Accepted Manuscript Title: 22q11.2 Deletion Syndrome and Obstructive Sleep Apnea Author: William P. Kennedy Pamela A. Mudd Meg A. Maguire Margaret C. Souders Donna M. McDonald-McGinn Carole L. Marcus Elaine H. Zackai Cynthia B. Solot Thornton B.Alexander Mason Oksana A. Jackson Lisa M. Elden PII: DOI: Reference:
S0165-5876(14)00316-4 http://dx.doi.org/doi:10.1016/j.ijporl.2014.05.031 PEDOT 7150
To appear in:
International Journal of Pediatric Otorhinolaryngology
Received date: Revised date: Accepted date:
2-3-2014 23-5-2014 25-5-2014
Please cite this article as: William P.Kennedy, Pamela A.Mudd, Meg A.Maguire, Margaret C.Souders, Donna M.McDonald-McGinn, Carole L.Marcus, Elaine H.Zackai, Cynthia B.Solot, Thornton B.Alexander Mason, Oksana A.Jackson, Lisa M.Elden, 22q11.2 Deletion Syndrome and Obstructive Sleep Apnea, International Journal of Pediatric Otorhinolaryngology http://dx.doi.org/10.1016/j.ijporl.2014.05.031 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
22q11.2 Deletion Syndrome and Obstructive Sleep Apnea
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William P. Kennedyi, Pamela A. Mudda, Meg A. Maguireii, Margaret C. Soudersiii, Donna M. McDonald-McGinnc, Carole L. Marcusiv, Elaine H. Zackaic, Cynthia B. Solotb, Thornton B. Alexander Masonv, Oksana A. Jacksonb, Lisa M. Eldena
Corresponding Author:
an
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William Kennedy Division of Otolaryngology The Children’s Hospital of Philadelphia 34th Street and Civic Center Boulevard 1 Wood Center Philadelphia, PA 19104 (215) 590-3440 [email protected]
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22q11.2 Deletion Syndrome and Obstructive Sleep Apnea William P. Kennedy, Pamela A. Mudd, Meg A. Maguire, Margaret C. Souders, Donna M. McDonald-McGinn, Carole L. Marcus, Elaine H. Zackai, Cynthia B. Solot, Thornton B. Alexander Mason, Oksana A. Jackson, Lisa M. Elden
Ac ce pt e
Abstract Otolaryngologic problems are common in the 22q11.2 deletion syndrome (DS) population. Structural anomalies and retrognathia may predispose these patients to obstructive sleep apnea (OSA). The current association of OSA in this population is not defined. Objective: 1) Define the frequency of OSA in 22q11.2 DS patients referred for polysomnography (PSG) 2) Determine if OSA is present before and/or after surgery to correct velopharyngeal insufficiency (VPI) 3) Determine effect of prior adenotonsillectomy on OSA following VPI surgery.
Methods: Retrospective review of children treated from 2006-2013 in a tertiary care setting identified by ICD-9 758.32 (velocardiofacial syndrome) and 279.11 (DiGeorge syndrome). Surgical history and PSG data were abstracted from the identified records.
Page 1 of 13
Results: We identified 323 patients with 22q11.2DS; 57 (18%) were screened at any point in care using PSG and 15 patients had PSG at multiple time points in care. In most cases, indication for PSG was sleep disordered breathing or pre-operative planning. Overall, thirty-
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three patients met criteria for OSA on PSG, accounting for 10.2% of our study population; however, the percentage of patients with OSA was significantly higher within the group of 57
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patients (58%) who were screened with PSG.
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Twenty-one of the screened patients (54%) had PSG prior to any pharyngeal surgery and had mild to severe OSA (obstructive apnea/hypopnea index (AHI): median 5.1/hr, range 1.9-
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25.6). Eighteen patients had PSG after adenotonsillectomy; 8 of these patients (44%) had mild to moderate OSA (median AHI 2.95/hr, range 1.9-5.4). Seventeen patients had PSG after VPI
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surgery (palatopharyngeal flap (PPF) n=16, sphincteroplasty n=1). 9 of these patients (53%) had mild to severe OSA (median AHI 3/hr, range 1.9-15). Patients who underwent
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adenotonsillectomy prior to VPI surgery had similar prevalence of OSA (50%, n=12) than those
Ac ce pt e
who did not (OSA: 60%, n=5, p=0.70). Most children had mild OSA. Conclusion: Prevalence of OSA in this population of 22q11.2 DS patients is higher than expected in the general population. OSA risk is highest after VPI surgery, and may be decreased by adenotonsillectomy. Providers should have awareness of increased prevalence of OSA in patients with 22q11.2 DS. Close monitoring for OSA is warranted given the likelihood of subsequent surgical intervention that can worsen OSA.
Keywords: 22q11.2 Deletion Syndrome; velocardiofacial syndrome; DiGeorge syndrome; obstructive sleep apnea; velopharyngeal insufficiency
Page 2 of 13
1. Introduction: 22q11.2 deletion syndrome (DS) occurs in approximately 1 in 4000 live births and is identified in most patients with DiGeorge, velocardiofacial, and conotruncal anomaly face
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syndromes [1]. In addition to the characteristic pattern of conotruncal cardiac anomalies, a significant number of common otolaryngologic problems are found within these syndromes [2].
cr
Patients with 22q11.2 DS present with structural anomalies including retrognathia [3], which
us
may predispose them to obstructive sleep apnea (OSA) [4, 5, 6]. The prevalence of OSA in this population has not previously been studied.
an
The majority of 22q11.2 DS patients have palatal anomalies, including palatal clefting and velopharyngeal insufficiency (VPI) in the absence of overt or submucous cleft palate [2, 7].
