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The Familial Aggregation of Pediatric Obstructive Sleep Apnea Syndrome
Alexander Ovchinsky, MD;
Madu Rao, MD;
Irwin Lotwin;
Nira A. Goldstein, MD
Arch Otolaryngol Head Neck Surg. 2002;128:815-818.
ABSTRACT
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Objective To determine the role of genetic mechanisms in the development of pediatric
obstructive sleep apnea syndrome (OSAS).
Design Genetic-epidemiologic survey of families of index children with laboratory-confirmed
OSAS.
Setting Tertiary care academic medical center.
Participants Six-hundred nap polysomnograms performed in our institution's pediatric
sleep laboratory over a 6-year period (1994-2000) were reviewed, and the 497
children who tested positive for OSAS were selected. A caretaker of 200 of
these index patients was contacted, and 115 were enrolled in the study.
Intervention and Main Outcome Measure Questionnaire-type telephone interviews were conducted with the current
caretakers of the index patients to assess the distribution of sleep-disordered
breathing in the first-degree relatives.
Results Data were collected for 445 first-degree relatives (256 adults and 189
children) of the 115 index patients. Habitual snoring was found in 194 (43.6%)
of the family members, while symptoms highly suggestive of OSAS (nighttime
"gasping for air" or "cessation of breathing") were found in 91(20.4%). Sixty-eight
(26.6%) of the adult first-degree relatives and 23 (12.2%) of the pediatric
first-degree relatives had symptoms highly suggestive of OSAS. Of the 115
index children, 50 (43.5%) had at least 1 relative with symptoms highly suggestive
of OSAS; 6 (1.3%) of the first-degree relatives had sleep study results positive
for OSAS, 4 (0.9%) were using nasal continuous positive airway pressure, and
21 (4.7%) had prior surgery for the treatment of OSAS.
Conclusion Considering the established prevalence of OSAS in the general population
(2%-4%), the results of this study support a familial basis for this disorder.
INTRODUCTION
OBSTRUCTIVE SLEEP apnea syndrome (OSAS) is a disorder characterized
by episodic upper airway obstruction during sleep that is associated with
reduction of oxyhemoglobin saturation or hypercarbia. It has been shown that
the lifetime risk of developing OSAS in children is about 2%,1
and the prevalence of OSAS in the general population is about 3% to 4%.2 Sleep apnea causes excessive daytime sleepiness, snoring,
and nonrestorative sleep. In its severe form, OSAS may result in significant
physiological and psychological abnormalities such as cor pulmonale, developmental
delay, failure to thrive, or even death.
Previous studies have suggested that the main risk factors for OSAS
are obesity, male sex, middle age, and the presence of a narrow airway.3-4 In adults, it has also been associated
with several anatomical abnormalities such as macroglossia, smaller airway
volume, and a low-set hyoid bone. In younger individuals, the mechanism of
the disease is different. It is associated mainly with immaturity of the respiratory
center in infants and adenotonsillar hypertrophy in children.5
The first report of familial obstructive sleep apnea was published by
Strohl et al6 in 1978. Since then, a few studies
supported the role of genetic mechanisms in the etiology of OSAS.7-9 Despite these reports,
no previous attempts have been made to evaluate the role of familial factors
in the pathogenesis of OSAS in children, in whom the proposed pathophysiologic
mechanism of OSAS, namely, adenotonsillar hypertrophy, is different from the
adults.
PARTICIPANTS AND METHODS
We reviewed 600 nap polysomnograms performed at our institution's pediatric
sleep laboratory over a 6-year period (1994-2000) and 497 children had sleep
study results positive for OSAS. The criteria for a positive study result
were a respiratory disturbance index score of 5 or greater or the presence
of moderate or severe desaturations during sleep (arterial oxygen saturation
[SaO2]<92%). We were able to contact a caretaker of 200 index
patients, 115 of whom were enrolled in the study. The study was approved by
the institutional review board at SUNY Health Science at Brooklyn, Brooklyn,
NY.
Standardized questionnaire-type telephone interviews were conducted
with the current caretakers of the index patients to assess the distribution
of sleep-disordered breathing in the first-degree relatives (parents and siblings).
