European Journal of Medical Genetics xxx (2016) 1e9

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European Journal of Medical Genetics

journal homepage: http://www.elsevier.com/locate/ejmg

Clinical research

A structured assessment of motor function and behavior in patients

with Kleefstra syndrome
Susanne Schmidt a, 1, Heidi E. Nag a, Bente S. Hunn a, Gunnar Houge b, Lise B. Hoxmark a, *
a
Frambu Resource Centre for Rare Disorders, Siggerud, Norway
b
Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway

a r t i c l e i n f o a b s t r a c t

Article history: The present study aimed to further our understanding of Kleefstra syndrome, especially regarding motor
Received 4 March 2015 function and behavioral characteristics. In total, four males and four females between two and 27 years of
Received in revised form age with a genetically confirmed diagnosis of Kleefstra syndrome and their parents participated in this
18 January 2016
study. Four patients had 9q34.3 deletions that caused Euchromatin Histone Methyl Transferase 1
Accepted 21 January 2016
Available online xxx
(EHMT1) haplo-insufficiency, and four patients harbored EHMT1 mutations. The motor function was
evaluated via systematic observation. Standardized assessments such as the Vineland Adapted Behavior
Scales II (VABS II), the Social Communication Questionnaire (SCQ) and the Child or Adult Behavior
Keywords:
Kleefstra syndrome
Checklist (CBCL, ABCL) were used for the behavioral assessment. All patients showed a delayed devel-
Rare disorder opmental status. Muscular hypotonia and its manifestations were present in all patients, regardless of
Motor function their age. The mean values for all VABS II domains (communication, socialization, daily living skills, and
Behavior motor skills) were significantly lower than the mean of the reference population (p < 0.001), but similar
Autism spectrum disorders to other rare intellectual disabilities such as Smith-Magenis syndrome and Angelman syndrome. The
Sleep results from the SCQ indicated that all patient values exceeded the cut-off value, suggesting the possi-
Growth bility of autism spectrum disorder. The behavioral and emotional problems assessed by CBCL and ABCL
were less frequent. In conclusion, patients with Kleefstra syndrome present with a broad range of clinical
problems in all age groups and are therefore in need of a multidisciplinary follow-up also after their
transition into adulthood.
© 2016 Elsevier Masson SAS. All rights reserved.

1. Introduction of the Euchromatin Histone Methyl Transferase 1 (EHMT1) gene,

Kleefstra syndrome, also known as chromosome 9q34.3 dele-
tion syndrome (Harada et al., 2004; Neas et al., 2005; Yatsenko
et al., 2009) 9q-syndrome or 9q subtelomeric deletion syndrome
(OMIM #610253), is a rare disorder with a core phenotype that
consists of intellectual disability, developmental and speech delay,
muscular hypotonia and certain facial characteristics (Stewart and
Kleefstra, 2007; Kleefstra et al., 2010). In addition, features such
as congenital heart defects, recurrent infections, feeding problems,
gastro-esophageal reflux, epilepsy, obesity and behavioral and
sleep problems have been associated with this disorder (Kleefstra
et al., 2010). Kleefstra syndrome is caused by haplo-insufficiency
* Corresponding author. Frambu Resource Centre for Rare Disorders, Sandbakk-
veien 18, 1404 Siggerud, Norway.
E-mail address: lbh@frambu.no (L.B. Hoxmark).
1
Present address: Premier Research, Durham, NC, USA.
which is one of the genes in the 9q34.3 region (Kleefstra et al.,
2009). The majority of patients with Kleefstra syndrome (>85%)
have a 9q34.3 microdeletion, and the remaining patients have an
EHMT1 mutation (Willemsen et al., 2011). The size of the deletion or
the type of the mutation may vary, but a genotype-phenotype
correlation has not yet been identified (Kleefstra et al., 2009).
Among the rare non-recurrent chromosomal imbalances, 9q34.3
deletions are not uncommon. To date, just over 100 patients with
Kleefstra syndrome have been described in the literature
(Willemsen et al., 2011). The prevalence is unknown, and many
cases are likely to remain undiagnosed, especially those with
EHMT1 mutations.
Kleefstra syndrome has only recently been described and is
considered a rare disorder. Data on this syndrome are scarce,
especially regarding motor function and behavioral characteristics,
as well as sleep and growth (Verhoeven et al., 2009; Verhoeven
et al., 2409). Therefore, we conducted a structured assessment of
a group of Norwegian patients with Kleefstra syndrome. The aim of

http://dx.doi.org/10.1016/j.ejmg.2016.01.004
1769-7212/© 2016 Elsevier Masson SAS. All rights reserved.

Please cite this article in press as: Schmidt, S., et al., A structured assessment of motor function and behavior in patients with Kleefstra
syndrome, European Journal of Medical Genetics (2016), http://dx.doi.org/10.1016/j.ejmg.2016.01.004
2 S. Schmidt et al. / European Journal of Medical Genetics xxx (2016) 1e9