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Previous literature suggests that up to 37% of patients with cleft palate require surgery to correct VPI [8], generally through pharyngeal flap surgery or sphincter pharyngoplasty. Surgery to
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correct VPI carries a risk of causing or exacerbating OSA due to alteration of the naso/oro-
Ac ce pt e
pharynx which carries a potential for airway compromise [9]. In the 22q11.2 DS population, a wide posterior pharyngeal flap is often necessary due to the craniofacial dimensions and severity of the velopharyngeal dysfunction. Given the increased risk of OSA, some VPI treatment paradigms recommend that adenotonsillectomy be performed prior to pharyngeal flap surgery in order to minimize incidence of OSA postoperatively [10]. Little is known about OSA in the 22q11.2 DS population, with only one case report describing a child with 22q11.2 DS with both obstructive and central sleep apnea. Tonsillectomy benefited the patient by decreasing her respiratory disturbance index and improving nadir oxygen saturation [11]. It is well established that adenotonsillectomy is effective in treating OSA in
Page 3 of 13
nonsyndromic patients [12]. Surgeons may be reluctant to perform adenotonsillectomy in patients with 22q11.2 DS as adenotonsillectomy has been shown to uncover or worsen VPI [13]. It is important to define the baseline frequency of OSA in in 22q11.2 DS patients since
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many 22q11.2 DS patients have VPI and corrective surgery may cause or worsen OSA [14]. The current study sought to determine the prevalence of OSA in 22q11.2 DS patients referred for
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polysomnography (PSG) through a retrospective review of patients treated at the Children’s
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Hospital of Philadelphia (CHOP) from 2006 to 2013. Secondary objectives evaluated presence of OSA before and/or after surgery to correct VPI, and the effect of adenotonsillectomy on OSA in
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this patient population. 2. Methods:
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After institutional review board approval was obtained, we conducted a retrospective chart review of consecutive patients seen between January 1, 2006 and July 1, 2013 at CHOP.
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Consent was waived for this retrospective study. Potential cases were identified by querying
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billing records for International Classification of Diseases, Ninth Revision (ICD-9) codes 758.32 (velocardiofacial syndrome) and 279.11 (DiGeorge syndrome). Inclusion criteria were male or female patients up to age 18 with documented 22q11.2 DS who were evaluated at CHOP. The following data were collected from patient medical records: age, gender, diagnosis, surgical history, Pediatric Sleep Questionnaire (PSQ) [15] scores, and PSG dates and results, including obstructive apnea hypopnea index (AHI), nadir oxygen saturation, and peak end-tidal CO2. PSG was performed and scored using American Academy of Sleep Medicine pediatric criteria [16]. PSG results were categorized by time point in care using the following designations: pre-surgical intervention, post-adenotonsillectomy, or post-surgical intervention for VPI. Surgical interventions for VPI were defined as posterior pharyngeal flap (PPF) surgery or sphincter
Page 4 of 13
pharyngoplasty. OSA was defined as AHI ≥ 1.5 [17, 18]. Statistical significance was evaluated using a Kruskal-Wallis test for comparison of AHIs between pre-intervention, postadenotonsillectomy, and post-VPI surgery cohorts. The Wilcoxon rank-sum test was used to
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evaluate the effect of prior adenotonsillectomy on OSA following VPI surgery. In both cases, a p value < 0.05 was considered significant.
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3. Results:
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The search of billing records for the diagnosis of velocardiofacial syndrome or DiGeorge syndrome yielded 323 total patients, of whom 57 (18%) were screened at any point in care using
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PSG. Table 1 shows the demographic and clinical characteristics of the screened population. In the cohort of patients not included in the study who had 22q11.2DS but were not screened with
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PSG (n=266), 40 (15%) had either adenotonsillectomy or adenoidectomy, 44 (17%) had palate surgery for VPI (38 PPF and 6 cleft palate repairs) and, 16 of the patients that had surgery for
Ac ce pt e
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VPI (all PPF) had prior adenotonsillectomy or adenoid surgery. Of our studied cohort of patients who had 22q11.2DS and were screened with PSG (n=57), 32(56%) had either adenotonsillectomy or adenoidectomy, 22 (38.6%) had palate surgery for VPI (all PPF) and, 16 patients that had PPF had prior adenotonsillectomy or adenoid surgery. Twenty of the patients (35%) had completed a sleep questionnaire (PSQ). PSQ results did not correlate with AHI.
Fifteen (26%) of the patients screened received PSGs at multiple time points in care, and only two were screened at all three time points in care—prior to any pharyngeal surgery, after adenotonsillectomy, and after VPI surgery. Of the 57 patients screened by PSG, 33 (58%) met diagnostic criteria for OSA at some point in care (median AHI 4.2/hr, range 1.9-25.6).
Page 5 of 13
Overall, 39 (53%) of the screened patients had PSG prior to any pharyngeal surgery (preintervention). Indication for PSG was most often to evaluate sleep disordered breathing (n=31), but also included preoperative planning for PPF surgery (n=6). Indication for PSG was
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unavailable for 2 patients. Of this group, 21 (54%) had mild to severe OSA with a median AHI of 5.1/hr (range, 1.9-25.6) (Figure 1). The median nadir oxygen saturation for the patients with
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OSA was 86% (range, 67%-92%) and median peak end-tidal CO2 was 54 mm Hg (range 41-62).
case, VPI surgery was performed despite OSA (Figure 2).
