American Journal of Respiratory and Critical Care Medicine

As compared with control subjects, children with Down syndrome have different size and shape relationships among tissues composing the upper airway, which may predispose them to obstructive sleep apnea (OSA). We hypothesized that Down syndrome children without OSA have similar subclinical differences. We used magnetic resonance imaging to study the upper airway in 11 Down syndrome children without OSA (age, 3.2 ± 1.4 yr) and in 14 control subjects (age, 3.3 ± 1.1 yr). Sequential T1- and T2-weighted spin-echo axial and sagittal images were obtained. We found a smaller airway volume in subjects with Down syndrome (1.4 ± 0.4 versus 2.3 ± 0.8 cm3 in controls, p < 0.005). Subjects with Down syndrome had a smaller mid- and lower face skeleton. They had a shorter mental spine–clivus distance (5.7 ± 0.6 versus 6.2 ± 0.4 cm, p < 0.05), hard palate length (3.2 ± 0.4 versus 3.7 ± 0.2 cm, p < 0.005), and mandible volume (11.5 ± 3.7 versus 16.9 ± 2.9 cm3, p < 0.0005). Adenoid and tonsil volume was significantly smaller in the subjects with Down syndrome. However, the tongue, soft-palate, pterygoid, and parapharyngeal fat pads were similar to those of control subjects. This study shows that Down syndrome children without OSA do not have increased adenoid or tonsillar volume; reduced upper airway size is caused by soft tissue crowding within a smaller mid- and lower face skeleton.

Down syndrome (trisomy 21) is the most common genetic cause of developmental disability and mental retardation, with an incidence of 1 per 660 live births (1). Obstructive sleep apnea (OSA) is common in this group and noted in 30–60% of subjects (2-5). Anatomical factors related to the Down syndrome phenotype have been attributed to the causation of OSA in this group. These include midfacial and mandibular hypoplasia (5-7), enlarged tongue (8, 9), adenoid and tonsilar hypertrophy (8), laryngotracheal anomalies (10), and obesity (2). Reduced neuromuscular tone has also been suspected of having a role in the development of OSA in these subjects (1, 2).

However, in most cases, children with Down syndrome who have been treated for upper airway obstruction by a single approach such as tonsillectomy, adenoidectomy, uvulopalatopharyngoplasty, or tongue reduction surgery improve only partially (2-5, 10, 11). This suggests that in Down syndrome subjects with OSA, airway patency may be compromised at various sites because of the interaction of several tissues reducing airway size. Moreover, it is conceivable that Down syndrome subjects with no apparent OSA have anatomical alterations in the upper airway structure similar to those with OSA, but to a lesser extent.

Traditional methods to evaluate the upper airway in children with Down syndrome include plain lateral neck radiograph, cephalometric measurements, airway fluoroscopy, and nasal pharyngoscopy (3, 5, 8, 10). However, these methods provide only limited information regarding the entire upper airway structure. Modern imaging techniques such as computed tomography scan (CT scan) and magnetic resonance imaging (MRI) provide more comprehensive anatomical details of these structures (12, 13).

MRI has been used in adults to study the anatomy of the upper airway and its contribution to the pathogenesis of sleep apnea (13-15). Although imaging studies have been reported in children, none, to our knowledge, have used MRI to investigate the upper airway in children with Down syndrome.

We hypothesized that upper airway anatomy in children with Down syndrome who do not have OSA differs significantly of that found in normal children. We were motivated by the concept that even though they did not have OSA they might have compromise of the upper airway. We therefore designed a case control study and analyzed in detail the upper airway and surrounding tissues in this group and in control subjects by MR imaging.

Study Group

The study was approved by the Institutional Review Board of the Children's Hospital of Philadelphia (Philadelphia, PA). Informed consent was obtained from each subject's parents.

Subjects with Down Syndrome

Eleven children with Down syndrome (age, 3.2 ± 1.4 yr) were recruited by advertisement through the Division of Human Genetics of the Children's Hospital of Philadelphia and the Down Syndrome Interest Group of Pennsylvania.

