. Previous studies have del subgroup, whereas individuals with PWS UPD found relatively high rates of OC-type symptoms in indi- tended to have higher rates of OC behaviors that viduals with PWS with 37–58% having symptoms such mimic those commonly observed in autism spectrum as those described above [13]. In a small study, State disorder (ASD) [84]. et al. [76] also found high rates of OC symptoms and concluded that OC symptoms are prominent in the Observable behaviors PWS behavioral phenotype. However, in a longitudinal Obsessive compulsive behaviors in PWS vary in intensity follow-up of over 250 people with PWS, Dykens and and scope. However, as described above, there is a con- Roof [69] found that only 8% of their sample met full stellation of behaviors that are common in this popula- DSM-5 criteria [62] for diagnosis of obsessive compul- tion, including insistence on “sameness” in certain sive disorder (OCD). Many of the repetitive rituals routines and need to know/tell/ask, collecting items of participants with PWS engaged in did not meet the interest/“hoarding,” checking behaviors (e.g., checking standards for performing behaviors related to obsessive on collected items of interest), and repetitive rewriting, thoughts and fears (illness, germs, cleanliness). Ho and arranging, and rearranging. Dimitropoulos [78] also found that the obsessions in PWS often did not map onto the typical preoccupations Assessment of the behavior in OCD such as worries about germs, contamination, Previous research and clinical trials in PWS have religion, or others being harmed. One of the most employed the Children’s Yale Brown Obsessive Compul- predominant OC behaviors in PWS is repetitive ques- sive Scale [4, 85] to assess OC behaviors. The CY-BOCS tioning, which may be related to resistance to change. is a well-validated frequently used measure of OCD but For families, this behavior can be a source of consider- includes some items that are not pertinent to PWS. able day-to-day frustration, requiring active behavioral Although helpful in describing some of the salient OC management strategies [79]. Clinical observations and symptoms in PWS, the CY-BOCS does not capture the several studies suggest that for many individuals with broader manifestations of anxiety in PWS as noted PWS the OC behaviors may bring enjoyment and are above. soothing in nature, which is different from what is ob- served in OCD [80–82]. Additionally, the Diagnostic Rigidity in PWS Manual-Intellectual Disability-2 [70] notes that for many Definition individuals with intellectual disability including PWS, Rigidity in PWS is defined as ardent inflexibility with re- obsessive and compulsive behaviors often do not cause spect to certain routines, concepts, or ways of thinking clinically significant distress for the person, although ag- with vigorous resistance to change. Rigidity can also be gressive behaviors may occur if the person is prevented characterized as “black & white thinking” and a resist- from engaging in the behavior, which is different from ance to considering information or evidence that might classic OCD. Differences between PWS-associated OC conflict with the rigidly held belief. People with PWS behaviors and classic OCD are also supported by neuro- can demonstrate both cognitive and behavioral rigidity. imaging studies, which found some similarities but also differences in cerebral circuitry activation in PWS com- Description pared to classic OCD [83]. Another principal difference Parents and clinical experts report that people with PWS is that in DSM-5 OCD definition, the symptoms are often have rigid thinking styles and behaviors that “ego-dystonic,” that is the person has insight that their interfere with daily functioning. Individuals with PWS thinking is irrational but cannot stop the thought or commonly show a strong resistance to change [17]. This behavior. In most cases of OC behaviors in individuals difficulty with change of routine and inflexibility in PWS with PWS, this insight is not present. may be linked to a cognitive deficit in task switching [56, There is limited data on age of onset, frequency, or 57]. Task switching requires being able to move from possible genetic subtype differences in OC symptoms in one task to a different task in a timely manner, an area PWS. Clinical observations and parent reports suggest of difficulty for individuals with PWS [56, 86]. Schwartz et al. Journal of Neurodevelopmental Disorders (2021) 13:25 Page 7 of 13 Studies assessing age of onset of rigidity behaviors in described rigidity characteristic of PWS. The MERS- PWS have not been conducted to date. However, clinical PWS scale measures 3 domains that reflect rigidity: be- observations suggest that many individuals with PWS havioral rigidity, cognitive rigidity, and a protest domain. exhibit behaviors reflecting resistance to change and in- The MERS-PWS is currently being tested as a secondary flexibility at a young age, generally before starting outcome measure in a clinical trial examining challen- school. Dykens et al. [87] found that compulsivity and ging behaviors in adolescents and young adults with insistence on