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Patients with OSA from this cohort were managed with adenotonsillectomy or CPAP. In one
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Eighteen (32%) of the patients screened, including 7 from the pre-intervention cohort, had a PSG post-adenotonsillectomy. Indication for PSG was to evaluate sleep disordered
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breathing (n=5), preoperative evaluation for PPF (n=5), or postoperative evaluation of adenotonsillectomy efficacy (n=5). Indication was not available for 3 patients. Eight patients
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(44%) in this group had OSA with a median AHI of 3/hr (range 1.9-5.4) (Figure 1). The median
Ac ce pt e
nadir oxygen saturation for the patients with OSA was 88% (range, 75%-91%) and median peak end-tidal CO2 was 52 mm Hg (range 40-69). Subsequent interventions for patients with OSA following adenotonsillectomy were revision adenotonsillectomy, management with continuous positive airway pressure (CPAP). VPI surgery was performed in 4 patients despite OSA (Figure 3).
Seventeen patients (23%) of the screened cohort had a PSG following VPI surgery (PPF n=16, sphincteroplasty n=1). Indication for PSG was for sleep disordered breathing (n=7), or for post-surgical evaluation (n=9). Indication was unavailable for one patient. Of these, 9 (53%) had OSA with a median AHI of 3/hr (range 1.9-15) (Figure 1). Median nadir oxygen saturation for patients with OSA was 88% (range 86%-90%) and median peak end-tidal CO2 was 53 mm Hg
Page 6 of 13
(range 45-59). Patients with OSA from this cohort were managed with either PPF revision, CPAP, or had mild OSA which was not considered clinically significant (Figure 4). Comparison of AHIs for patients with OSA in each cohort revealed borderline significant
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differences between cohorts (p=0.057), with greatest severity in the pre-intervention cohort. PSG results from the post-VPI surgery cohort were subcategorized based on history of previous
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adenotonsillectomy. Patients who underwent adenotonsillectomy prior to VPI surgery had
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prevalence of OSA (50%, n=12) similar to those who did not undergo adenotonsillectomy (OSA: 60%, n=5)(Figure 5). There was no significant difference in severity of OSA between patients
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with prior adenotonsillectomy (n=6, median AHI=3.3, range 1.9-15) and those without prior adenotonsillectomy (n=3, median AHI=2.2, range 1.9-3, p=0.70).
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4. Discussion:
In this paper, we have shown that OSA is common in the 22q11.2 DS population. We
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have also examined AHI trends as they relate to point of intervention. The prevalence of OSA
Ac ce pt e
among all 22q11.2 DS patients screened by PSG was 58% and prevalence was relatively consistent at each PSG time-point—pre-intervention, post-adenotonsillectomy, and post-VPI surgery. It is difficult to assess OSA prevalence within the larger 22q11.2 DS population, as there was selection bias in which patients were referred for PSG. However, 33 of the 323 patients with a diagnosis of 22q11.2 DS had OSA confirmed by PSG. The prevalence of OSA observed in this study (10.2%) far exceeds the prevalence of OSA in the general pediatric population (13%) [19, 20], suggesting that children with 22q11.2 DS have a higher risk of developing OSA than other nonsyndromic children. Thus, identification and treatment of OSA in the 22q11.2 DS population may impact this group more positively than otherwise healthy children because
Page 7 of 13
22q11.2DS patients are more likely to have baseline abnormalities in cardiovascular and neuropsychological function which may be exacerbated by OSA [21, 22]. Prevalence of OSA remained relatively consistent across each point in care, but severity
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of OSA varied substantially. Median AHI was highest in the pre-intervention group and was lowest in the post-adenotonsillectomy group, with borderline significance (p=0.057) detected
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between the three cohorts. Additionally, the range of AHI was broadest in the pre-intervention
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cohort, suggesting that this group is more likely to have more severe OSA. Adenotonsillectomy has been found to be effective in treating OSA in the broader cleft palate population [23], which
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is consistent with our data. In patients with PSG following VPI surgery, median AHI was higher than in the post-adenotonsillectomy cohort, but was not as high as the pre-intervention cohort.
following pharyngeal flap surgery [24].
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These data are consistent with studies that found increases in AHI in nonsyndromic children
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Within the time period of the studied population an attempt to standardize pre-operative
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and post-operative work-up for VPI surgery was being developed in response to the suspected heightened prevalence of OSA in this population. At this time, all patients who are to undergo VPI surgery have a screening and post-operative PSG. Patients are referred for adenotonsillectomy if there is OSA as well as if there is tonsillar hypertrophy that would impact the success of PPF surgery.
The use of a screening tool, such as the PSQ may aid providers in the discussion of symptoms suggestive of OSA. The PSQ is utilized in our center as part of the patient intake in the multidisciplinary VPI clinic to screen for symptoms of OSA such as snoring and witnessed apnea. In general if there is a score of >8 the patients are referred for PSG.
However, the sleep
questionnaire results did not correlate with AHI results on those patients who had PSG. It is
Page 8 of 13
recommended that all children undergo routine screening for frequent snoring (>3x/week) [25]. Providers should have a low threshold for further evaluation either through PSG or referral to a sleep specialist or otolaryngologist given the increased prevalence of OSA in the 22q11.2DS
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population. There are several limitations to the conclusions of our study. First, this was a
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retrospective study with limited longitudinal data, making it difficult to assess OSA severity
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sequentially throughout time points in treatment. Also, there were relatively few patients in each cohort, and the study may have been underpowered. Future prospective analysis with more
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subjects may reveal significant differences in AHI between groups. 5. Conclusions:
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This study is one of the first to provide information regarding the prevalence of OSA in 22q11.2 DS patients and confirms that it is higher than expected in the general population.