this study was to further our understanding of this syndrome,
especially regarding motor function and behavioral characteristics,
as well as sleep and growth.
2. Patient data
In total, four males and four females between two and 27 years
of age with a genetically confirmed diagnosis of Kleefstra syndrome
and their parents participated in this study. Four patients had a
9q34.3 deletion with a deletion size between 270 and 690 kb,
whereas the other four harbored an EHMT1 mutation. Table 1
shows the details of each patient.
3. Methods
3.1. Recruitment
We aimed to recruit as many patients as possible from the entire
country. The only inclusion criterion was a genetically confirmed
diagnosis of Kleefstra syndrome, exclusion criteria were not
applied. As there is no central register for rare disorders in Norway,
potential patients were recruited via different channels. Frambu
Resource Centre for Rare Disorders (Frambu), one of nine state
financed centers of expertise administrated by the Norwegian Na-
tional Advisory Unit on Rare Disorders, has its own register, which
is based on informed consent. Frambu could therefore send in-
vitations to registered families with a child or a young adult with a
diagnosis of Kleefstra syndrome. Information regarding the study
was also published on the Frambu website (www.frambu.no) and
Facebook site. Additionally, the four Departments of Medical Ge-
netics in Norway were asked to send out invitations.
In total, nine families with a child or a young adult who was
tentatively diagnosed with Kleefstra syndrome responded to the
invitations, and all of them consented to participate in our study.
However, the review of the genetic work-up showed that one child
had a deletion of 9q34.3 that did not include the EHMT1 gene. This
child was excluded; therefore, eight patients with their families
remained in the study.
3.2. Study design
This study was designed as a cross-sectional study. All patients
were subjected to a structured observation by a pediatrician (S.S.)
and a physiotherapist (B.S.H.). The parents filled in the question-
naire developed for the purpose of this study as well as standard-
ized questionnaires and were interviewed by a special educator
(H.E.N.) using the Vineland Adaptive Behavior Scale II (VABS II). In
addition, information from the genetic analysis, medical records
from the national child care health centers and from the regional
habilitation centers were collected and reviewed.
3.3. Background data
A copy of the genetic analysis to confirm the diagnosis of
Kleefstra syndrome was obtained. The parents completed a ques-
tionnaire with 71 questions, including information on demography,
pregnancy and delivery, the child's first years of life, past and
present medical situation, perception problems (vision, hearing,

Table 1
Description of the study participants.

Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 Patient 7 Patient 8

Genetic work-up Deletion 9q34.3, 270 kb Deletion 9q34.3, 0.69 Mb Mutation Mutation Deletion Mutation Deletion Mutation
EHMT1 EHMT1 9q34.3, EHMT1 9q34.3, EHMT1
300 kb 480 kb
Age at inclusion (years, months) 27 18 4/12 17 6/12 6 4/12 4 5/12 3 2/12 2 3/12 7 9/12
Gender Female Male Female Male Female Male Male Female
Gestational age (weeks) 42 36 42 40 35 42 42 33
Birth weight (g, SD) 3840 (0.6) 1950 (
2.0) 4000 3100 2730 (0.4) 4200 4175 (1.3) 2845
(0.7) (
1.3) (1.3) (2.2)
Birth length (cm, SD) 49 (
0.7) 44 (0.5) 50 (0.0) 51 (0.3) 49 (0.8) 52 (0.5) 52 (0.5) missing
Head circumference at birth (cm, 34 (
0.7) 32 (
0.7) 36 (0.7) 35 (
0.8) 34 (0.7) 36 (0.0) 35 (
0.8) 33.5 (1.3)
SD)
Present weight (kg, SD) 90.2 (5.0) 86.7 (4.0) 55.2 (2.3) 26.3 (1.3) 20.3 (
0.7) 17.5 17.5 (1.8) 30.5 (0.7)
(
2.5)
Present height (cm, SD) 165 (
0.3) 164 (
2.0) 150 122 (0.3) 117 (2.3) 115 (5.0) 96 (2.0) 134 (1.3)
(
2.5)
Present head circumference (cm, 54.5 (
0.7) 54.5 (
1.6) 54.5 51 (
1.3) 48 (
2.0) 49 (
1.3) 49.5 (
0.7) 51.5 (0.7)
SD) (
0.7)
Cardiac defect (first years/ þ/þ þ/
þ/
þ/þ
/

/

/
þ/

currently)
Renal anomalies (first years/
/

/

/
þ/

/
þ/þ
/

/

currently)
Recurrent infections (first years/ þ/

/

/
þ/
þ/
þ/þ
/

/

currently)
Gastro-esophageal reflux (first þ/
þ/þ þ/
þ/
þ/þ þ/
þ/
þ/

years/currently)
Epilepsy (first years/currently) þ/
þ/þ
/

/þ
/

/

/

/

Problems with sucking/ þ þ þ þ þ þ þ þ
swallowing during newborn
period
Feeding difficulties (first years/
/

/

/

/
þ/þ þ/þ
/
þ/

currently)
Vision Hyperopic, impaired Hyperopic, impaired ? Normal Hyperopic Normal Normal Normal
stereoscopic depth stereoscopic depth
perception perception
Hearing Normal Normal Normal Impaired Impaired Impaired ? Normal
Increased pain threshold þ þ þ þ þ ? þ þ
þ
Present,
Not present, ?No information available.

