Seizure characteristics in pallisterkillian syndrome
Seizure Characteristics in Pallister–Killian SyndromeMeghan S. Candee,1* John C. Carey,2 Ian D. Krantz,3 and Francis M. Filloux11Division of Pediatric Neurology, Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, Utah2Division of Medical Genetics, Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, Utah; Intermountain Healthcare,Salt Lake City, Utah3Division of Human Genetics, The Children’s Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania,Philadelphia, Pennsylvania
Manuscript Received: 11 February 2012; Manuscript Accepted: 18 June 2012
Pallister–Killian syndrome (PKS) is a congenital disorder attrib-uted to supernumerary isochromosome 12p mosaicism. Cranio-
facial dysmorphism, learning impairment and seizures are
Candee MS, Carey JC, Krantz ID, Filloux. FM.
considered cardinal features. However, little is known regarding
the seizure and epilepsy patterns in PKS. To better deﬁne the
prevalence and spectrum of seizures in PKS, we studied 51
patients (39 male, 12 female; median age 4 years and 9 months;age range 7 months to 31 years) with conﬁrmed 12p tetrasomy. Using a parent-based structured questionnaire, we collected dataregarding seizure onset, frequency, timing, semiology, and med-
frequently identiﬁed in cells cultured from skin ﬁbroblasts or buccal
ication therapy. Patients were recruited through our practice, at
mucosa [Bielanska et al., 1996]. Given the mosaic nature of the
PKS Kids family events, and via the PKS Kids website. Epilepsy
condition, genetic diagnosis is often elusive as karyotypes per-
occurred in 27 (53%) with 23 (85%) of those with seizures having
formed only on blood cells may fail to identify the condition
seizure onset prior to 3.5 years of age. Mean age at seizure onset
[Horneff et al., 1993; Bielanska et al., 1996]. The PKS phenotype
was 2 years and 4 months. The most common seizure types were
is typically described by the presence of three general ﬁndings:
myoclonic (15/27, 56%), generalized convulsions (13/27, 48%),
craniofacial dysmorphism, cognitive impairment [Stalker et al.,
and clustered tonic spasms (similar to infantile spasms; 8/27,
2006] (ranging from moderate to severe intellectual disability), and
30%). Thirteen of 27 patients with seizures (48%) had more than
one seizure type with 26 out of 27 (96%) ever having taken
The majority of existing literature on PKS has focused on
antiepileptic medications. Nineteen of 27 (70%) continued to
reafﬁrming the craniofacial dysmorphisms (e.g., forehead promi-
have seizures and 17/27 (63%) remained on antiepileptic medi-
nence, temporal balding, and hypertelorism as shown in Fig. 1),
cation. The most commonly used medications were: levetirace-
associated congenital defects (e.g., diaphragmatic hernia, cleft
tam (10/27, 37%), valproic acid (10/27, 37%), and topiramate
palate, heart anomalies, etc.), physical exam ﬁndings (e.g., hypoto-
(9/27, 33%) with levetiracetam felt to be ‘‘most helpful’’ by
nia and anomalous skin pigmentation) and genotypic variations
parents (6/27, 22%). Further exploration of seizure timing,
observed [Smigiel et al., 2008]. Thus far, there does not appear to be
in-depth analysis of EEG recordings, and collection of MRI
a correlation between the proportion of tetrasomic cells and the
data to rule out confounding factors is warranted.
severity of a patient’s clinical presentation (i.e., severity of congeni-
tal abnormalities, survival, and degree of cognitive impairment)[Schinzel, 1991; Speleman et al., 1991]. Exploration of the critical
Key words: Pallister; Killian; seizures; epilepsy; 12p; tetrasomy
gene region of i12p responsible for PKS is ongoing.
