Sleep-disordered breathing in school-aged children with Prader-Willi syndrome

Abstract

Study Objectives:

Studies of sleep-disordered breathing (SDB) in children with Prader-Willi syndrome (PWS) have focused on early childhood and growth hormone (GH)–naïve children, but little is known about older children, including those on long-term GH therapy. This study aimed to describe the nature and prevalence of SDB in school-aged children with PWS in the growth hormone era.

Methods:

This retrospective single-center chart review included children aged 6–18 years with PWS who had overnight polysomnography not involving respiratory support over 5 years (2012–2017). The main outcome measures were the presence of obstructive sleep apnea, central sleep apnea, or hypoventilation defined by an elevated transcutaneous partial pressure of carbon dioxide (TcPCO₂) as per standard pediatric criteria.

Results:

Seventeen children (8 males; median age 11.6 years, range 6.6–16.1 years) were included. Fifteen demonstrated SDB of different types: central sleep apnea (18%), obstructive sleep apnea (24%), both obstructive and central sleep apnea (29%), or hypoventilation without obstructive or central sleep apnea (18%). Twelve (71%) children had evidence of hypoventilation. Those with hypoventilation had a higher central apnea-hypopnea index but no difference in the obstructive apnea-hypopnea index, age, sex, growth parameters, or the presence of scoliosis or sleep-related symptoms compared with those without hypoventilation.

Conclusions:

Sleep-related hypoventilation is common in school-aged children with PWS. The presence of central sleep apnea, including the quantification of central hypopneas, but not obstructive sleep apnea or clinical factors, predicted the presence of hypoventilation. Long-term polysomnography surveillance in children with PWS should include identification of central hypopneas and measurement of continuous pCO₂.

Citation:

Schaefer J, Davey MJ, Nixon GM. Sleep-disordered breathing in school-aged children with Prader-Willi syndrome. J Clin Sleep Med. 2022;18(4):1055–1061.

BRIEF SUMMARY

Current Knowledge/Study Rationale: Studies of sleep-disordered breathing in children with Prader-Willi syndrome have focused on early childhood and growth hormone–naïve children, but little is known about older children, including those on long-term growth hormone therapy. This study aimed to describe the nature and prevalence of sleep-disordered breathing in school-age children with Prader-Willi syndrome in the growth hormone era.

Study Impact: Sleep-related respiratory disorders of all types are frequent in school-aged children with Prader-Willi syndrome, with hypoventilation being a common feature. Hypoventilation is largely driven by the presence of central sleep-disordered breathing and is often present in the absence of sleep-related symptoms, underscoring the need for ongoing clinical surveillance and polysomnography in this condition throughout childhood, including continuous measures of pCO₂.

INTRODUCTION

Prader-Willi syndrome (PWS) is a genetic syndrome affecting approximately 4 per 100,000 live births.¹ Obstructive sleep apnea (OSA) is common in PWS due to features of the condition, including obesity, midface hypoplasia, viscous secretions, and low upper respiratory muscle tone.^2–4 People with PWS have abnormal respiratory drive, demonstrating reduced response to both hypoxia and hypercarbia,^4,5 as well as risk factors for restrictive lung disease, such as scoliosis, obesity, and reduced muscle tone, making them also at increased risk of central sleep-disordered breathing (SDB) and sleep-related hypoventilation.

Growth hormone (GH) therapy in PWS has been associated with the development of OSA in a subset of patients.^6–8 The impact on central SDB is less clear, with some studies showing improvement in the frequency of central respiratory events^7,9,10 and CO₂ responsiveness⁵ and others showing no impact on chemoreflex-mediated respiratory drive.¹¹

Many studies of children with PWS have focused on disorders of breathing in infancy, in early childhood, and in GH-naïve children. Thus, this case series aimed to describe the nature and prevalence of SDB in school-age children with PWS in the era of GH therapy, including relationships of SDB to clinical risk factors.

METHODS

All children aged 6–18 years with genetically confirmed PWS who underwent polysomnography (PSG) at the Melbourne Children’s Sleep Centre between January 2012 and March 2017 were identified from the Centre database. Five children had PSG for titration of overnight respiratory support (continuous positive airway pressure [n = 2] and bilevel noninvasive ventilation [n = 3]) being used for treatment of severe OSA refractory to surgical intervention and these children were not included in the cohort for analysis. A caregiver gave consent for clinical data to be used for research, with retrospective data collection approved by the Human Research Ethics Committee of Monash Health (approval number 04161C). Demographic and clinical data and anthropometric measurements were obtained from the medical record at the time of the sleep study, including the presence of sleep-related symptoms such as daytime somnolence, behavioral deterioration, or snoring. Overweight was defined as a body mass index (BMI) above the 85th percentile for age, and obesity was defined as a BMI above the 95th percentile for age.¹² Height-for-age z-score < −1.0 was considered impaired and < −2.0 severely impaired.

