Received: 30 March 2017 | Revised: 25 July 2017 | Accepted: 9 October 2017

DOI: 10.1002/ajmg.a.38525

ORIGINAL ARTICLE

A model to characterize psychopathological features in adults

with Prader-Willi syndrome

Denise Thuilleaux1 | Virginie Laurier1 | Pierre Copet1 | Julie Tricot1 |

Geneviève Demeer1 | Fabien Mourre1 | Maithé Tauber2 | Joseba Jauregi3

1 Centrede Référence Prader-Willi, Hôpital

Marin, APHP, Hendaye, France
2 Centrede Référence Prader-Willi, Hôpital
des enfants, CHU Purpan,, Toulouse, France
3 EuskalHerriko Unibertsitatea-University
of the Basque Country, Psychobiology,
Donostia, Spain
Correspondence
Virginie Laurier, Hôpital Marin de Hendaye,
APHP, Centre de Référence Prader-Willi,
64701, Hendaye Cedex, France.
Email: virginie.laurier@aphp.fr
High prevalence of behavioral and psychiatric disorders in adults with Prader-Willi
Syndrome (PWS) has been reported in last few years. However, data are confusing and
often contradictory. In this article, we propose a model to achieve a better
understanding of the psychopathological features in adults with PWS. The study is
based on clinical observations of 150 adult inpatients, males and females.
Non-parametric statistics were performed to analyse the association of psychopatho-
logical profiles with genotype, gender and age. We propose a model of psychiatric
disorders in adults with PWS based on cognitive, emotional and behavioural issues.
This model defines four psychopathological profiles: Basic, Impulsive, Compulsive, and
Psychotic. The Basic profile is defined by traits and symptoms that are present in
varying degrees in all persons with PWS. In our cohort, this Basic profile corresponds to
55% of the patients. The rest show, in addition to these characteristics, salient features
of impulsivity (Impulsive profile, 19%), compulsivity (Compulsive profile, 7%), or
psychosis (Psychotic profile, 19%). The analysis of factors associated with different
profiles reveals an effect of genotype on Basic and Psychotic profiles (Deletion: 70%
Basic, 9% Psychotic; Non-deletion: 23% Basic, 43% Psychotic) and a positive
correlation between male sex and impulsivity, unmediated by sex hormone treatment.
This is a clinical study, based on observation proposing an original model to understand
the psychiatric and behavioural disorders in adults with PWS. Further studies are
needed in order to test the validity of this model.

KEYWORDS
adults, behavior, Prader-Willi syndrome, psychiatric disorders

1 | INTRODUCTION
Prader-Willi Syndrome (PWS) is a developmental, neuroendocrine,
genetic disorder characterized by typical dysmorphic features and a
variable expression of somatic, cognitive, and behavioral symptoms
(Cassidy & Driscoll, 2009; Goldstone, Holland, Hauffa, Hokken-Koelega,
& Tauber, 2008). Epidemiological studies estimate a PWS incidence of 1
in 25,000 births and a population prevalence of 1 in 50,000 (Whittington
et al., 2001). PWS is a “contiguous gene syndrome,” resulting from an
absence of expression of the paternally derived alleles of maternally
imprinted genes in the q11-13 region of chromosome 15. In 70% of the
cases, the cause is a paternal deletion of 15q11-q13. The deletion can be
longer (Type I), shorter (Type II) (Christian et al., 1995), or a typical (Kim
et al., 2012). A maternal uniparental disomy (UPD) is found in 25% of
cases. In the remaining 3–5%, PWS is thought to be caused by either a
defect in the imprinting centre or by a balanced translocation involving a
breakpoint in 15q11q13 (Goldstone, 2004). The genetic region of PWS
contains a cluster of imprinted and non-imprinted genes, and their
respective contributions to the phenotypic features have not yet been
clearly established (Maina et al., 2007). Recently, small deletions of the

