International Journal of Pediatric Otorhinolaryngology 76 (2012) 972–975

Insomnia in Cornelia de Lange Syndrome§

Roy Rajan a, James R. Benke b, Antonie D. Kline c, Howard P. Levy d, Amy Kimball c, Tiffany L. Mettel b,Emily F. Boss b, Stacey L. Ishman b,*a Emory University, Department of Otolaryngology – Head and Neck Surgery, 1365 Clifton Road NE, Building A – Suite 2300, Atlanta, GA 30322, United Statesb Johns Hopkins, Department of Otolaryngology – Head and Neck Surgery, 601 N. Caroline St, 6th Floor, Baltimore, MD 21287, United Statesc Greater Baltimore Medical Center, Harvey Institute of Human Genetics, 6701 N. Charles St, Towson, MD 21204, United Statesd Johns Hopkins, Department of Medicine and McKusick-Nathans Institute of Genetic Medicine, 10753 Falls Rd, Suite 325, Lutherville, MD 21093, United States

A R T I C L E I N F O

Article history:

Received 25 November 2011

Received in revised form 6 March 2012

Accepted 10 March 2012

Available online 13 April 2012

Keywords:

Cornelia de Lange Syndrome

Insomnia

Sleepiness

Sleep

A B S T R A C T

Objective: Up to 55% of patients with Cornelia de Lange Syndrome (CdLS) experience sleep disturbance.

Prior evaluation of children without CdLS with similar intellectual disability and self-injurious behavior

suggests that sleep disturbances may be related to insomnia or circadian issues.

Methods: Caregivers of 31 patients (19 children) with CdLS completed a sleep history questionnaire

focused on sleep patterns and evening sleep behavior to screen for signs and symptoms of insomnia and

circadian rhythm disorders.

Results: The mean age of participants was 14.5 years (range 0.6–37). Major difficulty in falling asleep

(75% pediatric, 33% adult) and staying asleep (52% pediatric, 33% adult) was noted. Overall, time to sleep

onset was 27.0 � 17.6 min, however in those with stated sleep onset difficulty, average time to sleep was

37.8 � 16.4 min (p = 0.002). The mean number of pediatric nighttime awakenings was 1.5 overall and 2.1 in

those with stated sleep maintenance difficulties versus 0.7 and 1.5 respectively in adults. Children with CdLS

tended to fall back asleep slower (61.8 min) than adults (14.9 min), but none of the comparisons between

adult and pediatric sleep measures were significant. Greater than half of participants reported a family

member with a possible circadian rhythm disorder.

Conclusions: Symptoms suggestive of insomnia or circadian rhythm disorder are prevalent in this cohort

of children and adults with CdLS. Adults may have less severe symptoms than children, suggesting some

improvement over time although this study is underpowered for this analysis. Further studies are

necessary to better characterize sleep disturbance in the CdLS population.

� 2012 Elsevier Ireland Ltd. All rights reserved.

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International Journal of Pediatric Otorhinolaryngology

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1. Introduction

Cornelia de Lange Syndrome (CdLS), also known as Brachmann–de Lange Syndrome, is a rare genetic disorder with variablepenetration estimated to occur in 1:10,000–1:50,000 live births[1]. The genetic mutation is associated with genes on chromo-somes 5p13, 10q25, and Xp11 [2]. CdLS is characterized bymultiple anomalies, including distinctive facial features, hirsutism,growth retardation, musculoskeletal abnormalities, self-injuriousbehavior and intellectual disability. Craniofacial features includesynophyrs, arched eyebrows, long eyelashes, small upturnednostrils, widely spaced teeth, and microcephaly. Autism has alsobeen associated with CdLS.

§ Presented at the SENTAC Annual Meeting, Cincinnati, OH, December 2010.

* Corresponding author at: Johns Hopkins School of Medicine, Department of

Otolaryngology – Head and Neck Surgery, 601 N. Caroline St, Room 6231, Baltimore,

MD 21287, United States. Tel.: +1 410 502 3225; fax: +1 410 955 0035.