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Providers should have awareness of increased prevalence of OSA in patients with 22q11.2 DS.
Ac ce pt e
Close monitoring for OSA is warranted given the underlying structural anomalies and hypotonia that predispose them to OSA and the likelihood of subsequent surgical intervention that can worsen OSA.
6. Acknowledgements:
We thank Rachel S. Hammond, MS for her assistance with biostatistics.
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References 1. Botto LD, May K, Fernhoff PM, et al. A population-based study of the 22q11.2 deletion: Phenotype, incidence, and contribution to major birth defects in the population. Pediatrics.
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2003;112(1 Pt 1):101-107.
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2. Dyce O, McDonald-McGinn D, Kirschner RE, Zackai E, Young K, Jacobs IN.
Otolaryngologic manifestations of the 22q11.2 deletion syndrome. Arch Otolaryngol Head Neck
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Surg. 2002;128(12):1408-1412.
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3. Robin NH, Shprintzen RJ. Defining the clinical spectrum of deletion 22q11.2. J Pediatr.
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2005;147(1):90-96.
4. Rose E, Staats R, Thissen U, Otten JE, Schmelzeisen R, Jonas I. Sleep-related obstructive
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2002;110(2):392-396.
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disordered breathing in cleft palate patients after palatoplasty. Plast Reconstr Surg.
5. Guilleminault C, Pelayo R, Leger D, Clerk A, Bocian RC. Recognition of sleep-disordered breathing in children. Pediatrics. 1996;98(5):871-882.
6. Dempsey JA, Veasey SC, Morgan BJ, O'Donnell CP. Pathophysiology of sleep apnea. Physiol Rev. 2010;90(1):47-112.
7. Shprintzen RJ. Velocardiofacial syndrome. Otolaryngol Clin North Am. 2000;33(6):1217-40, vi.
8. Timmons MJ, Wyatt RA, Murphy T. Speech after repair of isolated cleft palate and cleft lip and palate. Br J Plast Surg. 2001;54(5):377-384.
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9. Shprintzen RJ. Pharyngeal flap surgery and the pediatric upper airway. Int Anesthesiol Clin. 1988;26(1):79-88.
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10. Chegar BE, Shprintzen RJ, Curtis MS, Tatum SA. Pharyngeal flap and obstructive apnea: Maximizing speech outcome while limiting complications. Arch Facial Plast Surg.
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2007;9(4):252-259.
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11. Heike CL, Avellino AM, Mirza SK, et al. Sleep disturbances in 22q11.2 deletion syndrome: A case with obstructive and central sleep apnea. Cleft Palate Craniofac J. 2007;44(3):340-346.
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12. Bhattacharjee R, Kheirandish-Gozal L, Spruyt K, et al. Adenotonsillectomy outcomes in
Crit Care Med. 2010;182(5):676-683.
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treatment of obstructive sleep apnea in children: A multicenter retrospective study. Am J Respir
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13. Milczuk HA. Effects of oropharyngeal surgery on velopharyngeal competence. Curr Opin
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Otolaryngol Head Neck Surg. 2012;20(6):522-526.
14. McDonald-McGinn DM, Kirschner R, Goldmuntz E, et al. The Philadelphia story: the 22q11.2 deletion: report on 250 patients. Genet Couns. 1999;10:11–24.
15. Chervin RD, Hedger K, Dillon JE, Pituch KJ. Pediatric sleep questionnaire (PSQ): Validity and reliability of scales for sleep-disordered breathing, snoring, sleepiness, and behavioral problems. Sleep Med. 2000;1(1):21-32.
16. The AASM Manual for the Scoring of Sleep and Associated Events: Rules, Terminology and Technical Specification. Iber C, editor. 2007. American Academy of Sleep Medicine.
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17. Marcus CL, Omlin KJ, Basinki DJ, et al. Normal polysomnographic values for children and adolescents. Am Rev Respir Dis 1992;146:1235-9.
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18. Witmans MB, Keens TG, Davidson Ward SL, Marcus CL. Obstructive hypopneas in children
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and adolescents: normal values. Am J Respir Crit Care Med 2003; 168:1540.
19. Ali NJ, Pitson DJ, Stradling JR. Snoring, sleep disturbance, and behaviour in 4-5 year olds.
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Arch Dis Child. 1993;68:360-366.
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20. Gislason T, Benediktsdottir B. Snoring, apneic episodes, and nocturnal hypoxemia among children 6 months to 6 years old. An epidemiologic study of lower limit of prevalence. Chest.
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1995;107:963-966.
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Cardiol. 2011;26(6):541-547.
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21. Monahan K, Redline S. Role of obstructive sleep apnea in cardiovascular disease. Curr Opin
22. Capdevila OS, Kheirandish-Gozal L, Dayyat E, Gozal D. Pediatric obstructive sleep apnea: Complications, management, and long-term outcomes. Proc Am Thorac Soc. 2008;5(2):274-282.
23. Muntz H, Wilson M, Park A, Smith M, Grimmer JF. Sleep disordered breathing and obstructive sleep apnea in the cleft population. Laryngoscope. 2008;118(2):348-353.