In contrast to what is known about the epilepsy characteristics of
other chromosomal disorders (e.g., Angelman [Minassian et al.,1998], Wolf–Hirschhorn (4pÀ) [Battaglia et al., 2009], inverted
duplication 15 [Battaglia et al., 1997], terminal deletion 1p36
Pallister–Killian syndrome (PKS), also known as Pallister mosaic
aneuploidy syndrome [Reynolds et al., 1987], is a rare sporadic
Meghan S. Candee, Division of Pediatric Neurology, Department of
disorder ﬁrst described in adults in 1977 by Pallister [Pallister et al.,
Pediatrics, Primary Children’s Medical Center, 100 N. Mario Capecchi
1977] and in children in 1981 by Killian and Teschler-Nicola
Drive, Salt Lake City, UT 84113. E-mail: email@example.com
. PKS is caused by the presence of a supernumerary isochro-
Article ﬁrst published online in Wiley Online Library
mosome (i12p) which confers tetrasomy. The chromosomal anom-
aly is often absent in peripheral blood lymphocytes but is more
AMERICAN JOURNAL OF MEDICAL GENETICS PART A
children had onset of clustered epileptic spasms after infancy(‘‘late-onset spasms’’) and one of these children had an EEGconsistent with ‘‘modiﬁed hypsarrhythmia.’’ Of these four chil-dren, one had onset of ‘‘massive myoclonic jerks’’ at age 13 monthsthat appeared photosensitive in nature, and clustered tonic spasmsonly emerged later at age 4 [Cerminara et al., 2010]. The last of theseﬁve children had onset of partial clonic seizures at age 5.5 yearsfollowed by the appearance of clustered tonic spasms in ﬂexion1 year later [Cerminara et al., 2010]. This prior data, though basedon a very small sample size, would suggest that children with PKScould be prone to later onset clustered spasms as a particularepileptic phenotype. Other case reports (Table I) suggest alternativeseizure semiology. For example, Smigiel et al.  reporteduncategorized seizures in a neonate with PKS, while Spelemanet al.  described two patients with generalized seizures whowere treated with valproic acid. Clearly, the existing informationavailable with respect to the seizure and epilepsy characteristics in
FIG. 1. PKS patient facial characteristics. Note hypertelorism,
PKS (Table I) is limited and presented in a fairly inconsistent and
temporal balding, forehead prominence, and macrostomia.
fragmentary manner. This is because seizures were never before thefocus of investigation as such. Further delineation of an epilepsyphenotype (or phenotypes) in PKS may aid in seizure diagnosis,
Bahi-Buisson et al., 2008a,b] and ring chromosome 20 syndromes
improve anti-epileptic management, and provide a better under-
[Inoue et al., 1997]), very little is known regarding the frequency of
standing of prognosis for families and physicians [Battaglia et al.,
seizures, age of onset, typical seizure types, response to treatment or
In the present paper, we describe the seizure characteristics of 51
Prior case series and meta-analyses (Table I) suggest seizure
patients with PKS, the largest cohort of such patients to be evaluated
prevalence in PKS to be in the vicinity of 42–59% [Bielanska et al.,
for seizures and epilepsy to date. This was made possible via web-
1996; Stalker et al., 2006]. However, these numbers are rough
based contact and alliance with the family support group for people
estimates, not to be mistaken for careful analysis of a particular
affected by Pallister–Killian syndrome [http://pkskids.net/].
To date, only three groups (Table I) have described the detailed
semiology and clinical characteristics of epileptic seizures in atotal of ﬁve children with PKS [Sanchez-Carpintero et al., 2005;
Fifty-one patients with a diagnosis of Pallister–Killian syndrome
Yamamoto et al., 2007; Cerminara et al., 2010]. Four of these
(39 males and 12 females), as conﬁrmed by parent-reported chro-
TABLE I. Pallister–Killian Syndrome Seizure Literature Review—Comparison between Previously Reported Pallister–Killian Syndrome
Neonatal–4 y Staring spells Æ quick head jerks,
Myoclonic, partial, ﬂex/extensor spasms
Mean 2 y 4 m Myoclonic, generalized, infantile spasm,
y, years; m, months; NR, not reported; CBZ, carbamazepine; CLB, clobazam; CNZ, clonazepam; DPH, diphenylhydantoin; ESM, thosuximide; LEV, levetiracetam; LTG, lamotrigine; OCBZ, oxcarbazepine;PHB, phenobarbitol; TPM, topiramate; VGB, vigabatrin; VPA, valproic acid; Vit B6, vitamin B6.
mosomal analysis, were included. Patients were identiﬁed initially
Informed consent was obtained as the study involved voluntary
via clinical contact, attendance at PKS support group meetings
provision of personal medical information and requested the
or by contact via notiﬁcations on the PKS Kids family web site
option (which patients could refuse) of future contact by
the investigators. The study was reviewed and approved by theInstitutional Review Board of the University of Utah in Salt LakeCity, UT.