E-mail address: Sishman1@jhmi.edu (S.L. Ishman).

0165-5876/$ – see front matter � 2012 Elsevier Ireland Ltd. All rights reserved.

doi:10.1016/j.ijporl.2012.03.008

Sleep disturbance has been reported in up to 55% of patientswith CdLS but has not been well-characterized. In a comparativestudy of the CdLS population and those with intellectual disability,Hall et al. noted settling problems in 26% and waking problems in31% of CdLS patients, suggesting an association with insomnia and/or circadian rhythm disorder [3]. Sleep disturbance has also beenreported in non-CdLS children with intellectual disability and self-injurious behaviors.

Individuals with Smith–Magenis syndrome (SMS) maintainsimilar characteristics to those with CdLS. Behavior issues, delayeddevelopment, distinguishable facial traits, and cognitive im-pairment characterize SMS. It is caused by a deletion of RAI1 onchromosome 17 at loci 11.2 [4]. SMS patients have significantintellectual disability and self-injurious behaviors, and 65–100% ofthe studied population present with a sleep disturbance. Difficul-ties reported include sleep onset insomnia, shortened sleepduration, frequent and prolonged nocturnal awakenings, excessivedaytime sleepiness, daytime napping, snoring, and nocturnalenuresis [5]. Potocki et al. further evaluated the link between sleepdisturbance in Smith–Magenis patients and melatonin excretion

Table 1Select questions pertaining to insomnia or circadian rhythm disorders.

Please circle the appropriate word that BEST describes your child’s current sleep patterns:

Choices for response: Never Rarely Occasionally Frequently Always

Currently, does your child have major problem(s). . .?–falling asleep

–staying asleep

–falling asleep after he/she wakes up

–awakening early in morning

Does your child currently have trouble falling asleep at bedtime?How long does it currently take your child to fall asleep (if known)?___ mins ___ hrs

Average number of times per night that your child wakes up: ____ times/night

How long does he/she stay awake (with middle of night awakenings)? __________

Does anyone in the family have the following sleep problems. . .. . .?Morning Lark (early riser) Mother (yes/no) Father (yes/no) Other Relative (yes/no)

Night owl (late night bedtime/late riser) Mother (yes/no) Father (yes/no) Other Relative (yes/no)

R. Rajan et al. / International Journal of Pediatric Otorhinolaryngology 76 (2012) 972–975 973

and found that melatonin insufficiency may play a significant rolein the sleep difficulties seen in this population [6]. The conse-quence of melatonin insufficiency is an increase in circadianrhythm disturbance or delayed sleep onset with dysregulation ofthe sleep–wake cycle. Because sleep disturbance seen in SMS issimilar to that seen in CdLS, we hypothesized that circadianrhythm disturbance may also play a role in the CdLS patients.

Although sleep disturbance is prevalent in individuals withdevelopmental and cognitive delay and is known to affectindividuals with various named syndromes, no published reportsspecifically evaluate insomnia or circadian rhythm disorders inpersons with CdLS. Therefore the objective of this report is todefine the prevalence of insomnia or circadian rhythm disorders inone cohort of patients with CdLS and compare sleep characteristicsbetween children and adults in this cohort.

2. Methods

Institutional Review Board approval was obtained from bothJohns Hopkins and Greater Baltimore Medical Center (GBMC) toadminister a sleep history questionnaire to families of patientswith CdLS at GBMC and through the CdLS Foundation. Approvalfrom the Board of Directors of the CdLS Foundation was alsoobtained. Caregivers of 31 patients with CdLS completed thevoluntary questionnaire. The survey includes questions onbehavioral traits and three validated sleep-specific tools, namelythe OSA18, the Pediatric Sleep Questionnaire (PSQ), and thePediatric Daytime Sleepiness Scale (PDSS). The survey also includesquestions previously used to evaluate sleep disturbance inindividuals with intellectual disability such as SMS [5]. For thisanalysis, 6 survey items were evaluated for characterization of