Exclusion criteria were as follows:

1. Likelihood of OSA (assessed by a standard questionnaire: see below)

2. Congestive heart failure

3. Contraindications for MR scanning such as ferromagnetic clips, implants, etc.

Control Subjects

Fourteen children with normal development and cognitive function (age, 3.3 ± 1.1 yr) matched to subjects with Down syndrome by age and sex, were recruited after careful selection from the group of patients who underwent head or neck MRI for other medical indications at the Children's Hospital of Philadelphia. All controls were questioned and examined before enrolment to ensure normal motor and cognitive milestones. In addition, subjects were excluded for the following:

1. Likelihood of OSA (assessed by a standard questionnaire: see below)

2. Evidence of a brain tumor or a seizure disorder requiring therapy

3. Genetic disorders associated with any craniofacial anomaly

4. Chronic respiratory disease, such as asthma, bronchopulmonary dysplasia

Sleep Questionnaire

A questionnaire regarding symptoms of sleep-disordered breathing, based on the one developed by Brouillette and coworkers (16) was used to assess the likelihood of OSA in all subjects. The questionnaire was completed by one of the parents before MRI. This questionnaire includes breathing-related queries such as whether the patient has “difficulty breathing during sleep,” “snoring episodes,” or “stops breathing during sleep.” All questions were answered on a 4-point scale, ranging from “never” to “constant.” On the basis of the questionnaire no subject with a score < −1 would be expected to have OSA, a score between −1 and 3.5 is considered indeterminate, and a score > 3.5 is considered highly predictive of OSA (16).

Overnight Polysomnography

For subjects having indeterminate OSA or positive scores, polysomnography was performed 0–4 wk before MRI. Subjects were studied in the Sleep Disorders Center at the Children's Hospital of Philadelphia. Subjects slept for about 8 h and did not receive any medications to induce sleep. Scoring of respiratory variables during sleep and sleep stages was performed on the basis of standards set by the American Thoracic Society and using the criteria of Rechtschaffen and Kales, respectively (17-19).

Magnetic Resonance Imaging

MRI studies were performed in the Department of Radiology at the Children's Hospital of Philadelphia. Control subjects underwent upper airway imaging after completion of clinical head or neck MRI.

Sedation Protocol

All subjects were sedated before MR imaging. The sedation protocol was intravenous pentobarbital at 2 mg/kg, in a slow push in increasing increments of 2 mg/kg until sleep. A maximum of three doses or a total dose of 200 mg was given. All subjects were monitored continuously by pulse oximetry and observed by a physician until recovery (∼ 1 h).

MRI was performed with a 1.5-T Siemens (Iselin, NJ) vision system. Images were acquired with a commercially available anterior– posterior volume neck or head coil. The patient's head was positioned supine with the soft tissue Frankfort plane (tragus of the ear to orbital fissure) perpendicular to the table. All images initially included a rapid spin echo sagittal localizing scan to confirm that the field-of-view and centering were appropriate (spin echo TR = 650 ms, TE = 14 ms, 192 × 256 matrix, slice thickness 3 mm, 1 acq, and FOV = 20 to 24 cm).

Sequential T1- and T2-weighted spin echo axial sections were obtained, spanning from the orbital cavity to the larynx. The following parameters were used for the T1-weighted images: TR = 650 ms, TE = 14 ms, 192 × 256 matrix, slice thickness 3 mm with distance factor 0, 1 acq, FOV = 20 to 24 cm, RECFOV 6/8; and for the T2-weighted images; TR = 6,000 ms, TE = 90 ms, 110 × 256 matrix, slice thickness 3 mm with distance factor 0, 1 acq, FOV = 20 to 24 cm, RECFOV 6/8. The following parameters were used for sagittal images spanning bilaterally from the midline T1: TR = 650 ms, TE = 14 ms, 192 × 256 matrix, slice thickness 3 mm with distance factor 0, 1 acq, FOV = 20 to 24 cm, RECFOV 8/8; and for the T2-weighted images: TR = 6,000 ms, TE = 90 ms, 132 × 256 matrix, slice thickness 3 mm with distance factor 0, 1 acq, FOV = 20 to 24 cm, RECFOV 8/8.

Image Processing and Anatomic Measurements

Measurements from MR images were made with software developed for image display and analysis known as VIDA (Volumetric Image Display and Analysis) (13, 20, 21). Soft tissue and bony structure segmentation was performed by manual tracing. The airway was segmented by intensity threshold, using the half-maximum value for the tissue/air boundary (20, 21).