Please cite this article in press as: Schmidt, S., et al., A structured assessment of motor function and behavior in patients with Kleefstra
syndrome, European Journal of Medical Genetics (2016), http://dx.doi.org/10.1016/j.ejmg.2016.01.004
 S. Schmidt et al. / European Journal of Medical Genetics xxx (2016) 1e9
and pain threshold), developmental milestones, nutrition, and
growth. The questionnaire was developed for the purpose of this
study based on a thorough literature review on Kleefstra syndrome.
3.4. Assessment of motor function and developmental status
All patients were subjected to a structured observation by a
pediatrician (S.S.) and a physiotherapist (B.S.H.) with emphasis on
motor function and developmental status. All observations
occurred in the Frambu gym with access to different activities and
equipment chosen specifically for this observation. Initially, the
patients were observed during a free activity period. Subsequently,
instructions were provided to evaluate several functions and skills,
focusing on developmental status, mobility, balance, stability,
muscle strength, and muscle tone. The findings were documented
in written form during and directly after the observation as quali-
tative data on a self-developed data sheet.
Furthermore, developmental milestone data were obtained
retrospectively from the parents via the completion of the ques-
tionnaire described in the background data section.
VABS II also contains items regarding development and motor
function. A special education teacher (H.E.N.) with previous expe-
rience using this tool in research administered the VABS II in the
present study, which is further described in the section on behav-
ioral assessment.
3.5. Behavioral assessment
The Vineland Adaptive Behavior Scales II (VABS II) survey
(Haukeland, 2011; Sparrow et al., 2005) is a semi-structured
interview of the parents or caregivers and assesses the everyday
behavioral functioning of children and adults from birth
throughout life. The scales yield standard scores (mean ¼ 100, one
standard deviation (SD) ¼ 15) in the domains of communication,
daily living skills, socialization, and motor function, as well as an
adaptive behavior composite. In the present study, the Norwegian
version of the scales based on Scandinavian normative data was
used. The Scandinavian version of the VABS II does not include an
age-equivalent score or comparison of standard scores with levels
of intellectual functioning. We therefore used the raw scores on the
subdomains from the Scandinavian version to calculate the age-
equivalent from the English version (Sparrow et al., 2005). We
also used the standard scores of the adapted behavior composite
score from the Scandinavian version to compare with levels of in-
tellectual functioning from the English version (Sparrow et al.,
2005). The VABS II survey is a standardized and validated tool.
Many studies have confirmed its reliability and validity; therefore,
this measure is one of the most widely used assessment tools of
adaptive behavior (Sparrow and Cicchetti, 1985).
The Social Communication Questionnaire (SCQ) is a standard-
ized screening tool for the evaluation of communication forms and
social function in children or adults to exclude an autism spectrum
disorder (ASD) (Rutter et al., 2003). The questionnaire can be used
from the age of four years and onwards, with a mental age of at
least two years. Without a standardized assessment of mental age
in this study, we used observation by a special educator (H.E.N.)
during free play in the kindergarten and school at Frambu to
consider the patients' mental age. All patients above the chrono-
logical age of four years were estimated to have a mental age of at
least two years, which were confirmed using age-equivalent scores
from VABS II for all except one patient. A score of 15 or above is
regarded as an indicator of possible ASD. In the present study, the
Norwegian version of the SCQ-Lifetime questionnaire was used
(Schjølberg and Tambs, 2005). The tool has been used in other
research studies of different genetic disorders (Magyar et al., 2012a;
Please cite this article in press as: Schmidt, S., et al., A structured assessment of motor function and behavior in patients with Kleefstra
syndrome, European Journal of Medical Genetics (2016), http://dx.doi.org/10.1016/j.ejmg.2016.01.004
3
Hall et al., 2010a). A good reliability was reported in the initial
standardization of the assessment tool, with a Cronbach's alpha of
0.84e0.93 across age groups, and a Cronbach's alpha of 0.81e0.92
across diagnostic groups (Rutter et al., 2003). The validity was also
measured in the initial standardization where Rutter et al. (Rutter
et al., 2003) found a correlation between SCQ and Autism Diag-
nostic Interview e Revised (ADI-R) of 0.71. Magyar et al. (Magyar
et al., 2012b) investigated the validity of SCQ in Down syndrome
(DS) and found that it did discriminate between the two groups of
children with DS with ASD and DS without ASD. Children with DS
and ASD obtained a significantly higher total score on the SCQ than
children with DS only.
The Child Behavior Checklist (CBCL) and Adult Behavior Check-
list (ABCL) evaluate the competencies of the patient as well as
behavioral and emotional problems during the past six months
(Achenbach and Rescorla, 2001, 2003, 2000). The CBCL is available
in different versions according to the patient's age (CBCL
1½e5 years and CBCL 6e18 years). The ABCL is directed toward
adults between 18 and 59 years of age. In the present study, the
Norwegian versions of the checklists was administered (Nøvik and
Heyerdahl, 2002). The CBCL and ABCL constitute a parental rating of
child or adult behavior problems and have been widely used in both
clinical and research settings (Welham et al., 2009; Flink et al.,
2012). There has been concern using CBCL/ABCL in populations of
individuals with intellectual disabilities (ID) since the tool is
developed and validated for a population of individuals without ID.
There has especially been raised concern using this tool in pop-
ulations of individuals with moderate, severe, or profound ID.
Research has documented that CBCL is better on revealing exter-
nalizing problems than internalizing problems in populations of
individuals with moderate to profound ID (Koskentausta et al.,
2004). Other studies support the cautious use of CBCL in adoles-
cents with a range of ID (Borthwick-Duffy et al., 1997; Dekker et al.,
2002). CBCL has also been used in research on Down syndrome
(DS), William syndrome (WS), PradereWilli syndrome (PWS) and
CHARGE syndrome. Graham et al. (Graham et al., 2005) found that
boys with CHARGE syndrome had fewer internalizing problems
than boys with PWS, and that the scores for externalizing problems
were similar to WS and DS, but lower than PWS.
3.6. Assessment of sleep
The Children's Sleep Habits Questionnaire (CSHQ) is a retro-
spective 45-items parental questionnaire (Owens et al., 2000). A
total score of 41 or more reflects a clinically relevant sleep problem.
The CSHQ is targeted to children from the age of four to 12 years.
We chose to use this assessment in the group of our patients even
though only three of the eight patients fulfilled the age criterion as
the CSHQ is one of only two recommended sleep questionnaires in
Norway. The other recommended scale is the Sleep Disturbance
Scale for Children which is validated for school children from six to
15 years. Due to the fact that the majority of our patients did not
fulfill the age criterion of the chosen CSHQ, we also performed a
manual review of all responses in the questionnaire in addition to
reporting the total score. In this study, the Norwegian version of the
questionnaire was used (Danielsen et al., 2013) and administered to