Fig. 1. Reported sleep difficult

insomnia and circadian rhythm dysfunction in patients with CdLS(Table 1). Two questions related to insomnia and circadian rhythmdisorders were evaluated on a likert scale with possible responsesof ‘‘never’’, ‘‘rarely’’, ‘‘occasionally’’, ‘‘often’’, or ‘‘always’’. Responsesof ‘‘occasionally’’, ‘‘often’’, or ‘‘always’’ were considered positive.Three questions evaluated specific time functions of sleepbehaviors. One question related to family history had sixcomponents with a yes/no binary response. As this survey wasnot originally intended to evaluate for circadian rhythm disorders,there were a limited questions that specifically addressed theirlikelihood except for those items related to family history. Resultswere compared to the general population. In addition, results foradults and children with CdLS were reported separately.

2.1. Statistical analysis

Descriptive statistics were carried out to examine thedistribution of measurement values. The unpaired t test withWelch correction was used for evaluation of differences betweenchildren and adults. The Fisher’s exact test was used to comparethe risk of insomnia in CdLS versus literature normative values forthe general population [7]. p values of <0.05 was consideredsignificant. Data was analyzed using Stata Statistical Software:Release 10.1 (Stata Corporation, College Station, TX).

3. Results

The mean age of patients was 14.5 years (range 0.6–37 years), ofwhom 19 were children (<18 years) and 12 were adults. Forchildren with CdLS, difficulty was reported in falling asleep (9/19,47%) and staying asleep (10/19, 53%) (Fig. 1). In the adults, 4/10

ies in children with CdLS.

Fig. 2. Reported sleep difficulties in adults with CdLS.

R. Rajan et al. / International Journal of Pediatric Otorhinolaryngology 76 (2012) 972–975974

(40%) reported difficulty falling asleep, and 4/10 (40%) reporteddifficulty staying asleep (Fig. 2).

The average time for sleep onset is 15–20 min as previouslyreported in a population without intellectual disability [7]. Forchildren with CdLS in the current study, the average time to sleeponset was 27.0 min, but this increased to 37.8 min (range 15–67 min) for those children who admitted to at least occasionalsleep onset insomnia (9 children).

Comparison between children and adults with CdLS of time tosleep onset, number of awakenings, and length of time awake atnight is shown in Table 2. The average time to fall back to sleeponce awake was 61.8 min (range 0–245 min) in the pediatricpopulation. Comparatively, in the adult population, this numberwas 14.9 min (range 2–30 min).

A family history of circadian rhythm disorders was alsoprevalent. A maternal family history of either a ‘‘lark’’ or ‘‘nightowl’’ was present in 15 of 29 participants (52%) (9 larks and 6 nightowls). 17/29 (59%) had a positive paternal family history (11 larks/6 night owls).

4. Discussion

This report is the first to describe insomnia and circadianrhythm dysfunction in a cohort of children and adults with CdLS. Inthe current study, over 50% of children and 30% of adults werefound to have difficulty in either initiating or maintaining sleep.This finding suggests that insomnia is more prevalent in peoplewith CdLS than in the general U.S. population. In addition, the

Table 2Child and adult CdLS patient sleep pattern data.

Number

Difficulty falling asleep

Difficulty staying asleep

Average sleep onset

Average sleep onset in those with occasional sleep onset insomnia

Average number of awakenings

Average number of awakenings in those with occasional sleep maintenance insomni

Average time to fall back asleep once awake

a Note: Two patients did not fill out these particular questions.

extended time to sleep onset in CdLS patients also suggests thatcircadian delays may play a role in the sleep disturbance previouslyreported in this population. Findings in this study also suggestthere may be improvement in insomnia symptoms with age, as thetime to sleep onset, the number of awakenings, and the time to fallback asleep once awake were all in the normal range in the adultpopulation, yet grossly elevated in the pediatric CdLS population.