sameness in routines or events were seen PWS. in 76–100% of the participants with PWS (4–21 years). Little is known about the variation of these behaviors Social cognition deficits in PWS over time, gender, or genetic subtype differences. It is Definition notable that although individuals with PWS have a range Individuals with PWS display significant difficulties re- of intellectual functioning from moderate intellectual lating to others, especially peers. The social difficulties disability (ID) to normal IQ (with some learning chal- seen in PWS are characterized by challenges with recip- lenges), the symptoms of rigidity in PWS are seen across rocal social communication, recognizing others’ emo- the spectrum of intellectual function in PWS, not just in tions, empathy, and accurate interpretation of social those with lower (or higher) IQ levels. Clinically, these cues. Social skills challenges in PWS can overlap with behaviors have a significant impact on adaptive function- those observed in ASD and are influenced by genetic ing and are among some of the most difficult behaviors subtype. for parents to manage. Description Observable behaviors Individuals with PWS struggle with reciprocal social Overt behaviors that appear to reflect behavioral rigidity communication and with recognizing emotions in in PWS can include needing to have things done a cer- others, especially negative emotions such as sadness, tain way, including in a particular order, time, or place; anger, and fear [88]. Related to this, individuals with difficulty with changes in the schedule or routine; and PWS have difficulty accurately processing faces [21, 89], difficulty transitioning from one activity to another (e.g., interpreting emotional valence in faces, being aware of brother must always sit in the seat behind the driver, other’s personal space, and show significant develop- hair must be worn a certain way every day, refusal to mental delay in “theory of mind” tasks [50, 89–91]. In a take medication if not given the right way). Rigidity can recent study, Dykens et al. [88] found that individuals be observed by the person with PWS getting stuck on a with PWS also have difficulties with accurately perceiv- certain thought or idea and excessive talking about that ing the intentions of others. The above social difficulties topic. Additional characteristics include inflexibility in could be due to differences in the way individuals with beliefs and difficulty considering a new perspective or PWS process incoming information, which could impact topic even when presented with conflicting information on social skills. Interestingly, a physiological basis for (e.g., only females can be teachers but their teacher is these deficits is likely, with genetic subtype differences male). Another common observable behavior reflecting evident in several studies. Individuals with the uniparen- rigidity in PWS is significant distress and protest when tal disomy [UPD] or imprinting defect [ID] genetic sub- the rigid behaviors, thoughts, or beliefs are challenged. types tend to have more difficulty with social Additionally, protest and distress behaviors in PWS are communication and are more likely to be diagnosed with often seen when the person with PWS expects some- ASD; however, all genetic subtypes of PWS (deletion, thing that then does not happen. UPD, ID) show social challenges [20, 89]. To date, no studies have found significant gender differences in so- Assessment of the behavior cial skills challenges in PWS. Commonly used behavior scales (e.g., CY-BOCS, Repeti- Although there is overlap between the social difficul- tive Behavior Scale-Revised- RBS-R) do not specifically ties seen in PWS and those observed in ASD, the preva- focus on rigidity. Two domains of the RBS-R do assess lence and nature of ASD in PWS has been the subject of needs for sameness and compulsivity in those with some debate among clinicians and researchers. Estimates autism spectrum disorder (ASD) or ID yet are not spe- of ASD in people with PWS has been as high as 41% cifically tailored to PWS. Some of the rigid behaviors [92]; however, Dykens et al. [87] used multimodal forms seen in PWS could be captured on the CY-BOCS, but of assessment including direct assessments of the person the instrument does not adequately capture the majority with PWS and an expert clinical panel and found a rate of these behaviors and does not focus on cognitive rigidity. of ASD diagnosis of just 12.3%. The majority of those The Montefiore-Einstein Rigidity Scale (MERS-PWS) meeting ASD criteria having the UPD genetic subtype. is currently being developed to capture the above The authors suggested that high rates of ASD in Schwartz et al. Journal of Neurodevelopmental Disorders (2021) 13:25 Page 8 of 13 previous studies were based solely on parent-reported characteristics in PWS (Fig. 1). It may not be feasible to screening questionnaires and thus may have overesti- tease apart these features as many individuals with PWS mated rates of ASD diagnosis. It should be noted, struggle with multiple behavioral challenges simultaneously. however, that although most of the children with PWS As an