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Behavioral phenotype in the 9q subtelomeric deletion syndrome A report about two adult patients.

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Neuropsychiatric Genetics
Behavioral Phenotype in the 9q Subtelomeric Deletion
Syndrome: A Report About Two Adult Patients
Willem M.A. Verhoeven,1,2* Tjitske Kleefstra,3 and Jos I.M. Egger1,4
Vincent van Gogh Institute for Psychiatry, Centre of Excellence for Neuropsychiatry, Venray, The Netherlands
Department of Psychiatry, Erasmus University Medical Centre, Rotterdam, The Netherlands
Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
Department of Clinical Psychology, Behavioural Science Institute, Radboud University Nijmegen, Nijmegen, The Netherlands
Received 16 April 2009; Accepted 25 June 2009
The 9q Subtelomeric Deletion Syndrome (9qSTDS) is clinically
characterized by mental retardation, childhood hypotonia, and
facial dysmorphisms. Haploinsufficiency of the EHMT1 gene
has been demonstrated to be responsible for its core phenotype.
In a significant number of patients behavioral abnormalities like
aggression, impulsivity, and chaotic behaviors are present as well
as epileptic phenomena. Reports about the developmental, behavioral, and neuropsychiatric aspects of 9qSTDS are scarce
and mostly limited to young patients only. In this report,
the behavioral and neuropsychiatric characteristics of one male
and one female middle-aged patient are described in whom
the genetic diagnosis, interstitial and telomeric 9q deletion,
respectively, was established recently. In both patients a remarkable sleep disturbance, characterized by frequent awakenings
and daytime sleepiness, was present as well as a prominent
apathy syndrome. The observed motor signs such as rigid flexure
of the arms and finger stereotypies persisted over a period of
many years and could therefore not be viewed as symptoms
of catatonia. It is concluded that the proposed behavioral
phenotype of 9qSTDS comprises at least an erratic sleep pattern
and an enduring severe apathy. 2009 Wiley-Liss, Inc.
Key words: 9qSTDS; behavioral phenotype; apathy; sleep disturbances; mental retardation
Submicroscopic deletions of the distal long arm of chromosome 9q
are relatively common and give rise to a clinically recognizable
phenotype referred to as the 9q Subtelomeric Deletion Syndrome
(9qSTDS; OMIM 610253). Although the deletions might vary
in size, it was shown that haploinsufficiency of the EHMT1
(Euchromatic Histone Methyltransferase 1) gene is responsible for
the core phenotype of 9qSTDS [Kleefstra et al., 2005, 2006a,b, 2009;
Yatsenko et al., 2009]. The key features of the syndrome are mental
retardation, childhood hypotonia, and a characteristic facial
appearance. In addition, congenital heart and renal defects, microcephaly, epilepsy, obesity, and behavioral problems are frequently
present [Dawson et al., 2002; Cormier-Daire et al., 2003; Stewart
2009 Wiley-Liss, Inc.
How to Cite this Article:
Verhoeven WMA, Kleefstra T, Egger JIM.
2010. Behavioral Phenotype in the 9q
Subtelomeric Deletion Syndrome: A Report
About Two Adult Patients.
Am J Med Genet Part B 153B:536–541.
et al., 2004; Yatsenko et al., 2005; Kleefstra et al., 2006b, 2009;
Stewart and Kleefstra, 2007].
Since information about the behavioral features of 9qSTDS
patients is virtually absent and the sparse data concern young
patients only, so far, it is not well understood whether there is a
specific set of behavioral attributes associated with the syndrome.
Therefore, in the present article, the developmental and behavioral
characteristics as well as the neuropsychiatric signs and symptoms
of two adult patients in their 50s with recently diagnosed 9qSTDS,
are described and discussed in detail in order to establish a
provisional behavioral phenotype.
Case Vignettes
Patient A is a 53-year-old female. She was the sixth child from nonconsanguineous healthy parents and had five siblings of whom the
eldest died from diphtheria at the age of 4. There was no family load
with mental retardation or neuropsychiatric disorders. Her father
and mother died aged 61 and 75, from colorectal cancer and cardiac
W.M.A. Verhoeven, T. Kleefstra, and J.I.M. Egger contributed equally to
this work.