Little research has been completed investigating the role ofobstructive sleep apnea (OSA) in adults or children with CdLS;although, it is commonly noted that many individuals with CdLSdisplay problems related to sleep [1,3]. Hall et al. determined that55–72% of individuals with CdLS display problems related to sleep[3]. Stavinoha et al. used an OSA18 questionnaire to screen forsleep disordered breathing (SDB) symptoms in patients with CdLSwith a score of 60 or greater suggesting the presence of moderateto severe OSA. In the study, 36% of CdLS participants had OSA18scores suggestive of moderate to severe OSA, much higher than theestimated 4% of the general population with OSA [8]. Earlyevidence supports the fact that individuals with CdLS may have ahigher prevalence of OSA than the general population althoughfurther study is necessary to draw significant conclusions.

Sleep disturbance has been increasingly described in patientswith CdLS. Berney et al. surveyed families or caregivers of 49children and adults with CdLS [9]. The level of intellectualdisability in this study ranged from mild to severe. Compositeresults were reported regarding positive responses to the presenceof one or more of the following: irregular sleep patterns, insomnia,interrupted sleep or excessive daytime sleepiness. At least one

Children Adults

19 12

9/19 (47%) 4/10 (40%)a

10/19 (52%) 4/10 (40%)a

27 min (p = 0.15) 16.8 min (p = 0.15)

36.6 min

Range: 15–67 min

31.6 min

Range: 15–60 min

1.5 times/night

Range: 0–4 times/night

0.7 times/night

Range: 0–2 times/night

a 2.0 times/night 1.5 times/night

61.8 min

Range: 0–245 min

14.9 min

Range: 2–50 min

R. Rajan et al. / International Journal of Pediatric Otorhinolaryngology 76 (2012) 972–975 975

positive response was seen in 55% of those surveyed, while 25% ofpatients, all with severe intellectual disability, had at least threesleep disturbances simultaneously. An additional study by Hallet al. found similar levels of sleep disturbance [3]; however, neitherhas reported symptom-specific data, making it difficult tocharacterize the prevalence of insomnia or circadian rhythmdisorders in this cohort.

A 2007 study by Kline et al. of 74 participants with CdLS, 62% ofwhom were children (<18 years), did report some specificsymptoms. In this report, 51% had difficulty in sleep initiation,65% had difficulty maintaining sleep, and 30% had consecutive dayswithout sleep. In contrast to the current study, Kline et al. foundthat the likelihood of sleep disturbance increased with increasingage [10].

The attribution of sleep disturbance to an underlying circadianrhythm disorder also has treatment implications. In SMS, forexample, there is anecdotal evidence which suggests thatnocturnal oral melatonin supplementation may improve sleepdisturbances [6]. In addition, there is significant evidence tosupport that exogenous melatonin has significant circadian phaseshifting properties in people without intellectual disability [11].Even more powerful than melatonin administration, phototherapyis widely used to advance or delay sleep–wake cycles successfully[12]. In addition, strict sleep hygiene has also been helpful in thetreatment of circadian rhythm disorders. Further study to confirmthe role of circadian rhythm disorders and investigate possibletreatment options may help to better understand sleep distur-bance in both SMS and CdLS.

This study had several limitations. First, the sample size ofpatients with CdLS was small. In addition, the voluntary nature ofthe questionnaire format allows for selection bias, as doescollection at a national meeting of patients with CdLS. Mostimportantly, the included sleep questionnaires were not allspecifically formulated to investigate the contribution of insomniaor circadian rhythm disorders to sleep disturbance in thispopulation. In order to address these issues, we suggest that astudy with questions focused specifically on insomnia andcircadian rhythm issues be carried out in a larger population.Ideally, this cohort would also undergo an objective assessment of

sleep including sleep logs, actigraphy, and an objective measure ofmovement that correlates well with sleep–wake cycles.

5. Conclusion

In this cohort, symptoms suggestive of insomnia or circadianrhythm disorders were reported in 30% of adults and 50% ofchildren with CdLS; rates higher than reported in the generalpopulation. The signs and symptoms were less common and lesssevere in adults than in children, although this difference was notsignificant. A larger sample size would be needed to investigatewhether there may be some improvement of sleep behavior overtime. Further studies are needed to better characterize sleepdisturbance in this population, and would ideally include the use oftools such as sleep logs, focused questionnaires and actigraphy.

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