Standard overnight attended PSG¹³ (Grael; Compumedics, Melbourne, Australia) included electroencephalogram, electrooculograms, submental electromyogram, anterior tibialis muscle electromyogram, electrocardiogram, thoracic and abdominal breathing movements (respiratory inductance plethysmography), transcutaneous partial pressure of carbon dioxide (TcPCO₂; TCM4/40; Radiometer, Denmark, Copenhagen), nasal pressure, oronasal airflow, and oxygen saturation (Radical oximeter; Masimo Corporation, Irvine, CA, USA; with 2-second averaging time). PSGs were manually scored using standard criteria.¹³ Total sleep time (TST) was the time spent asleep from sleep onset until the end of the study. Rapid eye movement (REM) sleep latency was the period from sleep onset to the start of the first period of REM sleep. Sleep efficiency was defined as the ratio of TST to the total time in bed. The arousal index is the total number of arousals per hour of TST. An obstructive apnea was defined as the cessation of airflow with ongoing respiratory effort; an obstructive hypopnea was defined as ≥ 30% decrease in airflow, associated with increased work of breathing and an arousal or ≥ 3% decrease in oxygen saturation; a central apnea was defined as cessation of airflow without inspiratory effort lasting either ≥ 20 seconds or at least the duration of 2 breaths and associated with an arousal or ≥ 3% oxygen desaturation; and a central hypopnea was defined as ≥ 30% decrease in airflow with reduced inspiratory effort and no paradoxical respiratory efforts or respiratory noise associated with an arousal or ≥ 3% oxygen desaturation. A mixed apnea included periods of both absent and obstructed inspiratory efforts.¹³ An obstructive apnea-hypopnea index (OAHI) was defined as the total number of obstructive apneas, mixed apneas, and obstructive hypopneas per hour of TST. The presence of OSA was defined by an OAHI > 1 event/h; mild OSA was defined as an OAHI > 1 to ≤ 5 events/h, and moderate/severe OSA as an OAHI > 5 events/h. The central apnea-hypopnea index (CnAHI) was defined as the total number of central apneas and central hypopneas per hour of TST, with central sleep apnea (CSA) defined by a CnAHI of > 5.0 events/h. The total respiratory disturbance index (RDI) was the sum of central and obstructive indices. Hypoventilation was defined by American Academy of Sleep Medicine criteria, wherein TcPCO₂ is considered an acceptable surrogate for partial pressure of CO₂ (pCO₂).¹³ Awake TcPCO₂ > 50 mmHg recorded during the polysomnogram prior to sleep onset defined diurnal hypoventilation; TcPCO₂ > 50 mmHg for > 25% of TST or a ≥ 10-mmHg rise in TcPCO₂ from awake to asleep defined sleep-related hypoventilation. In order to capture children with early signs of hypoventilation, an average TcPCO₂ rise of ≥ 3 mmHg in REM sleep was used to define REM-related hypoventilation.

Statistical analysis

Stata version 16.0 (StataCorp, College Station, TX, USA) was used for statistical analysis. Continuous variables were compared between groups by Student’s t test for parametric data and Wilcoxon rank-sum test for nonparametric data. Fisher’s exact test was used to compare categorical variables between groups. Linear regression was used to examine the relationship between continuous variables.

RESULTS

Clinical and demographic characteristics of the 17 patients who met the inclusion criteria are shown in Table 1. The group included 11 children referred for routine PSG pre- or post-GH commencement (as required by local prescribing guidelines) in the absence of symptoms, and 6 children referred due to symptoms during the day (hypersomnolence, fatigue, behavioral deterioration) or night (snoring, increased work of breathing, witnessed apneas). Nine children (53%) were on GH at the time of the index PSG and had used GH for a median (interquartile range [IQR]) of 6.8 (3.2–8.0) years; this group had a lower mean BMI z-score than those not on GH (1.0 ± 1.4 vs 2.1 ± 0.6, P = .05) but no difference in height-for-age z-score (−0.5 ± 1.1 vs −1.0 ± 1.7, P = .48). Six participants (35%) had a history of scoliosis sufficiently severe to require bracing, casting, or surgical intervention. Studies were conducted on the patient’s usual medications, including 1 child on fluoxetine and estrogen, 1 on fluoxetine and risperidone, and 1 on atomoxetine.