24. Griner D, Sargent LA, Overmeyer CL. Changes in airflow dynamics after creation of pharyngeal flaps in nonsyndromic children. Ann Plast Surg. 2013;70(5):517-520.
25. Marcus, Carole L., et al. "Diagnosis and management of childhood obstructive sleep apnea syndrome." Pediatrics 130.3 (2012): e714-e755.
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Clinical Characteristics of Screened Patients (n=57) 25 (43.9%) Male sex 6.4 (0.8-15.9) Age at First PSG (years) 15 (26.3%) Number of Patients with Multiple PSGs 74 Number of PSGs Number of Patients who had PSG at Various Time Points Pre-intervention 39 (52.7%) Post-T&A 18 (24.3%) Post-VPI Surgery 17 (23.0%) 33 (58%) Number of patients who had OSA on any PSG
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Data displayed as N (%) or median (range)
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Table 1. Clinical characteristics of screened patients.
Division of Otolaryngology, Children’s Hospital of Philadelphia, Philadelphia, PA, United States Division of Plastic Surgery, Children’s Hospital of Philadelphia, Philadelphia, PA, United States iii Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, United States iv Division of Pulmonary Medicine, The Children’s Hospital of Philadelphia, Philadelphia, PA, United States v Division of Neurology, The Children’s Hospital of Philadelphia, Philadelphia, PA, United States ii
Page 13 of 13
S0165-5876(14)00316-4 http://dx.doi.org/doi:10.1016/j.ijporl.2014.05.031 PEDOT 7150
To appear in:
International Journal of Pediatric Otorhinolaryngology
Received date: Revised date: Accepted date:
2-3-2014 23-5-2014 25-5-2014
Please cite this article as: William P.Kennedy, Pamela A.Mudd, Meg A.Maguire, Margaret C.Souders, Donna M.McDonald-McGinn, Carole L.Marcus, Elaine H.Zackai, Cynthia B.Solot, Thornton B.Alexander Mason, Oksana A.Jackson, Lisa M.Elden, 22q11.2 Deletion Syndrome and Obstructive Sleep Apnea, International Journal of Pediatric Otorhinolaryngology http://dx.doi.org/10.1016/j.ijporl.2014.05.031 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
22q11.2 Deletion Syndrome and Obstructive Sleep Apnea
ip t
William P. Kennedyi, Pamela A. Mudda, Meg A. Maguireii, Margaret C. Soudersiii, Donna M. McDonald-McGinnc, Carole L. Marcusiv, Elaine H. Zackaic, Cynthia B. Solotb, Thornton B. Alexander Masonv, Oksana A. Jacksonb, Lisa M. Eldena
Corresponding Author:
an
us
cr
William Kennedy Division of Otolaryngology The Children’s Hospital of Philadelphia 34th Street and Civic Center Boulevard 1 Wood Center Philadelphia, PA 19104 (215) 590-3440 [email protected]
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22q11.2 Deletion Syndrome and Obstructive Sleep Apnea William P. Kennedy, Pamela A. Mudd, Meg A. Maguire, Margaret C. Souders, Donna M. McDonald-McGinn, Carole L. Marcus, Elaine H. Zackai, Cynthia B. Solot, Thornton B. Alexander Mason, Oksana A. Jackson, Lisa M. Elden
Ac ce pt e
Abstract Otolaryngologic problems are common in the 22q11.2 deletion syndrome (DS) population. Structural anomalies and retrognathia may predispose these patients to obstructive sleep apnea (OSA). The current association of OSA in this population is not defined. Objective: 1) Define the frequency of OSA in 22q11.2 DS patients referred for polysomnography (PSG) 2) Determine if OSA is present before and/or after surgery to correct velopharyngeal insufficiency (VPI) 3) Determine effect of prior adenotonsillectomy on OSA following VPI surgery.
Methods: Retrospective review of children treated from 2006-2013 in a tertiary care setting identified by ICD-9 758.32 (velocardiofacial syndrome) and 279.11 (DiGeorge syndrome). Surgical history and PSG data were abstracted from the identified records.
Page 1 of 13
Results: We identified 323 patients with 22q11.2DS; 57 (18%) were screened at any point in care using PSG and 15 patients had PSG at multiple time points in care. In most cases, indication for PSG was sleep disordered breathing or pre-operative planning. Overall, thirty-
ip t
three patients met criteria for OSA on PSG, accounting for 10.2% of our study population; however, the percentage of patients with OSA was significantly higher within the group of 57
cr
patients (58%) who were screened with PSG.
us
Twenty-one of the screened patients (54%) had PSG prior to any pharyngeal surgery and had mild to severe OSA (obstructive apnea/hypopnea index (AHI): median 5.1/hr, range 1.9-
an
25.6). Eighteen patients had PSG after adenotonsillectomy; 8 of these patients (44%) had mild to moderate OSA (median AHI 2.95/hr, range 1.9-5.4). Seventeen patients had PSG after VPI
M
surgery (palatopharyngeal flap (PPF) n=16, sphincteroplasty n=1). 9 of these patients (53%) had mild to severe OSA (median AHI 3/hr, range 1.9-15). Patients who underwent
d
adenotonsillectomy prior to VPI surgery had similar prevalence of OSA (50%, n=12) than those
Ac ce pt e
who did not (OSA: 60%, n=5, p=0.70). Most children had mild OSA. Conclusion: Prevalence of OSA in this population of 22q11.2 DS patients is higher than expected in the general population. OSA risk is highest after VPI surgery, and may be decreased by adenotonsillectomy. Providers should have awareness of increased prevalence of OSA in patients with 22q11.2 DS. Close monitoring for OSA is warranted given the likelihood of subsequent surgical intervention that can worsen OSA.