all patients regardless of their age. The psychometric properties of
the CSHQ have been investigated in children with behaviorally- and
medically-related sleep problems. CSHQ was found reliable with
internal consistency coefficients of 0.68 and 0.78 and a testeretest
correlation of 0.62e0.79 for the subscales. Validity was assessed by
comparing the results with a community sample where a statisti-
cally significant difference (p < 0.001) was found in 30 of 33 items
(Owens et al., 2000). The questionnaire has been widely used in
research with different patient populations, such as individuals
4 S. Schmidt et al. / European Journal of Medical Genetics xxx (2016) 1e9
with autism, psychiatric disorders, and developmental delay
(Hansen et al., 2011; Goodlin-Jones et al., 2009).
3.7. Assessment of growth
Current data on weight, height, and head circumference were
obtained (S.S.) during the standard physical examination. In addi-
tion, retrospective data regarding birth weight, birth length, and
head circumference at birth were collected from the parents and
growth charts were required from the national child care health
centres. The absolute values were converted into SD using a Nor-
wegian age- and gender-matched reference population (Knudtzon
et al., 1988). For prematurely born children, a Swedish reference
population was used to adjust for gestational age (Niklasson et al.,
1991).
3.8. Data analysis
A statistical analysis was performed using Excel or SPSS (Sta-
tistical Package for the Social Sciences) version 20 (IBM, Armonk,
NY, USA). The analyses included descriptive statistics to present the
mean and SD on VABS II, CBCL, ABCL, and SCQ. The Wilcoxon
signed-rank test was used to examine significant differences be-
tween the domain scores in VABS II. Pearson's and Spearman's
correlation and linear regression were utilized to examine the
correlation between age and the total sum score on the VABS II. The
T-scores obtained from the CBCL and ABCL were calculated with the
ASEBA (The Achenbach System of Empirically Based Assessment)
software. Statistical significance was defined as p < 0.05.
4. Results
4.1. Clinical data
Table 1 shows the clinical features of the eight patients in this
study.
All patients were born after uneventful pregnancies, and none
received the diagnosis during pregnancy. Half of the group was
admitted to the children's hospitals directly after birth, and three of
the eight experienced frequent admissions during the first years of
life.
All parents noted that the medical condition of their child sta-
bilized during the most recent years and that the number of ad-
missions to the hospital decreased. Another complaint reported in
addition to the conditions described in Table 1 was constipation
(n ¼ 3). One of these patients suffered an extremely severe episode
of constipation, and he was catatonic and apathetic and refused to
walk during this period. The symptomatology resolved after several
hospital admissions and a manual evacuation of the feces in general
anesthesia.
Whereas difficulties with sucking and swallowing were a very
common manifestation of muscular hypotonia in newborns (n ¼ 8),
feeding difficulties tended to be less frequent in older children.
Tube feeding after birth was necessary in four of the eight patients
for a period of one to seven weeks. None of the patients received a
percutaneous endoscopic gastrostomy (PEG). Increased appetite
and food-seeking behavior were observed in three of the eight
patients.
4.2. Developmental status and motor function
All parents assessed their children's developmental status as
delayed, and the developmental milestones are described in more
detail in Table 2.
Regarding motor function, all patients showed signs of
Please cite this article in press as: Schmidt, S., et al., A structured assessment of motor function and behavior in patients with Kleefstra
syndrome, European Journal of Medical Genetics (2016), http://dx.doi.org/10.1016/j.ejmg.2016.01.004
generalized muscular hypotonia, and regardless of age all exhibited
pes plano-valgus (“flatfeet”) as well as genua valga (“knock-knees”)
to varying extents. Almost all showed a stiff gait with increased hip
and knee flexion, reduced rotation of the spine, and reduced
movement of the upper extremities. Two patients showed signs of
an unstable spinal column. One patient exhibited signs of thoracic
kyphosis, and two patients had accented lumbar lordosis. The
musculature of the shoulder and neck was tight and tender in four
out of eight patients. Four of the eight patients displayed hyper-
mobility in several or all joints, and one patient experienced
habitual luxations of the shoulder. All but one patient also
demonstrated hypotonic facial musculature with varying signs,
such as an open mouth with a protruding tongue or drooling.
Regarding fine motor skills, all patients used both hands in
different activities but clearly preferred one side. Pincer and pencil
grasp were used in five of the older patients; however, the three
youngest children demonstrated a fisted or palmar grasp.
4.3. Growth data
The individual growth data are shown in Table 1. For the entire
patient population, the mean standard deviations (SD) were 0.4 for
the birth weight (range
1.3e2.2), 0.3 for the birth length
(range
0.7e0.8) and
0.05 for the head circumference at birth
(range
0.8e1.3).
Growth charts were available for all patients. Beginning at three
to six months of age, half of the group displayed a slower growth in
the head circumference than the reference population. At the time
of the study, all patients had a head circumference in the lower
normal range compared to the general population. Two patients
were obese with a BMI of 33.1 and 32.3. One of the obese patients
showed signs of food-seeking behavior.
4.4. Behavioral data from VABS II
All patients’ data on VABS II are shown in Table 3.
All patients displayed adaptive behavior composite at or below
the mean scores for age-matched controls, and most of the patients
(n ¼ 7) showed scores at or below
2 SD. The mean adaptive
behavior composite was 50 (range 20e77), which corresponded
to
2 SD or below compared to age-matched controls.
Correlation analysis revealed a significant negative correlation
between the adaptive behavior composite and age (r ¼
0.75,
p < 0.05). This finding indicates that a higher age may be associated
with lower scores of the adaptive behavior composite.
The mean values of the four domains were the following:
communication 47 (range 20e67), daily living skills 62 (range
33e102), socialization 58 (range 32e77), and motor skills 59 (range
50e69). The mean values of these domains were significantly lower
than the mean of the reference population (p < 0.001). The
communication score was significantly lower than the daily living
skills and socialization scores (p < 0.05). There were no significant
difference between expressive and impressive language within the
communication domain (p ¼ 0.078). The youngest child had the
highest score on the daily living skills domain; this score corre-
sponded to the mean of the reference population. A more thorough
investigation of this domain revealed that this child scored two SD
above the mean on domestic skills and two SD below the mean on
the personal skills. According to the parents, this child was espe-
cially eager to help with domestic chores, and this behavior results
in a high score for children of this age (approximately two years).
The mean age-equivalent for the domestic skills were signifi-
cantly higher (p < 0.05) than for all the other subdomains except
from written communication (p ¼ 0.061).
The patients' level of intellectual functioning showed a varying
 S. Schmidt et al. / European Journal of Medical Genetics xxx (2016) 1e9 5