Table 1.

Demographic, anthropometric, and clinical characteristics of the cohort (n = 17).

	Values
Age (y)	11.6 [9.8–14.4]
Male	8 (47%)
BMI-for-age z-score	+1.9 [+1.1, +2.4]
Healthy weight	4 (24%)
Overweight	3 (18%)
Obese	10 (59%)
Height-for-age z-score	−0.8 [−1.5, +0.2]
Impaired linear growth	7 (41%)
Severely impaired linear growth	3 (18%)
History of GH use	13 (74%)
Currently on GH	9 (53%)
Average age started GH for those ever on GH (y)	3.9 [1.6–8.7]
Average time on GH for those ever on GH (y)	4.7 [1.0–7.5]
Average time on GH for those currently on GH (y)	6.8 [3.2–8.0]
Significant scoliosis	6 (35%)
History of adenotonsillectomy	8 (47%)
Current supplemental oxygen	1 (5%)
Clinical sleep-related symptoms	6 (35%)
Diagnosis of narcolepsy	1 (6%)

Numerical variables are expressed as median [IQR]. Proportional variables are expressed as n (%). Significant scoliosis was defined as that requiring intervention (bracing, casting, or surgery). Clinical sleep-related symptoms were defined as those included in the referral for PSG or accompanying clinical letter. BMI = body mass index, GH = growth hormone, IQR = interquartile range.

Participants had a median of 4 (range 2–9) PSG studies each. Findings from the most recent PSG are reported in Table 2. Four children (24%) had a very short REM sleep latency of < 10 minutes including 1 child with a diagnosis of narcolepsy. The total arousal index was strongly correlated with the total RDI (r² = 0.42, P = .005), highlighting SDB as a significant contributor to sleep disturbance. One patient was given low-flow oxygen for half of the PSG, and so only data from the portion of the PSG in room air were used for analysis. All other studies were conducted in room air.

Table 2.

Polysomnographic findings in 17 school-aged children with Prader-Willi syndrome.

	Values
Sleep parameters
Total sleep time (min)	467 [429,478]
Sleep efficiency (%)	88 [85,90]
Arousal index (events/h)	10.8 [8.0,13.6]
REM sleep latency (min)	74 [20,92]
Periodic limb movement index (events/h)	0 [0,0]
Periodic limb movement index > 5/h	2 (12%)
Sleep-disordered breathing
Total RDI (events/h)	9.8 [3.9,14.8]
RDI in REM sleep (events/h)	25.4 [8.6,41]
CnAHI (events/h)	4.2 [1.9,11.1]
OAHI (events/h)	1.2 [0.3,3.8]
Awake SpO2 (%)	97 [96,98]
Desaturation index > 3% (events/h)	5.6 [2.7,11.2]
Desaturation events < 90% (events/h)	0.6 [0.3,2.9]
SpO2 nadir (%)	79 [75,87]
Average awake TcPCO2 (mmHg)	43 [41,49]
Average sleep TcPCO2 (mmHg)	47 [44,51]
TcPCO2 > 50 mmHg (% of total sleep time)	2 [0,66]
TcPCO2 >50 mmHg for > 25% of total sleep time	6 (35%)
Average TcPCO2 rise in REM sleep ≥3 mmHg	8 (47%)
Type and severity of sleep-disordered breathing*
Obstructive sleep apnea (OAHI > 1/h)	9 (53%)
Mild OSA	6 (35%)
Moderate or severe OSA	3 (18%)
Central sleep apnea (CnAHI > 5 events/h)	8 (47%)
Hypoventilation	12 (71%)
Diurnal hypoventilation	3 (18%)
Sleep-related hypoventilation (with normal   awake CO2)	3 (18%)
REM-sleep related hypoventilation only	6 (35%)
No obstructive or central sleep apnea	5 (29%)
No sleep-disordered breathing	2 (12%)

Data are expressed as median [IQR] or n (%). *Children may be included in > 1 category of sleep-disordered breathing, apart from those with “No sleep-disordered breathing” (n = 2) who had neither obstructive nor central sleep apnea and did not have hypoventilation. CnAHI = central apnea-hypopnea index, IQR = interquartile range, OAHI = obstructive apnea-hypopnea index, OSA = obstructive sleep apnea, RDI = respiratory disturbance index, REM = rapid eye movement, SpO₂ = oxygen saturation, TcPCO₂ = transcutaneous partial pressure of carbon dioxide.