Keywords: 22q11.2 Deletion Syndrome; velocardiofacial syndrome; DiGeorge syndrome; obstructive sleep apnea; velopharyngeal insufficiency
Page 2 of 13
1. Introduction: 22q11.2 deletion syndrome (DS) occurs in approximately 1 in 4000 live births and is identified in most patients with DiGeorge, velocardiofacial, and conotruncal anomaly face
ip t
syndromes [1]. In addition to the characteristic pattern of conotruncal cardiac anomalies, a significant number of common otolaryngologic problems are found within these syndromes [2].
cr
Patients with 22q11.2 DS present with structural anomalies including retrognathia [3], which
us
may predispose them to obstructive sleep apnea (OSA) [4, 5, 6]. The prevalence of OSA in this population has not previously been studied.
an
The majority of 22q11.2 DS patients have palatal anomalies, including palatal clefting and velopharyngeal insufficiency (VPI) in the absence of overt or submucous cleft palate [2, 7].
M
Previous literature suggests that up to 37% of patients with cleft palate require surgery to correct VPI [8], generally through pharyngeal flap surgery or sphincter pharyngoplasty. Surgery to
d
correct VPI carries a risk of causing or exacerbating OSA due to alteration of the naso/oro-
Ac ce pt e
pharynx which carries a potential for airway compromise [9]. In the 22q11.2 DS population, a wide posterior pharyngeal flap is often necessary due to the craniofacial dimensions and severity of the velopharyngeal dysfunction. Given the increased risk of OSA, some VPI treatment paradigms recommend that adenotonsillectomy be performed prior to pharyngeal flap surgery in order to minimize incidence of OSA postoperatively [10]. Little is known about OSA in the 22q11.2 DS population, with only one case report describing a child with 22q11.2 DS with both obstructive and central sleep apnea. Tonsillectomy benefited the patient by decreasing her respiratory disturbance index and improving nadir oxygen saturation [11]. It is well established that adenotonsillectomy is effective in treating OSA in
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nonsyndromic patients [12]. Surgeons may be reluctant to perform adenotonsillectomy in patients with 22q11.2 DS as adenotonsillectomy has been shown to uncover or worsen VPI [13]. It is important to define the baseline frequency of OSA in in 22q11.2 DS patients since
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many 22q11.2 DS patients have VPI and corrective surgery may cause or worsen OSA [14]. The current study sought to determine the prevalence of OSA in 22q11.2 DS patients referred for
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polysomnography (PSG) through a retrospective review of patients treated at the Children’s
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Hospital of Philadelphia (CHOP) from 2006 to 2013. Secondary objectives evaluated presence of OSA before and/or after surgery to correct VPI, and the effect of adenotonsillectomy on OSA in
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this patient population. 2. Methods:
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After institutional review board approval was obtained, we conducted a retrospective chart review of consecutive patients seen between January 1, 2006 and July 1, 2013 at CHOP.
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Consent was waived for this retrospective study. Potential cases were identified by querying
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billing records for International Classification of Diseases, Ninth Revision (ICD-9) codes 758.32 (velocardiofacial syndrome) and 279.11 (DiGeorge syndrome). Inclusion criteria were male or female patients up to age 18 with documented 22q11.2 DS who were evaluated at CHOP. The following data were collected from patient medical records: age, gender, diagnosis, surgical history, Pediatric Sleep Questionnaire (PSQ) [15] scores, and PSG dates and results, including obstructive apnea hypopnea index (AHI), nadir oxygen saturation, and peak end-tidal CO2. PSG was performed and scored using American Academy of Sleep Medicine pediatric criteria [16]. PSG results were categorized by time point in care using the following designations: pre-surgical intervention, post-adenotonsillectomy, or post-surgical intervention for VPI. Surgical interventions for VPI were defined as posterior pharyngeal flap (PPF) surgery or sphincter
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pharyngoplasty. OSA was defined as AHI ≥ 1.5 [17, 18]. Statistical significance was evaluated using a Kruskal-Wallis test for comparison of AHIs between pre-intervention, postadenotonsillectomy, and post-VPI surgery cohorts. The Wilcoxon rank-sum test was used to
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evaluate the effect of prior adenotonsillectomy on OSA following VPI surgery. In both cases, a p value < 0.05 was considered significant.
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3. Results:
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The search of billing records for the diagnosis of velocardiofacial syndrome or DiGeorge syndrome yielded 323 total patients, of whom 57 (18%) were screened at any point in care using
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PSG. Table 1 shows the demographic and clinical characteristics of the screened population. In the cohort of patients not included in the study who had 22q11.2DS but were not screened with
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PSG (n=266), 40 (15%) had either adenotonsillectomy or adenoidectomy, 44 (17%) had palate surgery for VPI (38 PPF and 6 cleft palate repairs) and, 16 of the patients that had surgery for
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VPI (all PPF) had prior adenotonsillectomy or adenoid surgery. Of our studied cohort of patients who had 22q11.2DS and were screened with PSG (n=57), 32(56%) had either adenotonsillectomy or adenoidectomy, 22 (38.6%) had palate surgery for VPI (all PPF) and, 16 patients that had PPF had prior adenotonsillectomy or adenoid surgery. Twenty of the patients (35%) had completed a sleep questionnaire (PSQ). PSQ results did not correlate with AHI.