Inclusion Criteria1. Any patient presenting (or having presented within the past
20 years) to the pediatric neurology or pediatric genetics divi-
sions at University of Utah Medical Center/Primary Children’sMedical Center with a diagnosis of Pallister–Killian syndrome
The parents of 51 children with a conﬁrmed diagnosis of PKS
was offered participation. In addition, patients/parents involved
completed our survey. The median age of all patients at the time of
in the international PKS Kids organization, families of patients
study was 4 years and 9 months with a range of 7 months to 31 years
visiting the PKS Kids web site, and families attending the
(Table II). Seizures/epilepsy affected 27 of the 51 patients (53%).
2009 or 2010 annual PKS Kids Family meetings were offered
Amongst patients diagnosed with seizures, the mean age was
8 years and 4 months, with a range of 19 months to 31 years
2. Parent-reported genetic diagnosis of PKS (i.e., mosaic tetrasomy
(Table III). An additional 10% of parents suspected that their
12p as conﬁrmed by ﬂuorescence in situ hybridization, in
child had seizures (Fig. 2). Taken together, 63% of patients
ﬁbroblast culture, or other tissue).
in our cohort were identiﬁed as having conﬁrmed or suspectedseizures.
More than half of the patients diagnosed with seizures (56%) had
seizure onset by 2 years of age, and nearly all of the patients withseizures (96%) had onset by 6 years (Fig. 3). The majority of
Patients (and their families) were excluded if the diagnosis of PKS
the patients (63%) had seizures during both the day and night.
had not yet been conﬁrmed by chromosomal analysis (i.e., if their
Twenty-two percent of parents reported that their child had ever
diagnosis was suspected purely based on clinical presentation).
experienced status epilepticus. The most common seizure types
Clinical details were obtained through a parent-based structured
noted in our cohort of children with PKS were (in decreasing order
questionnaire which was handed, mailed, or emailed to parents
of frequency, as shown in Fig. 4) myoclonic (15/27, 56%), general-
of children with PKS. The questionnaire included (but was not
ized convulsive (13/27, 48%), clustered tonic spasms (i.e.,
‘‘infantile’’ spasms though usually occurring beyond infancy; 8/27, 30%), brief staring episodes (5/27, 19%), and complex partial
seizures (3/27, 11%). Only one of the eight patients with clustered
tonic spasms (‘‘infantile spasms’’) had spasm onset prior to 2 years
* Seizure type, frequency, timing (day/night/both), dura-
of age. Nearly half of patients with seizures (13/27, 48%) had more
Ninety-six percent of patients with seizures had ever taken
antiepileptic medication with 56% having tried two or more
(Table III). Sixty-three percent of patients with seizures remained
on antiepileptic medication at the time of study. The most
frequently used medications were valproic acid (10/27, 37%),
levetiracetam (10/27, 37%), topiramate (9/27, 33%), phenobarbital(6/27, 22%), and lamotrigine (6/27, 22%; Fig. 5). The medications
Of note, precise delineation of seizure timing (e.g., while waking/
considered to be most helpful by parents were: levetiracetam (6/27,
awake/falling asleep/asleep, conditions which are not mutually
22%), and phenobarbital, valproic acid, topiramate, and lamotri-
exclusive in that patients can have seizures at multiple levels of
alertness) was not distinctly elucidated, largely because the questionpertaining to this information was only added into a later version ofthe survey. Direct parent interviews and/or phone/email contactwith parents was employed in order to ascertain speciﬁc details notfully clariﬁed in the initially completed survey (e.g., when a question
TABLE II. Selected Patient Characteristics
was left blank or incomplete). Copies of pertinent medical records(e.g., EEG and MRI reports) were also requested and are still being
collected at this time. As such, the EEG and MRI ﬁndings will not
be discussed here. No incentives for participation were offered or
Data from the collected surveys were summarized using descrip-
tive statistics such as percentages, means, and standard deviations.
AMERICAN JOURNAL OF MEDICAL GENETICS PART A
TABLE III. Seizure Patient Characteristics (n ¼ 27)
AEDs, antiepileptic drugs. aLikely confounded by longer spasm clusters.
FIG. 3. Timing of seizure onset. Fifty-six, eighty-ﬁve, and ninety-sixpercent of patients with seizures had seizure onset by 2, 3.5, and 6years, respectively.