Sleep-disordered breathing

Of the 17 children, 15 (88%) demonstrated SDB including CSA (n = 3, 18%), OSA (n = 4, 24%), both OSA and CSA (n = 5, 29%), and hypoventilation with a normal OAHI and CnAHI (n = 3, 18%) (Table 2). Overall, 12 children (71%) had hypoventilation.

Obstructive sleep apnea

Nine participants had OSA (53%), including 5 who also had CSA. Only 3 were classified as having moderate or severe OSA. Three patients (33%) with OSA had previously had adenotonsillectomy. There was no significant difference in BMI z-score between those with and those without OSA (median 1.9 vs 1.5, P = .96). Age, the proportion of males, height-for-age z-score, treatment with GH (ever or current), or the presence of significant scoliosis were not different between those with or without OSA. Oxygenation parameters (mean oxygen saturation [SpO₂], SpO₂ nadir, SpO₂ dips below 90%/h, and SpO₂ dips of ≥ 3%/h) were not significantly different between those with or without OSA. Six of the 9 children with OSA had hypoventilation: 4 in REM sleep only and 2 with diurnal hypoventilation. However, the proportion with a rise in TcPCO₂ > 3 mmHg in REM sleep was not different (3 [38%] without OSA and 5 [56%] with OSA; P = .64), suggesting that OSA was not the predominant driver of REM sleep–related hypoventilation.

Central sleep apnea

Eight children (47%) had CSA (including 5 who also had OSA), with a median CnAHI of 11.9 events/h (IQR 8.2–20.0). The majority of events were central hypopneas resulting in desaturation or arousal from sleep (Figure 1), with central apneas being less frequent (median 1.9/h; IQR 1.0–9.3 for those with CSA). Age, sex, BMI z-score, height-for-age z-score, or the presence of significant scoliosis were not different between those with or without CSA. Five (63%) of those with CSA were referred due to clinical symptoms, compared with 1 (11%) of those without CSA (P = .05). The SpO₂ nadir was not significantly different between those with or without CSA (75% vs 85%, P = .054), but those with CSA had more frequent desaturations < 90% (5.3 vs 0.3/h, P = .004) and desaturations of ≥ 3% (12.2 vs 2.7/h, P = .0005). All of the children with CSA had hypoventilation: 6 in REM sleep only (Figure 2), 1 with sleep-related hypoventilation, and 1 with diurnal hypoventilation. Average awake TcPCO₂, average sleep TcPCO₂, and percentage of TST with TcPCO₂ > 50 mmHg were not different between those with or without CSA, whereas all of those with CSA had an average rise in TcPCO₂ in REM sleep of ≥3 mmHg.

Figure 1. Two-minute epoch of polysomnography data showing an example of a central hypopnea during REM sleep, demonstrating reduced airflow and respiratory effort, without evidence of obstruction (in-phase respiratory effort and no sound on video recording).

The event is associated with a fall in SpO₂ from 98% to 93% (marked in shaded box). The whole period of REM sleep in which this event occurred was associated with a rise in TcPCO₂ of 7 mmHg, although this is not reflected in this 2-minute window. Channels are marked as follows from top to bottom: SpO₂, Nasal Pressure (measure of nasal airflow), Thermistor (heat sensor used as estimate of combined nasal and oral airflow), Abdo effort (respiratory movements measured by an abdominal RIP band), Thoracic effort (respiratory movements measured by a RIP band around the thorax), Sum RIP (signal calculated as sum of Abdo Effort and Thoracic Effort), and TcPCO₂. REM = rapid eye movement, RIP = respiratory inductance plethysmography, SpO₂ = oxygen saturation, TcPCO₂ = transcutaneous carbon dioxide.

Figure 2. PSG hypnogram of an 8.8-year-old male with Prader-Willi syndrome, referred for excessive daytime sleepiness.