Table 2
Developmental milestones of the study participants.

Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 Patient 7 Patient 8

Present age (years, months) 27 18 4/12 17 6/12 6 4/12 4 5/12 3 2/12 2 3/12 7 9/12
First smile (months) 4 6 1 7 2 1.5 1e2 10
Lifting up head and shoulders from prone position (months) ? 8 ? 9 4 4 ? 10
Crawling (months) 10 e 19 ? 14 13 7 18
Sitting independently (months) 10 12 9 18e20 8 10 ? 11
Walking independently (months) 23 24 24 26 24 30 20 28
Speaking single words (months) 12 60 15 ? 12 e 22 34
Speaking in two-word sentences (years) 4 7 e þ e e e þ
Speaking in sentences with several words (years) 6e7 10 e þ e e e þ
Understanding simple instructions þ þ þ þ þ þ þ þ
Riding a tricycle or a bike with training wheels (years) 5 12 6 ? 4 e e 5
Dress and undress with some help þ þ þ þ þ þ ? þ
Continence (years) 5 (day), 10 (night) þ Only partly (feces) Partly e e e 4.5
þ
Present,
Not present, ?No information available.

Table 3
VABS II scores in patients with Kleefstra syndrome.

Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient Patient Patient 8 Mean (all
6 7 patients)

Chronological age in 27 (324) 18:4 (220) 17:6 (210) 6:4 (76) 4:5 (53) 3:2 2:3 7:9 (93)
years:months (months) (38) (27)
Domain Scores Communication 46 33 20 50 54 67 53 52 47
Daily activities 50 47 33 61 61 71 102 70 62
Social skills 55 62 32 56 60 65 77 60 58
Motor skills Not Not availablex Not availablex 50 50 69 69 Not availablex 59
availablex
General adaptive behavior 41 39 20 51 54 66 77 55 50
Level of Intellectual Moderate Severe/ Profound/ Moderate/ Moderate/ Mild No Moderate/
Functioning deficit moderate severe deficit mild deficit mild deficit deficit deficit mild deficit
deficit
Age Equivalent (AE) Receptive communication 44 59 16 18 26 13 15 23 26.8
Expressive communication 52 30 19 38 18 25 16 52 31.3
Written communication 78 13 13 37 13 13 13 62 30.3
Personal skills 48 47 28 25 20 21 20 42 31.4
Domestic skills 89 91 41 55 35 32 47 91 60.1*
Community skills 73 40 18 37 29 30 25 59 38.9
Interpersonal Relationship 43 47 11 36 16 16 15 38 27.8
Play and leisure 64 90 10 15 15 15 13 26 31.0
Coping skills 43 55 18 25 30 26 31 37 33.1
Gross motor skills Not Not availablex Not availablex 37 27 27 21 Not availablex 28.0
availablex
Fine motor skills Not Not availablex Not availablex 38 28 25 24 Not availablex 28.8
availablex
Mean AE individual patients 59.3 52.4 19.3 32.8 23.4 22.1 21.8 47.8

The numbers in bold are means.

*p < 0.05 compared with the other domains/subdomains, xonly available for patients younger than 7 years of age.

degree from profound and severe deficits to no deficit in intellec-

tual functioning. This variation also follows their age, with the
youngest patient presenting with no deficit in intellectual func-
tioning and the oldest patients being in the categories of profound
and severe deficits of intellectual functioning.

4.5. Behavioral data from CBCL and ABCL

The CBCL and ABCL results are presented in Fig. 1. The total
problems domain scores of six of the eight patients (75%) were at
the borderline clinical or in the clinical range. The internalizing and
externalizing domain scores of three patients (37.5%) were at the
borderline clinical or in the clinical range. Two other patients
showed domain scores ranging from borderline clinical to clinical.
The mean score of the internalizing domain was 60.2 (range 51e71) Fig. 1. T-scores for internalizing problems, externalizing problems, and total problems
domains in the Child Behavior Check List or Adult Behavior Check List (CBCL or ABCL)
and that of the total problems domain was 62.9 (range 51e73); both for patients with Kleefstra syndrome. The dashed line below indicates the borderline
of these mean scores were in the borderline clinical range. How- clinical range (T-scores between 60 and 63), and the dashed line above represents the
ever, the mean externalizing domain score (59.5, range 48e70) was clinical range (T-score of 64 or above).