Including 51 patients with PKS, this is the largest cohort to date ofpatients with PKS to be evaluated for seizures and epilepsy. Our data
Although it has been previously suggested that most of the
conﬁrm that seizures are a common occurrence in children with
patients with PKS who are going to develop seizures do so shortly
PKS, affecting more than 50% of children by age 2 years.
after birth [Schinzel, 1991], our data suggest otherwise as only
Our total of 63% of patients with conﬁrmed or suspected seizures
eleven (35% or about one third) of the patients with seizures had
is noticeably higher than some previously reported prevalence
seizures prior to 1 year of age and neonatal seizures were only
estimates (e.g., 42% noted by Bielanska et al. [1996) but quite
reported in one child (2%). Likewise, our ﬁndings do support the
similar to that noted by Reynolds et al.  in their case series of
notion suggested in the ﬁve previously described patients [Sanchez-
10 patients and one stillborn fetus with PKS (i.e., 70%; also see
Carpintero et al., 2005; Yamamoto et al., 2007; Cerminara et al.,
Table I). The inclusion of many very young children in our cohort
2010 also see Table I] that late onset spasms (occurring after 1 year
along with the broad spectrum of seizure types diagnosed and the
of age, and hence after the typical age of onset for ‘‘infantile
suspicion (on behalf of parents) that their children have seizures
spasms’’) may represent a relatively common epileptic pattern
which are not always formally diagnosed, suggest that seizures may
for children with PKS. Although 22% of parents reported that
be even more common than we report here. This emphasizes the
their child had ever experienced status epilepticus, based on subse-
importance of following this cohort into the future as well as the
quent careful review of our survey data, we believe this number to be
need to expand the awareness of practitioners in looking for seizures
falsely elevated secondary to parental reporting of longer clusters of
tonic spasms as continuous seizure activity. Our ﬁnding that 70%
FIG. 4. Common seizure types. More than half of the patients withseizures had demonstrated myoclonic seizures while nearly halfhad experienced generalized convulsions. Nearly half (48%) had
FIG. 2. Seizure prevalence. Note that 63% of the patients in our PKS
more than one seizure type. *Seven out of eight patients with
cohort had been diagnosed or were suspected of having seizures.
‘‘infantile spasms’’ (87.5%) had onset at later than 2 years.
mal, often exhibiting a so-called ‘‘split-brain’’ pattern [Ohtsukaet al., 1993; Aicardi, 2005].
Based on the above observations, we hypothesized that children
with PKS may also exhibit some predictable epilepsy or seizurepatterns. Our data so far, modestly support this hypothesis. Asreported by parents, the seizure pattern/epilepsy syndrome associ-ated with PKS is characterized by the following key elements: (1)absence of neonatal seizures; (2) onset by 2–5 years of age; (3) mixedseizure types with a predominance of myoclonic seizures and late-onset clustered tonic spasms (‘‘late-onset infantile spasms’’ withonset at greater than 1 year of age); (4) rarity of convulsive status
FIG. 5. Anti-epileptic medications most frequently used and noted to
epilepticus; and (5) periods of relative refractoriness.
be ‘‘most helpful.’’ While valproic acid and levetiracetam were most
Although there does not appear to be a correlation between the
commonly used, levetiracetam was identiﬁed as the most
proportion of tetrasomic cells and the severity of a patient’s clinical
presentation, further examination of the scope of seizure severitywithin this population, when combined with genetic analysis, mayshed light on the neurophysiologic mechanism of seizures in PKS. Alonger term goal of our research is to identify optimal management
(19/27) of our patients with seizures continued to have seizures
strategies for the treatment of seizures in PKS. While we have
despite 63% (17/27) remaining on anti-epileptic medication dem-
limited information in this respect thus far, it appears that the
onstrates a presumed medication-refractory nature of seizures in
majority of children diagnosed with seizures have required a trial of
PKS. In the absence of long term follow-up data, it is not possible to
more than one AED. Though levetiracetam has been identiﬁed by
propose a single medication or speciﬁc regimen likely to be most
parents as the most commonly effective single agent in this cohort, it
effective for all or a majority of PKS children.
is by no means consistently effective. No other AED stands out as the
Unfortunately, the relatively young age of many of our patients
obvious second choice (see also Gerstner et al., 2008 for description
limits our ability to accurately assess long-term prognosis in
of valproate-associated encephalopathy in a child with PKS). Only
children with PKS. However, it is interesting to note that the
two patients in our cohort have required or been treated with the
two oldest patients studied (now aged 29 and 31 years) are currently
ketogenic diet. None had undergone vagal nerve stimulator im-
seizure free. One of these two adults with PKS also appears to be one
plantation. The latter two observations may speak to the relative
of the ‘‘higher-functioning’’ individuals in our cohort.