example, the anxiety, OC behaviors, rigidity, and assessed in the Dykens et al. [87] study did not meet cri- temper outbursts observed in PWS appear to have signifi- teria for ASD, a large majority had some level of social cant overlap. One theory is that similar psychological or skill difficulties, especially in the area of reciprocal social physiological phenomenon and/or cognitive mechanisms, interactions. such as difficulties with task switching or emotion regula- tion, may underlie these behavioral challenges. However, Observable behaviors further research is needed to advance our understanding of Observable behaviors that reflect the social skills chal- the possible mechanisms underlying these key behavioral lenges in PWS can manifest as lack of or minimal recipro- features in PWS. Overlap of symptoms in mental health cal conversation. The person with PWS typically focuses and behavioral disorders can be seen in the general popula- the conversation on a narrow range of topics they are in- tion as well, for example, in anxiety and depressive mood terested in, with repetitive features in the conversation. disorders [96]. This overlap of symptoms and behaviors People with PWS may tend to play with younger children across different mental health conditions and features may and struggle more with peers. Difficulty in maintaining occur due to universal dimensions of distress or negative personal space (e.g., standing too close) is also common affect, as well as to shared genetic and neurobiological [89]. Social cognitive difficulties have been shown in chil- aspects of these mental health conditions. This is likely a dren as young as 3 years old [93]. Older children and factor in PWS as well. However, in PWS, it may not be adults with PWS may behave in ways that reflect feelings possible to separate out aspects of each of the behavioral of being easily slighted; they may be quick to become frus- challenges unless and until we have effective treatments for trated or angry and take things personally. People with that feature. Additionally, one treatment in PWS may PWS often have difficulty modifying their social behavior address multiple behavioral features seen in the syndrome to fit changing situations as they arise. Temper outbursts, related to overlapping neurobiological mechanisms and/or difficulties with routine change, and ritualistic and repeti- genetic factors. tive behaviors, as mentioned above, are common in PWS and present unique challenges in the social arena. Conclusions and limitations The primary aim of this paper is to review the current Assessment of the behaviors knowledge base regarding the defining features of the Currently, there are no measures that are specific to behavioral phenotype in PWS and provide consensus assess social skills challenges in PWS. However, some definitions of these behavioral features based on the studies exploring social challenges in PWS have work of the PWS-CTC Behavior Outcomes Working employed the Social Responsiveness Scale (SRS) and the Group. Developing a unified understanding of the PWS Social Competence Inventory [94], which are parent- behavioral phenotype is important as interventions and rated inventories [89]. These are well-validated measures to assess social challenges in those with ASD or ID. Other studies have used emotion recognition tasks or vi- gnettes to assess social perceptions. Some of the social challenges seen in PWS are captured by these measures, but they do not adequately assess the breadth of unique social challenges seen in PWS. A combination of parent, clinician, and teacher rating scales, in addition to direct patient measures (e.g., face/emotion tasks), may be necessary to fully capture the nature of social skills chal- lenges in PWS. Tools like the ADOS-2 [95] and other clinician-rated assessments are recommended especially when assessing for ASD. Relying on parent assessments only may give an incomplete picture of the social skills deficits observed in PWS [87]. Overlap of PWS behavioral symptoms and features As is apparent from the above descriptions, there can be Fig. 1 Key interrelated behavioral features of PWS significant overlap of features among the various behavioral Schwartz et al. Journal of Neurodevelopmental Disorders (2021) 13:25 Page 9 of 13 treatments for PWS are moving forward, and the backpack that was near the coaching bench and behaviors reviewed in this paper are currently or likely quickly took something out and poured it in her soon to be targets of treatment studies. This paper also mouth, swallowing hard. Her mother ran to her highlighted some of the assessment tools that are cur- and asked her what she ate but she put her hands rently available and under development, which may be over her mouth and would not talk. Her mother useful in measuring these features in PWS. Although the raised her voice in tears asking, “What did you get?” current paper discusses the use of several measurement Everyone at the ballpark was looking at them. J tools, it was beyond the scope of this paper to provide a never admitted to what she ate but had food around complete assessment of available behavioral assessment