Please cite this article in press as: Schmidt, S., et al., A structured assessment of motor function and behavior in patients with Kleefstra
syndrome, European Journal of Medical Genetics (2016), http://dx.doi.org/10.1016/j.ejmg.2016.01.004
6 S. Schmidt et al. / European Journal of Medical Genetics xxx (2016) 1e9
in the normal range.
4.6. Behavioral data from SCQ
The SCQ was administered to parents of patients aged four years
or older. Thus, data from six patients were received and are shown
in Fig. 2. All patients had a score of 15 or above, indicating the
presence of possible ASD. The mean score was 22.8 (range 17e28),
which is a score clearly above the cut-off of 15.
4.7. Sleep problems
The results from the CSHQ are shown in Fig. 3. Data were
received from seven of the eight patients; one family did not
correctly complete the questionnaire. Three families reported sleep
problems in their child, as indicated by a score of 41 or higher. The
mean score for all patients was 38.7 (range 32e46). A manual re-
view of all the responses in the questionnaire showed that in five of
the patients the parents reported that their child appeared sleepy
during daytime at least two to four days the last week, and that six
of the patients were sleeping restless and moved a lot during the
night. Three of the patients had problems sleeping other places
than at home.
4.8. Additional findings on behavioral data from observation and
record review
During the observation of the patients by pediatrician (S.S.) and
physiotherapist (B.S.H.) the following observations were noted:
One of the patients did not follow any verbal instructions. Three of
the patients showed ASD symptoms such as no eye contact, self-
stimulation, and repetitive verbal behavior. Hand biting was
observed in one patient; the skin of the hand in this patient was
hard and thickened, indicating a possible common habit. One of the
patients had a very low threshold of frustration, saying “I don't
want to do this”, “it is enough now”, etc, even faced with simple
tasks.
A review of the patients’ records from the habilitation centers
revealed anecdotal information that two of the patients had a
history of self-injuring behavior, mostly hand biting when frus-
trated. Two of the patients had a history of aggressive behavior.
Fig. 2. Total Scores of the Social Communication Questionnaire (SCQ) in patients with
Kleefstra syndrome. The dashed line marks the cutoff for possible autism spectrum
disorders.
Please cite this article in press as: Schmidt, S., et al., A structured assessment of motor function and behavior in patients with Kleefstra
syndrome, European Journal of Medical Genetics (2016), http://dx.doi.org/10.1016/j.ejmg.2016.01.004
Fig. 3. Scores of the Children's Sleep Habits Questionnaire (CSHQ) in patients with
Kleefstra syndrome. The dashed line represents the cutoff that indicates the occur-
rence of clinical significant sleep problems.
5. Discussion
Kleefstra syndrome is a recently described, rare genetic disorder.
Data on this disorder, especially on the formal evaluation of fea-
tures, such as ASD, sleep problems and growth, are lacking.
Therefore, we aimed to further understand this syndrome in this
study, with a special focus on developmental status and motor
function, behavioral characteristics, sleep, and growth. To the best
of our knowledge, this report is the first study that details a
multidisciplinary, structured assessment of patients with Kleefstra
syndrome. By choosing these methods we were able to contribute
with new quantitative and qualitative data to the description of the
phenotype of patients with Kleefstra syndrome.
Overall, the clinical picture we found in Norwegian patients
with Kleefstra syndrome is similar to the findings described in the
literature. An interesting point is that in the literature >85% of the
patients have a deletion of 9q34.3 and the remaining have a mu-
tation in the EHMT1 gene, whereas in this study we found 50% with
a deletion, and 50% with a mutation. This distribution might have
influenced our findings. However, as there so far is no genotype-
phenotype established we can't be sure in which way our find-
ings might have been influenced by this distribution of mutations
and deletions. The distribution between mutations and deletions
might also change in the future, as the use of new technology might
help to diagnose patients who previously didn't receive a diagnosis
of Kleefstra syndrome. We were able to identify eight patients in
Norway with this disorder, whereas only about 100 are described in
the literature worldwide. After finishing this study, we have
registered at Frambu four more Norwegian patients with Kleefstra
syndrome. This apparently high number of patients in Norway
could be explained by the wide-spread use of new genetic tech-
nology in Norway (Prescott, 2013), but could also be due to an
underreporting of patients in other countries or due to the fact that
potential patients remain undiagnosed in other countries.
A motor delay was observed in our patients during the struc-
tured observation and this is in accordance with previous reports
(Kleefstra et al., 2010). In addition, the results from the motor skills
domain of VABS II, in which tested patients scored lower than the
reference population, support this finding.
Muscular hypotonia was commonly observed in our patients.
The occurrence of childhood hypotonia has been previously
described; however, the hypotonia was assumed to improve over
time (Kleefstra et al., 2009). In contrast, we found that hypotonia
 S. Schmidt et al. / European Journal of Medical Genetics xxx (2016) 1e9
was present in all patients regardless of age and thereby also
occurred in young adults. Muscular hypotonia and its manifesta-
tions are not specific to Kleefstra syndrome and are observed in
many other genetic conditions. In our patients, we noticed gener-
alized muscular hypotonia that involved the entire muscular sys-
tem, including the facial muscles. For example, facial hypotonia
may cause an open standing mouth with a protruding tongue.
Drooling occurs because swallowing is difficult with this condition.
The protruding tongue also contributes to delayed language
development and especially affects articulation. Furthermore, hy-
potonia and its manifestations, such as pes plano-valgus (“flatfeet”)
and genua valga (“knock-knees”), as well as a lack of trunk control
and coordination influenced the quality of the gait of our patients.
The combination of muscular hypotonia and lack of coordination
especially impacts on the execution of complex movements, such
as throwing, catching, or bouncing a ball. Only a few patients in this
cohort were able to execute these activities. Muscular hypotonia
also affected fine motor skills. For example, grasping was not
executed with the necessary strength to conduct activities like
writing with a pencil or getting dressed.
Based on these findings, we recommend that a physiotherapist
should periodically and as needed evaluate and follow up patients
with Kleefstra syndrome throughout their lifespan and not only
during childhood. The involved physiotherapist should mentor and