Axial Measurements

From a retropalatal axial T1-weighted image at the level of the maximal tonsillar cross-sectional area we determined the areas of the tonsils, pterygoids, parapharyngeal fat pads, and airway cross-section (Figure 1). In addition, we measured on other axial images the largest adenoid area, maximum maxilla width, and the internal distance between mandibular heads.

Sagittal Measurements

From a midsagittal T1-weighted image we determined the cross-sectional areas of the adenoid, soft palate, tongue, mandible, hard palate, and the combined nasopharyngeal and oropharyngeal airway (Figure 2). We measured the length of the hard palate, defined from nasal spine to end of the palatine bone. We assessed mandible size by measuring the distance between mental spine and the clivus through the soft palate centroid (the average point of the spatial positions of all pixels within the soft palate region; Figure 2).

Volumetric Measurements

From adjacent axial slices we determined the volumes of the following: adenoid, tonsils, tongue, soft palate, mandible, and total nasal/ oral pharyngeal airway. The anatomic structures were manually traced on a slice-by-slice basis (Figure 1). Volumetric measurements (except tonsils and adenoid) were made from adjacent axial T1-weighted slices spanning from the base of the orbital cavities to the epiglottis. For measurements of adenoids and tonsils we used T2-weighted images because of its better resolution of lymphoid tissue. Measurement of tonsillar volume combines that of the right and left tonsils.

Data Analysis

We hypothesized that children with Down syndrome without OSA have a smaller upper airway in comparison with matched control subjects. Therefore, the primary outcome variable set was defined as (1) axial retropalatal airway cross-sectional area, (2) total midsagittal airway cross-sectional area, and (3) the total nasopharyngeal/oropharyngeal airway volume. Secondary outcome measures were considered as hypothesis generating and included lengths, areas, and volumes of the soft tissues, lymphoid, and bony structures of the midface and lower face.

Mean and standard deviation were used to summarize continuous variables. For comparisons between the groups for demographics, questionnaire data, and MRI data we used two-tailed unpaired t test, Wilcoxon rank test, or χ2 test as appropriate. p Values of < 0.01 and < 0.05 were considered significant for the primary and secondary outcome variables, respectively.

We studied 11 children with Down syndrome, average age 3.2 ± 1.4 yr (age range, 1.8–6.0 yr; 6 males and 5 females), and 14 control subjects with an average age of 3.3 ± 1.1 yr (age range, 1.7– 6.7 yr; 4 males and 10 females). Three additional subjects with Down syndrome were excluded from our study because they had evidence of OSA as noted by questionnaire (score > 3.5) and polysomnography. The Down syndrome group was not significantly different from control subjects with respect to age, sex, and weight (13.6 ± 4.6 versus 15.3 ± 2.6 kg). However, they were 9% shorter (88 ± 11 versus 97 ± 8 cm; p < 0.05). All control subjects had normal development and cognitive function, with no respiratory disorders or craniofacial anomalies. The primary indications for head or neck MRI in control subjects were the following: single seizure/febrile convulsion (four subjects), migraine/headache (four subjects), head concussion (three subjects), toe walking (one subject), scoliosis (one subject), and eye injury (one subject). Thus, none of these clinical indications would be expected to affect the upper airway.

Sleep Questionnaire

All control and Down syndrome subjects were screened by the sleep questionnaire developed by Brouillette and coworkers (16) to exclude the possibility of OSA. All control subjects had scores < −1 and as a group had a mean apnea score of −3.6 ± 0.4, indicating the absence of OSA. This score did not differ significantly from the Down syndrome group mean score of −2.6 ± 1.3. As mentioned above, three additional subjects with Down syndrome were excluded from the study because of evidence of OSA shown by both the questionnaire and polysomnography. Of the 11 subjects with Down syndrome who were studied, 3 had apnea scores between −1 and 3.5; however, they showed no evidence of OSA by polysomnography and therefore were included in the analysis. The latter subjects had an apnea index of 0.3 (0–0.9) and a mean respiratory disturbance index of 2.3 (0.2–4.8), both within the normal range in our laboratory.