*Correspondence to:
Willem M.A. Verhoeven, Vincent van Gogh Institute for Psychiatry, Centre
of Excellence for Neuropsychiatry, Stationsweg 46, 5803AC Venray, The
Netherlands. E-mail:,
Published online 29 July 2009 in Wiley InterScience
DOI 10.1002/ajmg.b.31015
arrest, respectively. Pregnancy was complicated by jaundice in the
25th week. The patient was born after an uncomplicated delivery
with a birth weight of 3,000 g. In the first year she suffered from two
severe gastrointestinal infections necessitating a short hospitalization. From the age of 1 year, a marked delay of language and speech
development became apparent. Thereafter, her development
showed a marked delay of all milestones and she was subsequently
hospitalized in an institute for mental retardation at the age of
3 years. At the age of 10 years, neuropsychiatric examination
demonstrated a height of 137 cm (<1 SD), a weight of 34 kg
(<1 SD), a skull circumference of 48.5 cm (< 2 SD), and a thoracolumbal scoliosis. Facial dysmorphisms were noted, comprising
depressed nose bridge and synophrys/straight eyebrows. Motor
behavior was characterized by an anteflected position, hyperkinesia, stereotypies, rigidity, valgus deformities of knees and feet (genu
and talipes valgus), and slight hypotonia with normal reflexes.
Because of challenging behaviors, she was treated with several
psychotropics. At the age of 16 years, tonic–clonic seizures and
absences developed for which treatment was started with phenobarbitone that was later changed to valproic acid. Since seizures
persisted and bizarre and chaotic behaviors became more prominent, 4 years later she was referred to the Department of Child
Neurology at a University Hospital for diagnostic re-evaluation.
There was microcephaly (OFC 50.5 cm), hypertrichosis of the
limbs, fine-motor dyspraxia, marked kyphoscoliosis with gibbous
deformity, and a fixed, downward rotated flexion of the hands.
With respect to communicative skills, she responded to auditory
and visual stimuli and showed some understanding of simple
monosyllabic words and of daily routines. Her behavior was
characterized by hyperactivity and aggressive outbursts, particularly self-hitting, biting, and scratching of others. There were sleep
disturbances, in that she had frequent periods of nocturnal activities
and episodes of sleep during the day. EEG recording demonstrated
spikes and spike-and-wave discharges with a variable localization
but most pronounced left temporal. Pneumencephalography revealed only a slight general atrophy. A diagnosis of severe mental
retardation and epilepsy was made. The etiology was hypothesized
to be an intra-uterine infection. No signs of mental deterioration
were observed.
During subsequent decades, aggressive, chaotic, and impulsive
behaviors gradually diminished, seizures occurred only incidentally
and she became progressively immobile. Treatment with valproic
acid was continued (600 mg daily; plasma concentration 50 mg/L)
and all psychotropics were gradually stopped. Orofacial stereotypies and sleep disturbances, particularly frequent awakenings,
persisted. Because of reduced exercise tolerance and marked
inactivity during her late 40s, cardiac examination was performed
that, however, disclosed no explanation for these complaints. Given
the family load with colorectal malignancies, a colonoscopy was
carried out which did not reveal any abnormalities.
Actual examination at the age of 53, disclosed a severe mentally
retarded friendly female (estimated IQ <30) with short stature
and microcephaly (51.0 cm; 2.0 SD). She had several facial
dysmorphisms, comprising straight eyebrows with synophrys,
depressed nasal bridge, brachycephaly, short forehead with low
hairline, big and short nose, everted and thickened lower lip
with thin upper lip, and prognathism. Regarding hands and feet,
camptodactyly of the left proximal interphalangeal joints and
hyperextension of the distal interphalangeal joints of both thumbs,
and partial cutaneous syndactyly of the index and middle toes with
hallux valgus were present. Apart from the serious kyphoscoliosis,
the patient presented with a bizarre and distinctive posture with
staring, lack of spontaneous movements, rigid flexure of both arms,
and twisted hands with inward rotated thumbs. Her behavior was
characterized by extreme hypoactivity with minimal responses
to environmental stimuli and complete loss of curiosity and
self-initiated behavior, stereotypical protruding tongue movements, and buzzing noises with varying intensity and tonality
dependent on the emotional state. Although her affect was clearly
flattened, it modulated with environmental events. Language was
restricted to a few elementary words. Communication was mainly
non-verbal, using gestures and signs of daily routines without,
however, active environmental engagement. Her sleep–wake
activity pattern showed a peculiar dyssomnia with daytime
sleepiness at inappropriate times and places, difficulty getting to
sleep, and intermittent wakefulness during the night.
Patient B is a 59-year-old male. He was born from nonconsanguine parents after an uncomplicated pregnancy and
delivery. His birth weight was 4,200 g. He was the second of four
children and had two healthy brothers and one healthy sister. His
family history showed no mental disorders nor mental retardation.