supervise parents and other caregivers and encourage them to
motivate the patient to perform different physical activities
throughout the day. In younger children, this motivation should be
completed via play; however, in older individuals, daily activities,
such as swimming, riding, and dancing, are highly recommended.
Patients should also participate in regular physical activities at
school and not be excused from sports lessons.
Furthermore, we found that only two of the participants in our
study were obese. A higher frequency (approximately 50%) of
obesity has been previously reported to be associated with this
syndrome (Kleefstra et al., 2010, 2009). We noticed in our study
food-seeking behavior as well as overeating in some of our patients
with Kleefstra syndrome. This behavior reminded of a similar
behavior in patients with PradereWilli syndrome; however, the
eating behavior in patients with Kleefstra syndrome needs further
observation and characterization in future studies. The obesity in
our patients might partly be explained by their physical inactivity
as well as food-seeking behavior and overeating. A dietician should
be contacted when food-seeking behavior is observed.
Interestingly, half of the patients showed a slower head
circumference growth during their first year of life. This observa-
tion is important and can be interpreted as an early clinical sign of
Kleefstra syndrome. Slower head circumference growth is also
observed in Rett syndrome (Hagberg, 2002) and should prompt
immediate investigation.
In this study, the results from VABS II revealed compromised
adaptive behavior in all patients with significantly lower scores in
all four domains (daily living skills, socialization, motor skills, and
communication) compared to the reference population. Compared
to other rare disorders with a variety of ID, these results are similar
to the adaptive behavior of individuals with Smith-Magenis syn-
drome (SMS) and Angelman syndrome (AS). In a study by Madduri
et al. (Madduri et al., 2006) the mean adaptive behavior composite
score of patients with SMS was 48.3 with a range of <20e73, which
is similar to the results in the present study with a mean of 50 and a
range of 20e77. In a study of AS, a mean adaptive behavior com-
posite score of 49 was reported, with a range of 25e92 (Peters et al.,
2004). Both these disorders are described with a spectrum of
adaptive behavior and cognitive abilities, even though AS usually is
described as a disorder with severe ID, and SMS mostly is described
as a disorder with moderate ID. In another rare disorder,
Please cite this article in press as: Schmidt, S., et al., A structured assessment of motor function and behavior in patients with Kleefstra
syndrome, European Journal of Medical Genetics (2016), http://dx.doi.org/10.1016/j.ejmg.2016.01.004
7
PradereWilli syndrome (PWS), Milner et al. (Milner et al., 2005)
found a mean adaptive behavior composite score of 62. PWS is
often described as a disorder with moderate or mild ID. The find-
ings from our study suggest that the adaptive behavior of patients
with Kleefstra syndrome might be more similar to the adaptive
behavior of individuals with SMS and AS than to that of the in-
dividuals with PWS. Adaptive behavior describes the social
competence and ability to live independently. Interestingly, one of
the oldest patients in our study exhibited the lowest adaptive
behavior scores. This finding is confirmed by the age-equivalent
score and the level of intellectual functioning, and may be
explained by the availability of targeted actions for children with ID
in kindergarten and schools today compared to several years ago.
Another possible explanation might be that the pace of the devel-
opment of adaptive behavior skills slows or even halts with age.
Such slowing could explain why the gap between the oldest pa-
tients with Kleefstra syndrome and the reference population is
wider than that between the younger patients with the syndrome
and the references. A similar decrease of adaptive behavior with
age has been found in two studies of individuals with Fragile X
syndrome (FXS) (Fisch et al., 1999; Klaiman et al., 2014), whereas
another study of individuals with FXS was unable to replicate these
findings (Di Nuovo and Buono, 2011). The observed decrease in
adaptive behavior was explained by a slowing of the acquisition of
skills with increasing age. However, this requires further investi-
gation, and a longitudinal study to explore possible changes over
time is necessary.
The age-equivalent scores revealed a significant higher score in
the domestic subdomain than the other subdomains. This was the
subdomain where the youngest patient had the highest score, but
this was also true for all the other patients, and could be one of the
strengths of these patients with Kleefstra syndrome.
Furthermore, the lowest VABS II scores were found in the
domain of communication, and this finding was supported by
earlier descriptions (Stewart and Kleefstra, 2007; Kleefstra et al.,
2010). Only approximately half of our patients could communi-
cate in short sentences. In general, language development was
delayed or disturbed, but according to information from the par-
ents, several of our patients learned to speak after four years of age.
This finding implies that language training should continue into
school age. We noticed that speech comprehension appeared to be
better in these patients than expressive language, even though this
is not supported by the VABS II results where we found no signif-
icant difference between expressive and impressive language. This
probably needs to be investigated further with more specific lan-
guage assessments. We also observed that patients without
expressive language communicated via music and song. Our
experience is that music appears to give us an opportunity to
communicate with patients with Kleefstra syndrome and should be
used as an integral part in daily life activities. Music therapy has
proved useful for improving social skills for example in patients
with autism (Ghasemtabar et al., 2015).
The literature describes that adolescents with the syndrome
show behavioral changes, such as apathy or catatonia, and that
these changes may resolve in adulthood (Kleefstra et al., 2009). One
of our patients showed similar behavior; however, a severe episode
of constipation caused these symptoms. Therefore, common con-
ditions, such as constipation, should be dismissed when evaluating
patients with Kleefstra syndrome or other rare genetic conditions.
Surprisingly, all patients in our study scored above the cut-off
level in SCQ regardless of their age, indicating the possible pres-
ence of ASD. Because the SCQ is considered to be a screening tool,
the results must be confirmed with more in-depth assessments.
Earlier studies reported autistic-like features in childhood but no
prevalence (Stewart and Kleefstra, 2007). One of the oldest patients
8 S. Schmidt et al. / European Journal of Medical Genetics xxx (2016) 1e9
had an age-equivalent score on the VABS II indicating a mental age
below two years of age. This finding indicates that the SCQ results
need to be interpreted in this patient with caution. However, this