Am J Med Genet. 2017;1–7. wileyonlinelibrary.com/journal/ajmga © 2017 Wiley Periodicals, Inc. | 1

2 |
SNORD 116 gene had been shown to reproduce, albeit moderately, the
entire phenotype of PWS (Bieth et al., 2014; de Smith et al., 2009; Duker
et al., 2010; Sahoo et al., 2008).
Psychopathological features, including behavioral disturbances and
psychiatric disorders, are now considered to be critical issues in PWS. In
recent years, care of the somatic aspects of the illness has progressed due
to earlier diagnosis, hormone substitution therapy, and other advances in
symptom management. However, improvement of psychopathological
aspects has been poor and they have become the greatest challenge to
provide a better quality of life for patients and their families.
A review of previous reports in the field of psychopathology in PWS
shows the existence of two main approaches: behavioral and
psychiatric. Most behavioral research was performed asking relatives
and caregivers to complete questionnaires in the form of checklists of
adaptive and maladaptive behaviors. These inventories were created for
typically developing people or adapted to a population with intellectual
disability but none was specific to a PWS population. They reported a
high prevalence of maladaptive behaviors even compared to people
with similar intellectual disability due to other aetiologies (Clarke, Boer,
Chung, Sturmey, & Webb, 1996; Dykens & Kasari, 1997; Sinnema, Boer,
et al., 2011; Verhoeven, Egger, & Tuinier, 2007). Besides the typical
hyperphagia, challenging behaviors commonly described in people with
PWS include stubbornness, temper tantrums, skin picking, compulsive-
ness, mood fluctuations, and disruptive behavior (Clarke et al., 2002;
Einfeld, Smith, Durvasula, Florio, & Tonge, 1999; Jauregi, Laurier, Copet,
Tauber, & Thuilleaux, 2013). Behavioral disturbances have also been
reported to have a different typology or severity as a function of
genotype. For example, m-UPD subtype displays fewers obsessive-
compulsive and ritualistic behaviors (Dykens & Roof, 2008; Milner et al.,
2005) and higher prevalence of communication disturbances and social
withdrawals (Jauregi et al., 2013).
The second approach is oriented to describing psychiatric
comorbidities in people with PWS. The method of most of these
studies is based on the use of psychiatric screening instruments,
sometimes adapted to a population with intellectual disability. Usually,
the informants are also the relatives and caregivers. In some cases, the
assessment is performed by a clinical expert, using a structured or
semi-structured interview. Their aim was the diagnosis of psychiatric
disorders belonging to current nosological classifications. From this
perspective, a broad array of comorbid psychiatric illnesses has been
described with prevalence of up to one third of the individuals with
PWS (Dykens & Shah, 2003). The most frequently cited disorders were
affective disorders with or without psychotic symptoms (Sinnema,
Einfeld, et al., 2011; Soni et al., 2008), atypical psychosis (Verhoeven &
Tuinier, 2006; Vogels et al., 2004), obsessive compulsive disorder
(Clarke et al., 2002; Wigren & Hansen, 2003), attention
deficit/hyperactivity disorder (Wigren & Hansen, 2005), and pervasive
developmental or autistic-like disorder (Descheemaeker, Govers,
Vermeulen, & Fryns, 2006; Dimitropoulos & Schultz, 2007). The
development of psychiatric disorders in PWS is influenced by genetic,
biological, and environmental factors (Soni et al., 2007).
An increased risk of developing psychotic disorders has been
associated with the UPD genotype (Boer et al., 2002; Verhoeven,
THUILLEAUX ET AL.
Tuinier, & Curfs, 2003; Vogels, Matthijs, Legius, Devriendt, & Fryns,
2003; Yang et al., 2013).
Both behavioral and psychiatric approaches lead to controversial