His mother was 75 years old and healthy. His father died at the age of
80 from gastric cancer. During his infancy there were serious
feeding problems. At the age of 6 months, he underwent chirurgical
correction of an umbilical hernia and some years later of an inguinal
hernia. He had some fever convulsions at the age of 6 years. His
development showed delayed milestones with independent walking
from the age of 24 months and speaking first simple words just
before pre-school age. During the first years of elementary school,
development of speech remained restricted to incomprehensible
one-word sentences whereas other capacities such as color discrimination and sense of time, were globally undisturbed. From the age of
nine, special education was necessary because of severe learning
disabilities. In subsequent years, no major behavioral disturbances
occurred albeit that marked motivational and psychomotor deficits
became apparent. These problems resulted in a first psychological
assessment at the age of 16 that disclosed a developmental age of
about 5 years with severe mental retardation (total IQ: 30) and
a remarkable loss of initiative. At the age of 19, his behavioral
problems increased to such an extent that admission to a day
activity center was required. During his 20s, major domestic
changes occurred resulting in the patient living alone with his
parents. Moreover, both were suffering from severe health problems. These life events disrupted the patient’s daily structure and
were accompanied by a progressive deterioration of his behavior
with sudden aggressive events during which he seemingly lost the
contact with his familiar environment, and during which he
grasped other people. As a consequence he was institutionalized
at the age of 29.
Prior to permanent admission, the patient underwent a psychiatric and neurological examination. No psychiatric symptoms
could be established and it was concluded that the disturbances
in mood and behavior were socially mediated and covaried with
contextual events. Symptomatic treatment with benzodiazepines
was started. To exclude an epileptic origin of his episodic aggressive
outbursts, the patient was referred to a neurologist. At examination,
a severe psychomotor retardation with microcephaly (OFC
not mentioned) and mild facial dysmorphisms (not specified)
were observed, as well as staring with a fixed gaze and an explosive,
repetitive, meaningless single-word-speech. In addition, there were
frequent myoclonic twitches, hypokinesia, slight hypertonia, and
rigid movements. EEG recording after sleep deprivation showed no
abnormalities, especially no epileptic phenomena. A provisional
diagnosis of partial complex epilepsy was given and the patient was
treated with carbamazepine that, however, was discontinued some
months later due to the absence of any effect on the paroxysmal
temper tantrums.
During the first years of institutionalization, his behavior
repertoire remained unchanged and the patient was treated with
benzodiazepines for regularly occurring sleep disturbances with
nightly wandering and daytime irritability. Routine cytogenetic
investigation showed a normal 46,XY karyogram and no fragile-X.
At the age of 36, psychological re-evaluation was performed that
showed no signs of cognitive decline as compared to the findings at
institutionalization 7 years before. Main findings were marked loss
of initiative and minimal task orientation, alternated with irritable
and chaotic behaviors. Over subsequent years, the patient was
symptomatically treated with benzodiazepines and pipamperone,
40 mg twice daily. Five years later, after an increase of the dose of
pipamperone to 120 mg daily, drowsiness developed together with
hypoactivity, posturing of the head, and virtual no interaction with
the external world. Discontinuation of pipamperone resulted in
remission of all neurological symptoms. Shortly thereafter, the
patient manifested with one tonic–clonic seizure. Neurological
examination, including EEG-recording and CT-scanning revealed
no abnormalities. Antiepileptics were not started. Because of
persisting disinhibited behaviors, the patient was referred to a
psychiatrist and diagnoses of autistic disorder and schizophrenia
were made. Thereafter he was treated with several antipsychotics
and benzodiazepines without, however, any effect. At the age of
45 years, severe regurgitation with weight loss occurred for which an
eosophagogastroduodenoscopy was performed that revealed cardia
deficiency only. One year later, rumination with stereotyped
tongue movements worsened and became paralleled by sudden,
weekly occurring, short lasting periods with severe hypertonia
and, consequently, serious falls. Extensive neurological assessment,
including 24 hr EEG-recording, showed no abnormalities. Cardiological examination, however, demonstrated paroxysmal atrial
fibrillation. After pacemaker implantation, such episodes never
Actual examination at the age of 59 years showed a severe
mentally retarded patient (estimated IQ: 25–35) with virtually
absent speech, short stature, and microcephaly (2nd centile). There
were several facial dysmorphisms including mild mid-face hypoplasia, low hairline, arched eyebrows, depressed nasal bridge, and
everted lower lip. He presented with stereotypic orofacial movements (tongue protruding), staring look, rigidity in walking,
general lack of spontaneous movements, fixed bended arms, and
finger stereotypies. There was no functional communication or
interaction, but only passive recognition of daily routines. The
patient showed no self-initiation, although he responded to simple
verbal instructions. His sleep pattern was characterized by frequent
awakenings for several hours during which he showed nonintentional behaviors.