patient had a high SCQ score of 24 and showed a behavior with both
stereotypies and social functioning problems.
Studies using SCQ found a varying degree of scores above the
cut-off for ASD in diagnoses such as Fragile X syndrome (FXS)
(18.8% in girls, 58.7% in boys), Cornelia de Lange syndrome (CdLS)
(41.2%) and Down syndrome (19.4%) (Hall et al., 2010b; Moss et al.,
2008, 2013). Oliver et al. (Oliver et al., 2011) found similar results
within several rare disorders (Angelman syndrome 66.3%, CdLS
78.7%, Cri-du Chat syndrome 40%, Smith-Magenis syndrome 68.4%,
and FXS 83.6%), using the Autism Screening Questionnaire, a similar
autism screening tool. As a consequence, this high prevalence of
possible ASD should prompt early diagnostic evaluation and po-
tential behavioral interventions in patients with Kleefstra syn-
drome. A clinical follow-up regarding ASD is advised when a
patient is diagnosed with Kleefstra syndrome. In connection with
the assessment of autistic features and communication skills,
problems with vision, hearing, and pain threshold were observed
quite frequently in the present study. An increased pain threshold
was observed in all patients, and vision and hearing problems were
noted in half of the patients. Therefore, patients should be screened
for vision and hearing impairment, and possible problems should
be dealt with as early as possible to facilitate optimal child
development.
The emotional and behavioral problems assessed by the CBCL
and ABCL frequently occurred in the borderline clinical range
(n ¼ 6) but were less frequent in the clinically significant range
(n ¼ 4). Therefore, attention should be paid to emotional and
behavioral problems. A study by Dekker et al. (Dekker et al., 2002)
compared two groups of patients, one with mild to moderate ID,
and another one with mild to borderline ID, including patients with
Down syndrome and Fragile X syndrome. In the study, around 40%
in both groups scored in the borderline and clinical range on both
internalizing and externalizing problems, which is similar to our
findings. On the Total problems domain Dekker et al. found
approximately 50% of the patients in both groups scoring in the
borderline and clinical range, which is lower than our finding of
about 75%. However, drawing conclusions from this small group is
difficult; a larger patient sample needs to be assessed.
Earlier research on Kleefstra syndrome has reported significant
sleep problems (Verhoeven et al., 2011). In the present study,
almost half of the patients reported significant sleep problems. This
finding confirms earlier findings and indicates that sleep problems
frequently occur in Kleefstra syndrome. The review of the re-
sponses to the questions also revealed that almost all of the pa-
tients were restless during sleep and tired when they woke up. This
indicates that it is important to investigate each child's quality of
sleep, and more research is necessary regarding Kleefstra syndrome
and sleep.
The strength of the present study is the use of standardized,
validated tools, such as the VABS II, SCQ, CBCL, and ABCL, which
allows the results to be compared to other studies of patients with
Kleefstra syndrome or other rare genetic disorders. The use of these
tools also allowed us to confirm previously reported anecdotal
findings on behavior in patients with Kleefstra syndrome.
One of the limitations studying rare disorders is the sample size.
The small sample size limits the use and relevance of statistical
analyses. The significance of some of the findings in our study
needs to be interpreted with caution and will need to be confirmed
in future studies. However, we think that our report of eight per-
sons with this rare disorder is relevant as only 114 cases of Kleefstra
syndrome were documented in 2012 (Kleefstra, 2012) and that the
results contribute considerably to the research on Kleefstra
Please cite this article in press as: Schmidt, S., et al., A structured assessment of motor function and behavior in patients with Kleefstra
syndrome, European Journal of Medical Genetics (2016), http://dx.doi.org/10.1016/j.ejmg.2016.01.004
syndrome.
Another limitation involves the design of the study. The cross-
sectional design provides only a “snap-shot” of the patients at a
given time but does not provide any information regarding their
development over time. A longitudinal follow-up of these patients
is required to answer questions regarding their development over
time and possible behavioral changes. It is a limitation of this study
that some of the assessments are not primarily developed for
persons with intellectual disabilities. The lack of standardized
determination of mental age is also a limitation of our study, so that
the results should be interpreted with caution and in all future
studies mental age should be evaluated using a standardized
assessment. The lack of standardized measures regarding motor
function is yet another limitation, especially as no comparison to a
reference population can be provided. However, the observations
were conducted in a systematic way, by the same two observers in
all patients ensuring the same approach for all observations. The
use of both the Scandinavian and the English version of the VABS II
manual gave us additional information; however, using two
different manuals is not recommended and might have influenced
the results. Furthermore, only one researcher administered and
scored the VABS II. Ideally, two researchers should score the VABS II
survey, and the inter-rater reliability should be assessed.
6. Conclusion
Muscular hypotonia and its manifestations were observed in all
patients with Kleefstra syndrome in this study, and these features
persisted into adulthood. Behavioral issues, such as significantly
compromised adaptive behavior or possible autistic behavior, were
present in all patients, and sleep problems were also noted in
almost half of the patients. Obesity was not frequently observed. In
conclusion, patients with Kleefstra syndrome present in all age
groups with a broad range of clinical problems. Therefore, these
patients require a multidisciplinary follow-up that continues after
their transition into adulthood.
Ethics
This study was approved by the South-Eastern Regional Com-
mittee for Medical and Health Research Ethics, Norway. Informed
consent was obtained from the parents or legal guardians of the
participants.
Conflicts of interest
Dr. Susanne Schmidt reports a grant from the Norwegian
Directorate of Health, during the conduct of the study. All other
authors declare that they have no conflict of interest.
Acknowledgments
We would like to extend our gratitude to the families and their
children with Kleefstra syndrome who were willing to participate
in this study. We also thank the four Departments of Medical Ge-
netics in Norway (University Hospitals of Oslo, Trondheim, Bergen,
and Tromsø) for their help with patient recruitment. Furthermore,
we are grateful to our colleagues at Frambu who supported us in
numerous ways to conduct this study, especially Vivi Bergsager
Eriksen and Berit Hundal.
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