results and do not provide an overview of the real adaptation problems
of people with PWS. Thus, for example, there is no agreement on the
pertinence of including PWS between autistic spectrum disorders
(Dimitropoulos & Schultz, 2007) or on the traits that define the
behavioral phenotype (Jauregi et al., 2013). The aim of our study is to
propose a model of psychopathological aspects of PWS from a
different perspective, which, beyond a descriptive listing of behavioral
or psychiatric symptoms, reveals the global functioning of the persons
as a parameter that determines their adaptive capacities. Thus, based
on our clinical experience with almost 300 patients followed up on a
regular basis, we propose a model of psychopathological features that
describes four main profiles in PWS. Furthermore, we have analyzed
their distribution in a large cohort of adults as well as the influence of
genotype, gender, and age.
2 | METHO D
2.1 | Conditions of the clinical observation:
Qualitative study
The proposed model is based on the extensive experience of the
authors in the management of adults with PWS in a specialised centre
located in the Marin Hospital of Hendaia (Basque Country- France).
Created in 1999, it now has a capacity of 30 beds where adults with
PWS or PWS-like pathologies stay for intervals between 1 and
3 months, usually repeated with diverse frequencies. The hospital unit
belongs to the French Reference Centre for PWS and admits patients
coming from all regions in France.
This unit proposes a multidisciplinary approach to the syndrome.
Admissions are requested by the patient or his or her caregivers. The
purpose of the stay is firstly, to assess the psychosocial and medical
problems in order to define the needs of each individual and to propose
a personalized management strategy. In general, the challenges are
weight control, improvement of physical condition, care of medical
complications, promotion of psychological well-being, and social
adaptation. Furthermore, the stay provides a break for the family or
everyday residential routines. The admissions are scheduled months in
advance, never in response to an acute clinical situation.
Since its opening, nearly 300 patients have been admitted at
least once. During the weeks that they remain in the unit, patients
perform educational and therapeutic activities daily under the
management of the multidisciplinary team. The first and second
authors are the psychiatrist and clinical psychologist of the team.
Both have been part of the project since its beginning. They are the
main persons responsible for the project and they maintain a close
relationship with the patients throughout their stay, as individual and
group therapists. Furthermore, they lead the weekly staff meetings,
prescribe the treatment and the planning of activities for each
patient and deal with the relationships with external caregivers
and families.
THUILLEAUX ET AL.
This observation status allows hypothesizing a model that
accounts for the existence of different psychopathological profiles.
This model is entirely based on the subjective assessment and the
knowledge of the expert clinicians following a long experience with
these patients. Repeated presentations and discussions of this
proposal have been performed in meetings of the reference centre.
2.2 | Quantitative study
We performed a study in order to quantify the prevalence of the
described psychopathological profiles in a large sample of inpatients
with PWS and to analyse the correlations with genotype, gender,
and age. We included all subjects with a genetically confirmed
diagnosis who came during the year 2014 in our PWS unit and for
whom it was at least the second stay. This last criterion allowed us to
be more familiar with each individual's overall functioning and not
confound it with a reactive state to a first admission. Thus, our