her mouth and hands. tools and their potential utility in PWS. This paper rep- resents only an initial foray into this area. Future studies Feature: temper outbursts are needed to determine if existing measures for the assessment of behavioral challenges in individuals with 1. K is a 22-year-old male with PWS living at home intellectual disability can be validated for use in PWS or with parents and sister. He has aged out of school whether new PWS-specific assessments are needed. Fur- services and is now waiting for vocational services. ther work on the utility of advancing more appropriate He began having temper tantrums at age 8, and measures for PWS will be an ongoing focus for the they have gotten progressively worse, with broken PWS-CTC as well as for the field as a whole. furniture, scared family members, and calls to police. For example, K became upset when a PWS patient vignettes sporting event was rained out and he had to leave The following are PWS patient vignettes to highlight the the field unexpectedly. He became more agitated on behavioral features discussed in this paper. These the drive home, cursing and asking “why” he had to vignettes are not based on any one patient with PWS go home. His parents’ explanations about lightning but rather a combination of different behaviors observed and possible injury or death could not dissuade him by clinicians with experience working with individuals from the “unfairness” of the situation. He came with PWS. home, went to his room and within minutes had broken a lamp, his glasses, and ripped his shirt. He Feature: hyperphagia came out and threatened his mom and tried to hit her with a book. Dad intervened and finally had to 1. B. is an 18-year-old male with PWS living at home sit on his 150-lb son to keep him from injuring with parents and sister. He admits he is hungry “all himself or others. Police have been called by the time” but would not admit to taking food neighbors and his own parents, but besides taking around the house or at school. He has taken bolt him to the station or patrol car for a “scared cutters from the garage to break the locks on the straight moment,” they have no answers. He is pantry and has also used a screwdriver to take the usually quite tearful and remorseful after these hinges off locked cabinets to try to get at food. He tantrums blow over but admits he cannot control has convinced classmates that he did not have a them when they are happening. lunch after he ate it on the morning bus ride to 2. J is a 10-year-old girl living with PWS. While at school. He talks and thinks about food constantly school 1 day shortly after recess started, one of the but denies eating food when his mom finds teachers noticed J laying on the ground yelling, wrappers stuffed in his sneakers. He is clever and swatting, and biting anyone close to her. Then, a fast when it comes to obtaining food; he once stole loud pitched scream came from her that stopped more than 200 dollars from classmates during a the playground. J then got up and started running, play rehearsal to buy food from a convenience store. knocking anyone and anything in her path. She then Because he is so friendly and social, none of the kids curled up in a ball on the other side of the field and thought he could have done it. They often give him the teachers told everyone to give J space. She snacks and other food, because he asks “so nicely” finally calmed and then sat picking handfuls of even though they know he should not have it. grass. The vice principal came out to talk to J who 2. J. is a 10-year-old girl with PWS who was at her at first would not speak. As the principal talked brother’s baseball game, sitting in the stands with quietly to her, J. calmed down but seemed not to her mother. When her doll fell under the bleachers, recall the event. When asked how she was feeling, her mother let her go down and get it since she felt she said, “Fine.” She then got up to walk back to she could have “eyes on her” the entire time. As she her classroom. The principal noted that these returned from getting her doll, she reached into a episodes happen frequently. Schwartz et al. Journal of Neurodevelopmental Disorders (2021) 13:25 Page 10 of 13 Feature: obsessive compulsive behaviors deal of time trying to convince others that he is right. A is a 16-year-old girl with PWS who lives at home with These beliefs often are based on things he has read and her parents, attends a local high school, and receives facts that he believes. The preferences and opinions of special education services. Her father reports that A col- others do not deter him of his mission that he is right lects and hoards hundreds of rubber gloves and spends and that others are wrong. His parents are worried that countless hours sorting, piling, and rolling them into he won’t be able to ever maintain employment or social tight balls and then puts them in bins. She does not use connections because he cannot be dissuaded and that he the gloves. She does this activity for hours after school, cannot avoid arguing with and offending others. and if her father walks into her room, she must check Abbreviations the