In both patients, current routine cytogenetic investigation
showed normal karyotypes. Routine MLPA subtelomere deletion
testing demonstrated a submicroscopic deletion of the long arm of
chromosome 9 (9q34.3), in agreement with the diagnosis of
9qSTDS. A detailed summary of the characteristics is shown in
Table I.
This is the first report in which the developmental and behavioral
characteristics of two adult patients with a recently confirmed
diagnosis of the 9qSTDS, are extensively described. The phenotypical and molecular characteristics for both patients have been
reported previously, represented as Patient 4 (Patient A) and
Patient 8 (Patient B), respectively [Kleefstra et al., 2009]. The
9qSTDS is a genetic disorder that is considered as one of the most
common subtelomere deletion syndromes [Ravlan et al., 2006].
In both patients, analysis of global functioning showed a gradual
decline on the dimensions of goal-directed behavior, especially lack
of achievements in performing daily activities and increased dependency on others, and goal-directed cognition, notably interest
and curiosity. In general, a significant decrease of emotional
responsivity was present. These phenomena were suggestive for
an apathy syndrome. The remarkable sleep disturbance was unchanged in both over many years.
Regarding the 57-item Psychopathology Instrument for Mentally Retarded Adults [PIMRA; Matson et al., 1984], in both patients
eight key items were endorsed: flat affect (6), incoherent speech (8),
indifference (12), mood instability (15), loss of energy (21), social
withdrawal (38, 50), sleeping disorder (54), and concentration
difficulties (55). All these symptoms belong to the PIMRA subscales
referring to an affective or schizophrenic disorder that, however,
were both not opportune since the item content reflects a general
lack of spontaneous behavior and is not indicative for a depressive
or psychotic disorder. For the same reasons, a diagnostic label of
autistic disorder was inapplicable.
Although the 14-item Bush-Francis Catatonia Screening Instrument [BFCSI, Bush et al., 1996] showed positive scores for three
catatonic signs (immobility/stupor, severity two; staring, severity
three, and stereotypy, severity two), a diagnosis of catatonia was not
appropriate since these symptoms were present over a period
of several years and were all part of a behavioral syndrome characterized by the absence of goal-directed behavior and an almost
complete lack of emotional and social reciprocity. Moreover,
treatment with benzodiazepines, the first choice in case of catatonia
[Fink et al., 2006; Seethalakshmi et al., 2008], was proven to be
ineffective (Patient B).
Conceptually, apathy is closely linked to motivation and emotion but, because of difficulties in the delineation from other clinical
conditions that are associated with lack of motivation, and in the
absence of a clear definition, it has not been the object of systematic
evaluation until the nineties of the past century [Marin, 1990]. It
was then suggested to define apathy as a syndrome that is characterized primarily by an absence of motivation that cannot be
TABLE I. Summary of Characteristics of Two Middle-Aged Dutch Patients With 9qSTDS
Genetic defect
Level of mental retardation
Previous language development
Facial dysmorphisms
(History of) epilepsy
Fixed flexure arms and hands
Neuropsychiatric disorders in family
Motor activity
Restricted social interactions
Behavioral initiative
Emotional responsivity
Communication skills
Persistent sleep disturbances
Catatonic symptoms
PIMRAc total score
AESb total score
Patient A
53, female
Interstitial deletion
Severe (IQ <30)
Elementary words
0.6th centile
Very low
Virtually absent
Not present
Patient B
59, male
Telomeric deletion
Severe (IQ 25–35)
One word sentences
<2nd centile
Very low
Moderate to severe
Not present
Detailed phenotypical and molecular data of both patients are published in Kleefstra et al. [2009] as Patients 4 and 8, respectively.
PIMRA, Psychopathology Instrument for Mentally Retarded Adults [Matson et al., 1984].
AES, Apathy Evaluation Scale [Marin et al., 1991].
attributed to disturbances of intellect, emotion, or level of
consciousness. Subsequently, operational criteria for apathy as a
neuropsychiatric syndrome were conceptualized that included
deficits in three dimensions of motivation: goal-directed behavior,
goal-directed cognition, and emotional concomitants of goaldirected behavior [Marin, 1991]. Based on these criteria, the
18-item Apathy Evaluation Scale (AES) was constructed and tested
on the reliability and construct validity.