sample was composed of 150 subjects whose main characteristics
are presented in Table 1.
The data collection and analysis were conducted in compliance
with the World Medical Association Declaration of Helsinki.
The procedure for assessing psychopathological profiles was as
follows. At the end of the admission period, the first author
(psychiatrist) proposed the inclusion of the patients in one of the
four profiles. In parallel, another psychiatrist, with experience in
PWS but external to the unit, performed another assessment,
recording, through semi-structured staff meetings, the observations
of the multidisciplinary team (psychologist, nurses, educators). This
second diagnosis was based on the care team's knowledge of the
patient's daily functioning during the current stay. The concordance
rate for the total group reaches 73%: 63% for Basic profile, 79% for
Impulsive profile, 91% for Compulsive profile, and 89% for Psychotic
Profile. When diagnoses were not concordant, the discrepancies
were analyzed at a later joint assessment, and a consensus
was reached.
TABLE 1 Patient characteristics
Charateristics of the cohort
Total 150
Gender
Female/Male 81/69
Age
Mean age (range) 28.2 (18–53)
Median age 29
Genotype status
Deletion 99
Non deletion* 44
Others** 7 b. Poor social emotions, lack of empathy. Easily offended, preoccupa-
*Includes confirmed UPD, genetic confirmation without deletion, and
Imprinting defect.
**Includes translocation and genetic confirmation without more precision.
| 3
2.3 | Statistical analysis
Descriptive and analytical statistics were calculated in order to
compare the values of the subgroups. The χ2 test was used for
comparison of percentages. Test results were considered significant at
p ≤ 0.05.
3 | RESULTS
3.1 | The model: Four psychopathological profiles in
people with PWS
Direct observation of a large number of patients during long time
periods has led us to develop a model which classifies adults with PWS
into four categories, according to their dominant psychopathological
pattern: Basic, Impulsive, Compulsive, and Psychotic. These patterns
were defined taking into account the cognitive, emotional, and
behavioral outcomes as factors that determine the quality of patients’
adaptation in daily life functioning and their well-being.
These four profiles are organized in strata, with the first stratum as
the basis of the PW personality, present in all people with PWS with
varying intensity and defining the Basic state.
In some cases, the characteristics defining this Basic state are the
only factors limiting the adaptive capacity: these persons fall into the
category of Basic profile. Sometimes, beyond this basic personality,
individuals manifest additional symptoms that increase adaptive
problems due to the presence of severe impulsive, compulsive,
or psychotic features. These symptoms are superimposed on the basic
personality as a second stratum, and the patients are then included in the
Impulsive, Compulsive, or Psychotic profile, respectively. These four
patterns (Basic, Impulsive, Compulsive, and Psychotic) are persistent
characteristics of each individual. Beyond each pattern, acute forms of
psychiatric disorders may occur in form of disruptive crises, anxiety, and
depressive episodes or acute delusional states.
This model is schematically represented in Figure 1.
3.2 | Characteristics of the basic profile
3.2.1 | Main cognitive traits
a. Mild to moderate intellectual disability.
b. Rigid and perseverative thinking, difficulty adapting to changes.
c. Poor understanding of metaphors and double meaning sentences.
d. Time/space processing problems.
e. Pragmatic deficits, difficulty making decisions, and choices.
3.2.2 | Main emotional traits
a. Emotional lability, immaturity, and infantilism.
tion with “fairness.”