sole of his shoes and pockets to make sure that none PWS: Prader-Willi syndrome; UPD: Uniparental disomy genetic subtype; of her gloves have been inadvertently “picked up”. If her Del: Deletion genetic subtype; OCD: Obsessive compulsive disorder; parents try to limit this activity or keep her from obtain- OCB: Obsessive compulsive behaviors; ASD: Autism spectrum disorder; ID: Intellectual disability ing more gloves, she becomes hysterical and sometimes aggressive. She even insists on taking them on family Acknowledgements trips and recently to her grandfather’s funeral. Our thanks to Nathalie Kayadjanian for her thoughtful contributions to initial outline and initial draft of the manuscript. We also thank Caroline Vrana-Diaz (FPWR) for her editorial and administrative support. Finally, we thank the Feature: anxiety symptoms members of the PWS-Clinical Trial Consortium for their encouragement to M is an 11-year-old girl with PWS living with her par- pursue this work. ents and three siblings. She spends hours a day confirm- Authors’ contributions ing the daily schedule, asking many questions about who All authors contributed significantly to developing the conceptual will carry out daily care and academic activities, and underpinnings of the manuscript and participated in the writing and editing of the manuscript. The authors read and approved the final manuscript. needs to check in constantly with mom and a full-time care assistant. She becomes tearful if her mom reminds Funding her that her schedule is the same every day and the same Funding for this project was provided by the PWS-Clinical Trial Consortium (www.pwsctc.org)/Foundation for Prader Willi Research, who provides people will be helping her. She asks, “but what if it’s support in the form of publication costs. not?” What if’s rule her life, and M shuts down if care- givers try to discuss this with her. If they persist in this Availability of data and materials Not applicable M.’s behaviors escalate to crying and yelling. M asks more than 300 questions a day and does not trust her Declarations teacher, aides, and other school staff to help. The school Ethics approval and consent to participate had to call mom every day several times/day because of Not applicable this. Her anxiety behaviors at school became unmanage- able and her mom has chosen to homeschool her now. Consent for publication M is on more than 3 psychiatric medications, which Not applicable have helped “take the edge off,” but have not reduced Competing interests her anxiety to allow for increased functioning for M. LS is a consultant to and part of the Research Team at the Foundation for Prader Willi Research AC–no competing interests Feature: rigidity AD–no competing interests P is a 23-year-old male living with his parents. He went ED–no competing interests to a local school and graduated with a regular diploma, JD–no competing interests SE–no competing interests fulfilling all state requirements, and he yearns for a “real AH–no competing interests job”. He has been unable to keep employment because LR–no competing interests of his rigid behaviors. P feels that tasks should be ER–no competing interest PS is involved in clinical research funded by Soleno Therapeutics, Inc. & completed a certain way and is taken to arguing with Millendo Therapeutics, Inc. coworkers and bosses when he feels they are “wrong”. TS is an employee of Foundation for Prader Willi Research (FPWR) and He once was fired after arguing with a customer about Director of Research Programs at FPWR BT–no competing interests which dog food is best. P tried unsuccessfully to con- KW–no competing interests vince the customer that the food they wanted was not as good for their dog as another brand. The customer tried Author details 1 Foundation for Prader-Willi Research, Walnut, CA, USA. 2Department of to be good-natured, but eventually asked for a manager. Rehabilitation Medicine, University of Washington School of Medicine, P then tried to convince the manager “that no one Seattle, WA, USA. 3Endocrinology and Nutrition Department, Parc Taulí knows more about dogs than me”. He has many strongly University Hospital, Parc Taulí Research and Innovation Institute, Sabadell, Spain. 4Medicine Department, Autonomous University of Barcelona, Sabadell, held beliefs on everything (from best pizza in Baltimore Spain. 5Psychological Sciences, Case Western Reserve University, Cleveland, to worst gorilla exhibit in the USA) and spends a great OH, USA. 6Vanderbilt Kennedy Center for Research on Human Development, Schwartz et al. Journal of Neurodevelopmental Disorders (2021) 13:25 Page 11 of 13 Vanderbilt University, Nashville, TN, USA. 7Section of Genetics & Inherited Am J Ment Retard. 2001;106(1):39–51. https://doi.org/10.1352/0895-8017(2 Metabolic Diseases, Children’s Hospital Colorado, University of Colorado 001)106<0039:EOCBAT>2.0.CO;2. Anschutz Medical Campus, Aurora, CO, USA. 8Faculty of Medicine and Health, 16. Sinnema M, Einfeld SL, Schrander-Stumpel CTRM, Maaskant MA, Boer H, University of Sydney, Camperdown, NSW, Australia. 9Trinity College Dublin Curfs LMG. 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