The questionnaire consisted of general and epidemiological data, medical history,
and specific questions for OSAS symptoms including snoring, mouth breathing,
daily somnolence, tiredness, gasping and choking, nightly awakenings, apneic
episodes, restless sleep, and enuresis. Data regarding history of OSAS in
the first-degree relatives (ie, having a positive sleep study result or previous
surgery for OSAS) were also included in the questionnaire. Comparison of the
incidence of OSAS in the relatives of the index probands with the general
incidence of OSAS was performed using a confidence interval for binomial proportion.
RESULTS
There were 77 male (67.0%) and 38 female (33.0%) index subjects (Table 1): of these 115, 97 were African
American (84.3%); 11 were Hispanic (9.6%); 6 were white (5.2%); and 1 was
biracial (0.9%). The mean (range) age of the index subjects at the time of
the sleep study was 75 (7-217) months. Their mean (range) respiratory disturbance
index score was 28 (0.5-132.9). More than 50% of the index cases had no desaturations
on the sleep study, while 18.3% had severe desaturations. Seventy-two index
subjects (62.6%) underwent surgical treatment for OSAS.
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Table 1. Demographics, Sleep Study Test Results, and Surgical Treatment
of the 115 Index Patients With Pediatric OSAS*
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Data were collected for 445 first-degree relatives of the 115 index
cases (256 adults and 189 children) (Table
2). Habitual or disruptive snoring was present in 194 (43.6%) family
members, of whom 115 (59.3%) were adults and 79 (40.7%) were children or adolescents
(Figure 1). Interestingly, snoring
alone without symptoms of apnea or gasping was found only in 103 (23.1%) of
first-degree relatives.
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Table 2. Symptom Allocation in the First-Degree Relatives of the Index
Patients With Pediatric OSAS*
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Figure 1. First-degree relatives (adults
and children/adolescents) with habitual snoring.
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We considered the presence of symptoms of nighttime "gasping for air"
and "cessation of breathing" as highly suggestive of OSAS. Of the 445 first-degree
relatives, 91 (20.4%) were found to have at least 1 or both of the above symptoms:
68 were adults and 23 were children (Figure
2). Thus, 68 (26.6%) of all 256 adult first-degree relatives and
23 (12.2%) of all 189 pediatric first-degree relatives were found to have
symptoms highly suggestive of OSAS.
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Figure 2. First-degree relatives (adults
and children/adolescents) with symptoms highly suggestive of obstructive sleep
apnea syndrome (OSAS) (cessation of breathing and/or gasping).
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The presence of a cluster of certain symptoms in the first-degree relatives
with no history of gasping or cessation of breathing was considered as "suspicious
for OSAS." For adult first-degree relatives, there were 3 groups of symptom
clusters: (1) snoring and daytime somnolence; (2) snoring and enuresis; and
(3) snoring, restless sleep, and nightly awakenings. We found 15 adult first-degree
relatives to belong to group 1, 3 to group 2 and 13 to group 3 (Figure 3). Thus, 31 (12.1%) of the adult first-degree relatives
had symptoms suspicious for OSAS. For pediatric first-degree relatives, there
also were 3 groups of symptom clusters considered suspicious for OSAS, which,
in addition to the adult symptoms, required the presence of "mouth breathing"
in each of the cluster groups. Six children belonged to group 1 (snoring,
daily somnolence, and mouth breathing), 3 to group 2 (snoring, enuresis, and
mouth breathing), and 4 to group 3 (snoring, restless sleep, nightly awakenings,
and mouth breathing) (Figure 4).
Therefore, 13 (6.9%) of the pediatric first-degree relatives were found to
have symptoms suspicious for OSAS.
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Figure 3. Three groups of symptom clusters
"suspicious for obstructive sleep apnea syndrome (OSAS)" in the adult first-degree
relatives of the index patients with pediatric OSAS.
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Figure 4. Three groups of symptom clusters
"suspicious for obstructive sleep apnea syndrome (OSAS)" in the pediatric
first-degree relatives of the index patients with pediatric OSAS.