lesser severity of the seizure phenotype in these children. Although
Epilepsy is a common symptom of many congenital and/or
our data do not yet allow us to ﬁrmly describe the long-term
genetic syndromes that affect the nervous system. Some of these
epilepsy prognosis of these patients, they do suggest that the overall
are associated with speciﬁc epilepsy or electroencephalographic
severity of epilepsy in this population is relatively less than for
patterns [Battaglia et al., 1997, 2009; Inoue et al., 1997; Minassian
children with Aicardi syndrome, or with other epileptic encepha-
et al., 1998; Bahi-Buisson et al., 2008a,b]. For example, epilepsy is
lopathies of childhood (such as Lennox–Gastaut syndrome, Myo-
very common in children with Angelman syndrome and Wolf–
clonic Astatic Epilepsy, or Dravet syndrome). The potential for
Hirschhorn syndromes but differs substantially between the two. In
remission may be less than that observed in Wolf–Hirschhorn
the former, children often have mixed seizure types with frequent
syndrome, but better than for girls with Rett syndrome and
drop attacks and atypical absence seizures, accompanied by a
certainly those with Aicardi syndrome.
characteristic EEG pattern described as periodic, large amplitude,
Our survey-based study results are inherently limited by expec-
slow spike-wave discharges often occurring in prolonged clusters or
tation, recall and selection bias. Parents are not clinically trained
trains [Minassian et al., 1998; Korff et al., 2005; Valente et al., 2006;
to diagnose seizure activity and may over/under-report episodes.
Conant et al., 2009; Thibert et al., 2009]. A fair percentage of these
In addition, parents with a child with epilepsy were likely more
children will eventually go into remission [Uemura et al., 2005;
motivated to ﬁll out this questionnaire. Considerable variability
Valente et al., 2006; Thibert et al., 2009]. In contrast, more than 90%
with respect to parental interpretation of questions and terms was
of children with Wolf–Hirschhorn syndrome have epilepsy, but
noted as well. For example, some parents could describe a seizure
most have generalized tonic–clonic seizures and about half suffer
but not identify the category of seizure type. The differentiation
episodes of status epilepticus. However, the majority eventually
between the duration of a single seizure versus a cluster of seizures
experience full seizure control or remission in childhood
was not always entirely clear. We have tried and intend to continue
[Worthington et al., 2008; Battaglia et al., 2009]. Girls with Rett
to address such potential obstacles by conducting a thorough
syndrome have a mixture of seizure types, but, perhaps similar to
medical record review down the road. That being said, a
children with PKS, also have a variety of non-epileptic paroxysmal
questionnaire-driven approach is particularly helpful in the case
events which can confound management [Laan et al., 1998; Moser
of rare diseases for which ascertainment of cohorts of substantial
et al., 2007; Bahi-Buisson et al., 2008a,b; Buoni et al., 2008]. Finally,
size is challenging [Bahi-Buisson et al., 2008a,b; Battaglia et al.,
girls with Aicardi syndrome, experience early onset infantile spasms
2009; Thibert et al., 2009; Cardoza et al., 2011].
and typically suffer from lifelong, severe intractable epilepsy
In the future, a modiﬁed, more comprehensive survey aimed at
[Ohtsuka et al., 1993; Aicardi, 2005]. EEG patterns are very abnor-
capturing additional details pertaining to seizure timing and to
AMERICAN JOURNAL OF MEDICAL GENETICS PART A
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angelman syndrome caused by deletion of the chromosome 15q11–
A case of Pallister–Killian syndrome associated with West syndrome.
November 06, 2012 Financial Results Particulars Qtr Ending Qtr Ending Current Price: STOCK DATA VALUE PARAMETERS Quarterly Performance Robust growth in Sales – Driven by Lexapro Sales, other drivers are intact in near term: Net sales grew by robust 24% YoY to `2145.87 crore for the quarter ended September Latest Bookvalue (cons.) -Unit Curr. 2012 drive
Report 2003Perspective and action plan 2004PrefaceMy goal as Danish Minister for Gender Equality is to empower every girland boy, every woman and man to choose the life she or he wants. We must appreciate each individual’s resources and never let gender becomea barrier in working or private life. We must allow women to be executivesand give men the space to become fathers. To achieve this goa