Growth hormone treatment was used continuously from age 2.7 years, with normal PSG documented before and after commencing growth hormone. Brace was worn for scoliosis treatment, including on the night of the PSG. BMI at the time of the study was 18.7 kg/m² (z-score for age = +1.1). PSG shows no OSA but significant REM sleep–related hypoventilation due to predominantly central hypopneas. The mean rise in TcPCO₂ in REM sleep was 5 mmHg. There was an incidental finding of a sleep-onset REM sleep period. Panels are as follows from top to bottom: Hypnogram showing time in each sleep state across the night, Position (body position), Lights (marks the time the room light is turned off), Arousals (showing a vertical mark for each manually scored arousal from sleep), SpO₂ (oxygen saturation as %), TcPCO₂, and respiratory event panel showing a vertical mark for each scored respiratory event. BMI = body mass index, Cn.A = central apnea, Cn.Hyp = central hypopnea, Mx.A = mixed apnea, Ob.A = obstructive apnea, PSG = polysomnography, REM = rapid eye movement, RERA = respiratory event–related arousal, SpO₂ = oxygen saturation, TcPCO₂ = transcutaneous carbon dioxide.

Hypoventilation

Of the 12 (71%) children who had hypoventilation, 3 had diurnal hypoventilation, 3 had sleep-related hypoventilation (2 of whom had a further rise in REM sleep), and 6 had hypoventilation limited to REM sleep. Age, sex, BMI z-score, height-for-age z-score, or the presence of significant scoliosis were not different between those with or without hypoventilation (P > .05 for all). Only half of those with hypoventilation had sleep-related symptoms as the reason for the PSG. Nine (75%) had ever had treatment with GH (including those currently on treatment and those whose treatment had been discontinued), which was not different from the proportion in the group as a whole (P = 1.0). The CnAHI was significantly higher in the children with hypoventilation (8.2 events/h [IQR 3.3–15.8] vs 1.9 events/h [IQR 1.3–2.9], P = .04), whereas there was no difference in the OAHI in those with or without hypoventilation (1.1 events/h [IQR 0.3–3.6] vs 1.6 events/h [IQR 0.4–4.8], P = .71). Average SpO₂, SpO₂ nadir, and frequency of desaturation events < 90% were not different between these with or without hypoventilation, but the frequency of 3% dips in SpO₂ during sleep was higher in the group with hypoventilation (8.6/h [IQR 3.3–15.0] vs 1.9/h [IQR 1.9–4.5], P = .03).

DISCUSSION

In a group of school-aged children with PWS, three-quarters of whom had been treated with GH at some point in their life and half of whom were currently on GH, we demonstrated a mixture of OSA and CSA, many with concomitant evidence of hypoventilation. In addition, we found a distinct group of children who demonstrated hypoventilation during sleep without meeting the standard criteria for OSA or CSA. We did not find clinical factors that predicted the presence of hypoventilation, such as a higher BMI or the presence of significant scoliosis, and surmise that hypoventilation may be due to abnormalities of respiratory control specific to PWS. This conclusion is supported by the increased frequency of central hypopneas in those with hypoventilation, accompanied by more frequent desaturation events. Half of the children with hypoventilation were having a sleep study as part of routine monitoring before or during GH treatment and did not have sleep-related symptoms. These findings underline the increased risk of central SDB associated with hypoventilation and desaturation in school-aged children with PWS.

Previous studies of SDB in PWS have focused on OSA or the impact of GH treatment.^14–16 Findings in regard to the association of obesity and OSA have been variable, with some finding an association¹⁷ and others not.^6,18 Growth hormone has been implicated in sudden death in children with PWS, related to OSA.^16,19–21 PSG studies have found evidence that a subset of children develop OSA after initiation of GH^7,22 while many are unaffected.⁶ As anticipated from the literature,^6,7,23,24 we found high rates of OSA in our cohort, with more than half having OSA on PSG, but most cases were relatively mild.