c. Lack of inhibition, lack of shame.
d. Difficulties discriminating other people's emotions and intentions.
4 |
FIGURE 1 A model of psychopathological features in PWS: organization of clinical pattern in strata. [Color figure can be viewed at
wileyonlinelibrary.com]
e. Preoccupation with affective and sexual themes.
f. Social vulnerability, credulity (risk of physical mistreatment and
sexual abuse).
3.2.3 | Main behavioral traits
a. Compulsive food seeking and hyperphagia.
b. Other maladaptative behaviors (lying, stealing, hoarding,
collectionism. . .).
c. Arousal disorders, daytime sleepiness.
d. Poor and dysfunctional social relations.
e. Ritualistic behaviors.
f. Disruptive crises in reaction to frustration or misunderstanding of
the context.
g. Skin-picking, self-mutilations.
3.3 | Characteristics of the impulsive profile
This pattern is defined by the frequency and intensity of impulsive behavior,
verbal or physical aggressiveness against objects or persons. These traits,
present in the basic profile, are amplified and reach a level of frequency and
intensity that severely limit social adaptation. The main symptoms are:
a. Low tolerance to frustration, not only food-related
b. In reaction, severe disruptive crises with strong neurovegetative
activation
c. Auto- or hetero-aggressive acting out
d. Little respect of social norms, conflicts with the Law without feeling
guilty
e. Acute feeling of injustice, hyper-sensitivity to others’ judgment
3.4 | Characteristics of the compulsive profile
This pattern is defined by the frequency and intensity of compulsive
and ritualized behaviors. It is a prevalent feature in PWS but, in
these cases, its intensity becomes a major handicap for social
adaptation. The main symptoms are:
a. Intense rituals/stereotypes that severely affect everyday life.
b. Compulsive behaviors, normally without obsessive ideation or
anxiety.
THUILLEAUX ET AL.
c. Lack of awareness of the absurdity of the behavior.
d. Resistance to disruption of behavior, which can trigger tantrums.
e. Restricted and repetitive interpersonal interaction.
When rituals invade the person's life, hindering action, social
isolation sets in, leading to an autistic-like profile.
3.5 | Characteristics of the psychotic profile
In this pattern, the clinical picture is dominated by a psychotic
disorganization of ideas, emotions, and behavior that is persistently
present as a personality trait. The main symptoms are:
a. Loss of link with reality, with or without hallucinations.
b. Delusional ideation may be present, poorly structured and bizarre. It
is often difficult to differentiate between delusion and fabulation.
c. Strange and disorganized behavior, acting out unrelated to the
context.
d. Dysphoria, alternating excitement, and withdrawal.
e. Ambivalence, discordance between ideas and emotions.
f. Negative symptoms, that is, affective flattening, alogia, or avolition.
3.6 | The distribution of the four psychopathological
profiles in our cohort
In Table 2, we present the distribution of our cohort in the four
psychopathological profiles globally and separated by genotype,
gender, age, and male sexual hormone therapy.
4 | DISCUSSION
This study aims to contribute to the knowledge of psychopathological
features in adults with PWS. The method is based on clinical observation, a
classic form of analysis of the reality of the patients from a semiological
and phenomenological perspective. We think that this approach is
pertinent to establish a first overview of a poorly defined field in which
reports are often contradictory. In fact, most previous studies were
oriented to screening behavioral disorders and psychiatric symptoms,
using check-lists informed by caregivers or by semi-structured interviews.
This approach leads to associating patterns of behavior with psychiatric
THUILLEAUX ET AL.
| 5