Since apathy can occur both abruptly or as a gradual behavioral
change, a duration criterion was not included. In a group of healthy
elderly subjects, a mean total score on the AES of 26 was found and
for patients with Alzheimer’s dementia, stroke, and major depression of 45, 34, and 39, respectively (maximum score: 72) [Marin
et al., 1991]. In the following years, assessment of apathy as
operationalized with the AES, was demonstrated to provide reliable
and valid measures of diminished motivation in diverse clinical
conditions [Marin, 1996; Starkstein and Leentjes, 2008]. Since
apathy can be considered as an observable behavioral syndrome
comprising a quantitative reduction of voluntary behaviors, it was
hypothesized that the syndrome emerges as a consequence of
dysfunctions in the systems that produce and control self-generated
purposeful behavior, more specific the prefrontal-basal ganglia
circuits [Levy and Czernecki, 2006; Levy and Dubois, 2006]. As
a consequence, treatment studies with dopamine agonistic compounds and/or stimulants have been reported that, however, are
inconclusive with respect to their effectiveness on amelioration of
symptoms of apathy [Marin, 1996; Hardy, 2009].
In the here described patients, total scores on the AES of
62 (Patient A) and 60 (Patient B) were established, indicating a
severe form of apathy. Most prominent were the items that reflect
symptoms like anosognosia (15), avolition (3, 16), lack of initiative
(3, 17), motivation (18), general disinterest (4 and 5), and persistence (8). Such a constellation of symptoms points towards an
extreme reduction of self-generated voluntary and purposeful
behavior, and therefore apathy syndrome is the most appropriate
description of the observed clinical condition. The characteristic
sleep disturbance with several long-lasting nocturnal awakenings,
shows clinically some similarities with that observed in
Smith–Magenis syndrome (SMS; del 17p11,2). In SMS patients
a phase shift in the circadian rhythm of melatonin underlies the
pathognomonic sleep disturbance with prominent difficulties
falling asleep, short sleep cycles, frequent and prolonged nocturnal
awakenings, and excessive daytime sleepiness [Smith et al., 1998; De
Leersnyder, 2006]. Equivocal results have been reported after
treatment with melatonin or beta-blockers [De Leersnyder et al.,
2003; Wheeler et al., 2005; Gropman et al., 2007]. In the 9qSTDS,
however, no information is available about the pathophysiology of
the sleep disturbances.
Both patients have a submicroscopic deletion that share an
overlapping region of 450 kb comprising, apart from the EHMT1
gene, four other genes (ARRDC1, ZMYND19, WDR85, and
MRPL41; Though none of these genes
are yet known to be associated with human disease, it cannot be
unequivocally concluded that the observed signs and symptoms
derive from haploinsufficiency of the EHMT1 gene only. With
respect to the concept of a behavioral phenotype in general, it
should be stressed that, although there is no linear relationship
between genes and phenotype, the search for candidate genes has
given great impetus to a more functional classification of psychiatric disorders. An example can be found in the DISC1 gene that
originally was thought to be causally related to schizophrenia but
later turned out to be a genetic vulnerability factor predisposing for
an array of psychiatric symptoms across diagnostic boundaries
[Verhoeven et al., 2008].
In conclusion, the 9qSTD syndrome is constituted, in addition to
its phenotypic features, by the absence of speech development and
by aggressive behaviors in the first decades of life. From the
third decade on, a characteristic behavioral phenotype seems to
emerge that comprises a peculiar dyssomnia with frequent and
enduring nocturnal awakenings coinciding with non goaldirected behaviors and accompanied by daytime sleepiness, and
an absence of motivational behaviors that meet the criteria for
apathy syndrome. Thus, the here proposed behavioral phenotype
of 9qSTDS in adults comprises a specific sleep disturbance and
severe apathy. To substantiate the behavioral phenotype of
9qSTDS, further studies are warranted in adults with such a
This study is part of a collaborative project of the research group
‘‘Psychopathology and Genetics’’ of the Radboud University
Nijmegen and the Vincent van Gogh Institute for Psychiatry,
Venray. The authors are indebted to Mrs. Wendy van Zelst, clinical
geneticist of the Department of Clinical Genetics at the University
of Maastricht, for referral of Patient B; to the patients’ parents and
family and to the medical and nursing staff of the Dutch Institutes
for mental retardation ’s-Heeren Loo/Advisium in Geldermalsen
(Patient A), and Koraalgroep/Maasveld in Maastricht (Patient B),
for their cooperation.
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