Fifteen (26%) of the patients screened received PSGs at multiple time points in care, and only two were screened at all three time points in care—prior to any pharyngeal surgery, after adenotonsillectomy, and after VPI surgery. Of the 57 patients screened by PSG, 33 (58%) met diagnostic criteria for OSA at some point in care (median AHI 4.2/hr, range 1.9-25.6).
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Overall, 39 (53%) of the screened patients had PSG prior to any pharyngeal surgery (preintervention). Indication for PSG was most often to evaluate sleep disordered breathing (n=31), but also included preoperative planning for PPF surgery (n=6). Indication for PSG was
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unavailable for 2 patients. Of this group, 21 (54%) had mild to severe OSA with a median AHI of 5.1/hr (range, 1.9-25.6) (Figure 1). The median nadir oxygen saturation for the patients with
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OSA was 86% (range, 67%-92%) and median peak end-tidal CO2 was 54 mm Hg (range 41-62).
case, VPI surgery was performed despite OSA (Figure 2).
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Patients with OSA from this cohort were managed with adenotonsillectomy or CPAP. In one
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Eighteen (32%) of the patients screened, including 7 from the pre-intervention cohort, had a PSG post-adenotonsillectomy. Indication for PSG was to evaluate sleep disordered
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breathing (n=5), preoperative evaluation for PPF (n=5), or postoperative evaluation of adenotonsillectomy efficacy (n=5). Indication was not available for 3 patients. Eight patients
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(44%) in this group had OSA with a median AHI of 3/hr (range 1.9-5.4) (Figure 1). The median
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nadir oxygen saturation for the patients with OSA was 88% (range, 75%-91%) and median peak end-tidal CO2 was 52 mm Hg (range 40-69). Subsequent interventions for patients with OSA following adenotonsillectomy were revision adenotonsillectomy, management with continuous positive airway pressure (CPAP). VPI surgery was performed in 4 patients despite OSA (Figure 3).
Seventeen patients (23%) of the screened cohort had a PSG following VPI surgery (PPF n=16, sphincteroplasty n=1). Indication for PSG was for sleep disordered breathing (n=7), or for post-surgical evaluation (n=9). Indication was unavailable for one patient. Of these, 9 (53%) had OSA with a median AHI of 3/hr (range 1.9-15) (Figure 1). Median nadir oxygen saturation for patients with OSA was 88% (range 86%-90%) and median peak end-tidal CO2 was 53 mm Hg
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(range 45-59). Patients with OSA from this cohort were managed with either PPF revision, CPAP, or had mild OSA which was not considered clinically significant (Figure 4). Comparison of AHIs for patients with OSA in each cohort revealed borderline significant
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differences between cohorts (p=0.057), with greatest severity in the pre-intervention cohort. PSG results from the post-VPI surgery cohort were subcategorized based on history of previous
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adenotonsillectomy. Patients who underwent adenotonsillectomy prior to VPI surgery had
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prevalence of OSA (50%, n=12) similar to those who did not undergo adenotonsillectomy (OSA: 60%, n=5)(Figure 5). There was no significant difference in severity of OSA between patients
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with prior adenotonsillectomy (n=6, median AHI=3.3, range 1.9-15) and those without prior adenotonsillectomy (n=3, median AHI=2.2, range 1.9-3, p=0.70).
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4. Discussion:
In this paper, we have shown that OSA is common in the 22q11.2 DS population. We
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have also examined AHI trends as they relate to point of intervention. The prevalence of OSA
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among all 22q11.2 DS patients screened by PSG was 58% and prevalence was relatively consistent at each PSG time-point—pre-intervention, post-adenotonsillectomy, and post-VPI surgery. It is difficult to assess OSA prevalence within the larger 22q11.2 DS population, as there was selection bias in which patients were referred for PSG. However, 33 of the 323 patients with a diagnosis of 22q11.2 DS had OSA confirmed by PSG. The prevalence of OSA observed in this study (10.2%) far exceeds the prevalence of OSA in the general pediatric population (13%) [19, 20], suggesting that children with 22q11.2 DS have a higher risk of developing OSA than other nonsyndromic children. Thus, identification and treatment of OSA in the 22q11.2 DS population may impact this group more positively than otherwise healthy children because
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22q11.2DS patients are more likely to have baseline abnormalities in cardiovascular and neuropsychological function which may be exacerbated by OSA [21, 22]. Prevalence of OSA remained relatively consistent across each point in care, but severity
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of OSA varied substantially. Median AHI was highest in the pre-intervention group and was lowest in the post-adenotonsillectomy group, with borderline significance (p=0.057) detected
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between the three cohorts. Additionally, the range of AHI was broadest in the pre-intervention
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cohort, suggesting that this group is more likely to have more severe OSA. Adenotonsillectomy has been found to be effective in treating OSA in the broader cleft palate population [23], which
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is consistent with our data. In patients with PSG following VPI surgery, median AHI was higher than in the post-adenotonsillectomy cohort, but was not as high as the pre-intervention cohort.
following pharyngeal flap surgery [24].
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These data are consistent with studies that found increases in AHI in nonsyndromic children
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Within the time period of the studied population an attempt to standardize pre-operative
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and post-operative work-up for VPI surgery was being developed in response to the suspected heightened prevalence of OSA in this population. At this time, all patients who are to undergo VPI surgery have a screening and post-operative PSG. Patients are referred for adenotonsillectomy if there is OSA as well as if there is tonsillar hypertrophy that would impact the success of PPF surgery.