TABLE 2 Profiles distribution according genotype, gender, age, and males sex hormone therapy
Psychiatric profiles Basic percentage (n) Impulsive percentage (n) Compulsive percentage (n) Psychotic percentage (n)
Total group 55 (83) 19 (28) 7 (11) 19 (28)
Genotype
Deletion 70 (69) 14 (14) 7 (7) 9 (9)
Non deletion 23 (10) 25 (11) 9 (4) 43 (19)
p-value* <0.001 0.181 NS 0.938 NS <0.001
Gender
Females 63 (51) 10 (8) 11 (9) 16 (13)
Males 46 (32) 29 (20) 3 (2) 22 (15)
p-value* 0.061 NS 0.005 0.108 NS 0.496 NS
Age group
18–29 47 (36) 20 (15) 7 (6) 25 (19)
30–53 63 (47) 17 (13) 7 (5) 12 (9)
p-value* 0.068 NS 0.896 NS 0.963 NS 0.07 NS
Sex hormone therapy (Males)
Males non treated 38 (15) 33 (13) 0 (0) 30 (12)
Males treated 59 (17) 24 (7) 7 (2) 10 (3)
p-value* 0,136 NS 0,626 NS 0,338 NS 0,097 NS

*p-values from χ test.

2

NS, Non significant. Bold values are significant (p-value ≤0.05).

categories in a population with cognitive impairment and limited insight
capacities, that usually express mental states by behavioral features
(Holden & Gitlesen, 2008, 2009). Thus, we can find PWS associated with
different diagnoses of DSM depending on different authors, with a lack of
reliability and concordant results, and not always consistent with the
observed clinical reality. Furthermore, authors frequently resort to
comorbid or atypical diagnoses, which may be valid from a nosological
point of view but are not very relevant with a view to improving our
knowledge of patients’ real needs. In fact the rating scales that have been
validated for populations with intellectual disabilities have a limited utility
for PWS. It would be helpful to develop a specific tool that does not
currently exist.
Our approach attempts to overcome these difficulties by analyzing
the psychopathological profiles from a functional perspective, taking into
account patients’ overall functioning in daily skills and identifying the traits
and behaviors that are the main limiting factors to their social adaptation.
We believe that such an approach is justified by the very rare situation of
our centre, where an experienced team can observe the daily skills of a
large number of PWS patients for extended periods of time.
A weakness of this study concerns the evaluation method, based on
the subjective assessment of data from clinical observations in a semi-
structured form. The inclusion of subjects in any of the four proposed
profiles (Basic, Impulsive, Compulsive, and Psychotic) was easily
established in most cases, but in some (27%), the consensus of the
evaluation team was more difficult to reach. The higher discordance found
in the Basic group can be explained by the fact that patients in this group
also present symptoms described in the other profiles but in more
moderate way. A quantitative and subjective assessment could easily lead
to divergent assessments in a first time. In some cases, the difficulty came
from changes in behavior that can occur between two admission periods.
Thus, some impulsive or compulsive subjects can improve those traits,
reaching the level of the basic profile in successive stays, either due to the
effects of drug treatment or to a spontaneous evolution. Less frequently,
some patients may show an aggravation of the disorders in a second stay
for different reasons. In other cases, the difficulty comes from the overlap
of symptoms in two different situations. The first one is the case of
compulsive subjects exhibiting disruptive impulsive reactions if thwarted
in their rituals. The second is the case of compulsive profiles presenting an
autistic-like functioning and traits of a psychotic structure.
The reliability of our results and the extrapolation to global PW
population could be limited by factors such as recruitment bias or new
approaches to early treatment of the syndrome in different countries.
However, the large size of the sample and our admission policy allow us
to consider that our data represent a reliable image of the reality of
PWS today. The differences between genotypes are concordant with
previous reports and confirm that individuals with non-deletion
genotype (m-UPD) are more likely to present psychiatric disorders,
especially of a psychotic type. Gender strongly influences the
distribution of compulsive and impulsive profiles. Impulsivity is
much higher in males, perhaps because their disruptive episodes are
more challenging for the environment and, consequently, more salient
in the assessment process. Our data do not support the idea of a
negative effect of male sexual hormone replacement on impulsivity.
There is general consensus about the multifactorial determinism of
psychiatric disorders including genetic, biological, and environmental
factors. Psychiatric features in PWS must also be analyzed in similar terms.
6 |
Any of them could be considered prevalent so as to be taken as a PWS
phenotype. Impulsivity, compulsivity, or psychoses are not present in
most cases. Only hyperphagic behavior can be considered as a behavioral
phenotype. Due to other psychopathological issues, PWS is a factor that
increases the risk of cognitive impairments, more likely to be considered as
phenotypical: executive dysfunction, poor emotional regulation, deficit of
working memory, etc. Some increased risks could be linked to genetic
factors, that is, m-UPD and psychosis. In other cases, the interaction of
cognitive deficits and educational, familial, and social factors could explain
the presence and severity of behavioral and psychiatric disorders.
The model of four patterns of psychopathological profile in PWS
allows defining a PWS individual's main weaknesses for social
adaptation, guiding the design of a life project and prescribing the
most effective treatments, both psychological and pharmacological.
Further studies are needed to confirm this hypothetical model, using
more structured and reproducible assessment techniques.
ORCID
Virginie Laurier http://orcid.org/0000-0003-2244-0720
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How to cite this article: Thuilleaux D, Laurier V, Copet P,
et al. A model to characterize psychopathological features in
adults with Prader-Willi syndrome. Am J Med Genet Part A.
2017;1–7. https://doi.org/10.1002/ajmg.a.38525