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In addition, 50 (43.5%) of the 115 index children and adolescents had
at least 1 relative with symptoms highly suggestive of OSAS. Of the siblings
of the index cases, 55 (12.3%) had symptoms highly suggestive of OSAS (gasping
and/or apnea), 4 (0.9%) were using nasal continuous positive airway pressure,
and 21 (4.7%) had prior surgery for the treatment of OSAS. A total of 14 first-degree
relatives reported having a sleep study in the past: 6 had sleep study results
positive for OSAS, 5 were negative, and 3 of the first-degree relatives were
unsure about the results.
COMMENT
The present study shows that 20.4% (95% confidence interval, 16.8%-24.5%)
of first-degree relatives of 115 index cases with pediatric OSAS had symptoms
highly suspicious for OSAS (apnea and gasping) (Figure 5). Because the general incidence of this syndrome is from
3% to 4%,2 our study showed a significant increase
in OSAS frequency in the first-degree relatives of the index cases with sleep
apnea (P<.05), thus supporting a possible role
of genetic mechanisms in the etiology of this syndrome.
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Figure 5. First-degree relatives (adults
and children/adolescents) with symptoms either highly suggestive of or suspicious
for obstructive sleep apnea syndrome (OSAS).
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Our findings corroborate the results of a similar questionnaire-based
study by Redline et al,10 in which 21% of the
first-degree relatives of the index cases with OSAS were found to have OSAS.
Douglas et al,11 in a combined questionnaire-polysomnogram
study, also showed a similar (25%) incidence of this syndrome in the first-degree
relatives of patients with apnea. Other studies quote even higher incidences.12
The exact mechanism of OSAS inheritance is yet unknown. It has been
speculated that the genetic transmission of such OSAS risk factors as craniofacial
structure, body habitus, and ventilatory control mechanisms may play a role.
In the pediatric population, in whom adenotonsillar hypertrophy is considered
to be the main causative factor for OSAS, the role of inheritance is unclear.
It is possible that the genetic factors play a role in the etiology of adenotonsillar
hypertrophy per se or make it more significant by encoding for smaller airway
volumes.
The data presented in the present study are based on the responses to
the standardized questionnaire. The degree to which questionnaires allow for
accurate identification of sleep apnea is controversial. Several previous
studies that used both questionnaires and polysomnograms to diagnose sleep
apnea showed that the positive predictive value of questionnaires is considerably
high, ranging from 60% to 90%,13-14
thus supporting the questionnaire's validity in sleep apnea research. Reporting
bias, in which relatives of the index probands tend to overreport the symptoms,
must also be considered when using questionnaires as a research tool. The
study by Redline et al10 compared the frequency
of symptom reporting by the relatives of the patients with sleep apnea and
the control group. They found no significant overreporting of the symptoms
by the relatives of the index cases. Thus, although a reporting bias cannot
be completely excluded, it is unlikely to be the sole factor causing this
large difference in the prevalence of sleep apnea symptoms among the first-degree
relatives of the patient with OSAS.
CONCLUSIONS
The significant increase in the OSAS incidence among the first-degree
relatives of the children and adolescents with OSAS supports the role of genetic
factors in the etiology of this syndrome. Our study, along with the other
published studies, may have significant implications both in diagnosing and
caring for patients with sleep apnea. Families of children with OSAS need
to be counseled about the increased incidence of this syndrome in other siblings.
A physician should be highly suspicious for sleep apnea in a child who has
1 or more siblings diagnosed as having OSAS. This heightened awareness will
potentially provide for timely diagnosis of OSAS, thus decreasing the incidence
of potential long-term complications of this syndrome.
AUTHOR INFORMATION
Accepted for publication November 13, 2001.
This study was presented as a poster at the annual meeting of the American
Society of Pediatric Otolaryngology, Scottsdale, Ariz, May 9-12, 2001.
Corresponding author: Alexander Ovchinsky, MD, Department of Otolaryngology,
SUNY Health Science Center at Brooklyn/Long Island College Hospital, 134 Atlantic
Ave, Brooklyn, NY 11201 (e-mail: ovchinsa{at}hotmail.com).
From the Division of Pediatric Otolaryngology, Department of Otolaryngology
(Drs Ovchinsky and Goldstein), the Department of Pediatrics (Dr Rao), and
the College of Medicine (Mr Lotwin), SUNY Health Science Center at Brooklyn
and the Long Island College Hospital, Brooklyn, NY.
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