The use of a screening tool, such as the PSQ may aid providers in the discussion of symptoms suggestive of OSA. The PSQ is utilized in our center as part of the patient intake in the multidisciplinary VPI clinic to screen for symptoms of OSA such as snoring and witnessed apnea. In general if there is a score of >8 the patients are referred for PSG.
However, the sleep
questionnaire results did not correlate with AHI results on those patients who had PSG. It is
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recommended that all children undergo routine screening for frequent snoring (>3x/week) [25]. Providers should have a low threshold for further evaluation either through PSG or referral to a sleep specialist or otolaryngologist given the increased prevalence of OSA in the 22q11.2DS
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population. There are several limitations to the conclusions of our study. First, this was a
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retrospective study with limited longitudinal data, making it difficult to assess OSA severity
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sequentially throughout time points in treatment. Also, there were relatively few patients in each cohort, and the study may have been underpowered. Future prospective analysis with more
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subjects may reveal significant differences in AHI between groups. 5. Conclusions:
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This study is one of the first to provide information regarding the prevalence of OSA in 22q11.2 DS patients and confirms that it is higher than expected in the general population.
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Providers should have awareness of increased prevalence of OSA in patients with 22q11.2 DS.
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Close monitoring for OSA is warranted given the underlying structural anomalies and hypotonia that predispose them to OSA and the likelihood of subsequent surgical intervention that can worsen OSA.
6. Acknowledgements:
We thank Rachel S. Hammond, MS for her assistance with biostatistics.
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4. Rose E, Staats R, Thissen U, Otten JE, Schmelzeisen R, Jonas I. Sleep-related obstructive
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5. Guilleminault C, Pelayo R, Leger D, Clerk A, Bocian RC. Recognition of sleep-disordered breathing in children. Pediatrics. 1996;98(5):871-882.
6. Dempsey JA, Veasey SC, Morgan BJ, O'Donnell CP. Pathophysiology of sleep apnea. Physiol Rev. 2010;90(1):47-112.
7. Shprintzen RJ. Velocardiofacial syndrome. Otolaryngol Clin North Am. 2000;33(6):1217-40, vi.
8. Timmons MJ, Wyatt RA, Murphy T. Speech after repair of isolated cleft palate and cleft lip and palate. Br J Plast Surg. 2001;54(5):377-384.
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9. Shprintzen RJ. Pharyngeal flap surgery and the pediatric upper airway. Int Anesthesiol Clin. 1988;26(1):79-88.
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treatment of obstructive sleep apnea in children: A multicenter retrospective study. Am J Respir
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15. Chervin RD, Hedger K, Dillon JE, Pituch KJ. Pediatric sleep questionnaire (PSQ): Validity and reliability of scales for sleep-disordered breathing, snoring, sleepiness, and behavioral problems. Sleep Med. 2000;1(1):21-32.
16. The AASM Manual for the Scoring of Sleep and Associated Events: Rules, Terminology and Technical Specification. Iber C, editor. 2007. American Academy of Sleep Medicine.
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17. Marcus CL, Omlin KJ, Basinki DJ, et al. Normal polysomnographic values for children and adolescents. Am Rev Respir Dis 1992;146:1235-9.
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18. Witmans MB, Keens TG, Davidson Ward SL, Marcus CL. Obstructive hypopneas in children
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19. Ali NJ, Pitson DJ, Stradling JR. Snoring, sleep disturbance, and behaviour in 4-5 year olds.
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20. Gislason T, Benediktsdottir B. Snoring, apneic episodes, and nocturnal hypoxemia among children 6 months to 6 years old. An epidemiologic study of lower limit of prevalence. Chest.
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21. Monahan K, Redline S. Role of obstructive sleep apnea in cardiovascular disease. Curr Opin
22. Capdevila OS, Kheirandish-Gozal L, Dayyat E, Gozal D. Pediatric obstructive sleep apnea: Complications, management, and long-term outcomes. Proc Am Thorac Soc. 2008;5(2):274-282.
23. Muntz H, Wilson M, Park A, Smith M, Grimmer JF. Sleep disordered breathing and obstructive sleep apnea in the cleft population. Laryngoscope. 2008;118(2):348-353.
24. Griner D, Sargent LA, Overmeyer CL. Changes in airflow dynamics after creation of pharyngeal flaps in nonsyndromic children. Ann Plast Surg. 2013;70(5):517-520.
25. Marcus, Carole L., et al. "Diagnosis and management of childhood obstructive sleep apnea syndrome." Pediatrics 130.3 (2012): e714-e755.
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Clinical Characteristics of Screened Patients (n=57) 25 (43.9%) Male sex 6.4 (0.8-15.9) Age at First PSG (years) 15 (26.3%) Number of Patients with Multiple PSGs 74 Number of PSGs Number of Patients who had PSG at Various Time Points Pre-intervention 39 (52.7%) Post-T&A 18 (24.3%) Post-VPI Surgery 17 (23.0%) 33 (58%) Number of patients who had OSA on any PSG
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Data displayed as N (%) or median (range)
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Table 1. Clinical characteristics of screened patients.
Division of Otolaryngology, Children’s Hospital of Philadelphia, Philadelphia, PA, United States Division of Plastic Surgery, Children’s Hospital of Philadelphia, Philadelphia, PA, United States iii Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, United States iv Division of Pulmonary Medicine, The Children’s Hospital of Philadelphia, Philadelphia, PA, United States v Division of Neurology, The Children’s Hospital of Philadelphia, Philadelphia, PA, United States ii
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