Our study highlights the complexity of respiratory sleep disorders in PWS beyond the diagnosis of OSA. Dysfunction of the hypothalamus, central to many of the features of PWS, has been implicated in the development of hypoventilation and abnormalities of respiratory drive.^25,26 Obesity, hypotonia, and scoliosis are also potential contributors to hypoventilation. Increased central apneas have been described in PWS in infancy,²⁷ but several studies have reported low central apnea indices in children and adults with PWS.^6,8,17,18 However these studies did not report the presence of central hypopneas, where unobstructed respiratory efforts are insufficient to prevent desaturation, hypercapnia, and/or arousal from sleep—a type of event often poorly captured by traditional PSG scoring. Most did not assess or report measures of carbon dioxide. One reported PSG findings in 37 patients aged 1.2–24 years and found 62% had a peak pCO₂ > 50 mmHg, but the nature of SDB contributing to the hypercapnia was not defined.¹⁷ A study in adults found diurnal hypoventilation (defined by blood gases) without OSA in a small subset of patients (3 of 60, all obese) but continuous measurements of pCO₂ during sleep were not performed.²³ In our study, hypoventilation was most commonly confined to REM sleep, with normal gas exchange during wake and non-REM sleep for most participants. We have detailed for the first time this phenomenon of hypoventilation during sleep in school-aged children with PWS, sometimes in the absence of OSA or CSA as determined by traditional metrics, and often accompanied by desaturation (Figure 2). In our cohort, children with hypoventilation had increased central hypopneas and more frequent desaturation, which distinguishes this pattern from mildly increased pCO₂ that may be considered physiological in REM sleep. This hypoventilation appeared to be unrelated to age, obesity, or scoliosis; however, our study did not have sufficient power to assess the contribution of these potential factors in various combinations. Individuals with PWS have deletion of a gene (Necdin) that in animals results in central apnea, irregular breathing, and a blunted respiratory response to hypoxia.²⁸ Abnormal respiratory drive and blunted hypoxic and hypercapnic ventilatory responses in people with PWS^29,30 are likely explanatory factors for the hypoventilation seen in our study. The degree of hypoventilation experienced by children with PWS aged 2 months–14 years has previously been reported to be disproportionate to the severity of OSA when compared with typically developing children.³¹ The findings of that study are complementary to our own, with the current study highlighting the potential contribution of nonobstructive factors to hypoventilation in PWS. Half of the children with hypoventilation did not have sleep-related symptoms, and the frequent finding of hypercapnia in the absence of symptoms in this cohort highlights the importance of regular PSG including a continuous measure of pCO₂ in people with PWS, regardless of the presence of risk factors for OSA.

The natural history of hypoventilation in children with PWS is unknown. Although REM sleep only constitutes approximately one-quarter of total sleep, REM sleep–related hypoventilation in other conditions is seen as an early marker of eventual sleep-related hypoventilation and ultimately diurnal hypercapnia,^32,33 and treatment is likely to improve quality of life and possibly even survival.^34,35

The design of our study means that we are limited to describing sleep study findings in children referred for PSG and cannot infer the prevalence of the different types of SDB in the population of children with PWS as a whole. Exclusion from our cohort of children on continuous positive airway pressure or noninvasive ventilation for severe OSA would have led to an underestimation of the prevalence and severity of OSA in this age group. Given the complexity of PWS, many children had multiple comorbid conditions. The size and design of our study limit our ability to conclusively determine the impact of comorbid conditions individually or in combination on the presence or severity of SDB. We elected to include a ≥ 3-mmHg rise in pCO₂ from non-REM sleep to REM sleep in our definition of hypoventilation, keeping the definition broad, due to previous studies showing progression of REM sleep–related hypoventilation to sleep-related hypoventilation in other conditions.

Future areas of study could include longitudinal analysis of children with hypoventilation. We did not have a large enough sample size to meaningfully assess longitudinal changes for individuals within our study. Given the relative rarity of PWS, multicenter cohorts would likely be required to address this and also to better assess various predictors of hypoventilation that may allow development of recommendations for targeted sleep assessments.

CONCLUSIONS

Sleep-related respiratory disorders of all types were frequently demonstrated in school-aged children with PWS, including those on long-term GH therapy. Hypoventilation was common and was largely driven by the presence of central SDB, particularly central hypopneas. Abnormal respiratory drive related to PWS itself is a possible explanation. The high proportion of children affected by disorders of respiration during sleep, often in the absence of sleep-related symptoms, underscores the need for ongoing clinical surveillance and PSG in this condition throughout childhood, including identification of central hypopneas and continuous measures of pCO₂.

DISCLOSURE STATEMENT

All authors have participated in this work and have seen and approved the final manuscript. G.M.N. declares a research grant from the ResMed Foundation not related to the current work; M.J.D. and J.S. report no conflicts of interest. No funding was obtained for this study.

ABBREVIATIONS

AHI

apnea-hypopnea index

BMI

body mass index

CnAHI

central apnea-hypopnea index

CSA

central sleep apnea

GH

growth hormone

IQR

interquartile range

OAHI

obstructive apnea-hypopnea index

OSA

obstructive sleep apnea

pCO₂

partial pressure of carbon dioxide

PSG

polysomnography

PWS

Prader-Willi syndrome

REM

rapid eye movement

SDB

sleep-disordered breathing

SpO₂

oxygen saturation

TcPCO₂

transcutaneous carbon dioxide

TST

total sleep time