Magnetic Resonance Imaging

We noted no significant side effects of sedation in our subjects. Subjects with Down syndrome exhibited no evidence of apnea or significant arterial pulse oxygen desaturations during MRI and until full recovery.

Airway. The upper airway volume (nasopharyngeal and oropharyngeal) of children with Down syndrome was significantly smaller in comparison with the control group, 1.4 ± 0.4 versus 2.3 ± 0.8 cm3 (p < 0.005). Total midsagittal airway area was also smaller in children with Down syndrome, 1.7 ± 0.5 versus 2.7 ± 0.8 cm2 (p < 0.005). However, on the axial retropalatal level we found similar cross-sectional airway areas for both groups, 0.7 ± 0.2 versus 0.9 ± 0.4 cm2 (p = 0.26).

The sizes of the various tissues composing the upper airway structure of children with Down syndrome and control subjects as imaged by MR are presented graphically in Figures 3-5.

Soft tissues. The cross-sectional areas of the pterygoids, parapharyngeal fat pads, tongue, and soft palate obtained from axial and sagittal images are presented along with the volumetric measurements of the tongue and soft palate, in Figure 3. The volumes of the tongue and soft palate were similar in children with Down syndrome and in control subjects, 23 ± 7 versus 25 ± 4 cm3 and 1.6 ± 0.3 versus 1.9 ± 0.3 cm3, p = 0.36 and p = 0.15, respectively. The axial and sagittal cross-sectional areas of soft tissues were similar except for a significantly larger soft palate sagittal area, 1.9 ± 0.4 versus 1.3 ± 0.2 cm2, p < 0.0005, in children with Down syndrome.

Adenoids and tonsils. As can be noted from Figure 4, both the adenoid and tonsil volumes were significantly smaller in children with Down syndrome. The mean adenoid volume in children with Down syndrome was 2.1 ± 0.7 cm3 in comparison with 4.6 ± 1.4 cm3 in control subjects (p < 0.001). Similarly, tonsillar volume in children with Down syndrome was 2.8 ± 0.8 cm3, versus 4.3 ± 1.4 cm3 in control subjects (p < 0.01). A significantly smaller cross-sectional area of adenoids was noted on the axial plane but not on the midsagittal plane, 2.9 ± 0.8 versus 4.0 ± 0.8 cm2 (p < 0.005), and 1.9 ± 0.6 versus 2.2 ± 0.5 cm2 (p = 0.16). Finally, cross-sectional tonsils areas were similar, 2.8 ± 0.5 versus 3.1 ± 0.6 cm2 (p = 0.34) in both Down syndrome and control groups.

Facial skeletal structure. Figure 5 demonstrates the skeletal findings of our study. With respect to mandible dimensions, we noted that children with Down syndrome had a significantly smaller mandible volume compared with control subjects, 11.5 ± 3.7 versus 16.9 ± 2.9 cm3 (p < 0.0005). On the basis of mental spine–clivus distance in the sagittal plane, the mandible was found to be smaller in subjects with Down syndrome, 5.7 ± 0.6 versus 6.2 ± 0.4 cm (p < 0.05). However, the intermandibular head distance on an axial plane was similar in Down and control groups: 7.3 ± 0.8 versus 7.1 ± 0.5 cm, respectively. In addition, in children with Down syndrome the maxillary bone was narrower and the hard palate was significantly shorter, 4.6 ± 0.4 versus 5.0 ± 0.3 cm (p < 0.05) and 3.2 ± 0.4 versus 3.7 ± 0.2 cm (p < 0.005), respectively. The preceding findings suggest reduced mid- and lower face skeleton size in the subjects with Down syndrome in comparison with control subjects.

We used MRI to obtain length, area, and volume measurements of the upper airway and surrounding tissues of children with Down syndrome who had no evidence of OSA. Our measurements indicated a smaller upper airway and a smaller mid- and lower face skeleton in this group in comparison with normal subjects. Interestingly, adenoid and tonsil volumes of the children with Down syndrome were about half the size of those of control subjects. However, the tongue, soft palate, and pterygoid muscles surrounding the airway were similar in size to those found in the control group.

Children with Down syndrome are prone to develop OSA (2-4, 8). Obstructive sleep apnea in these subjects may lead to serious long-term complications such as pulmonary hypertension, cor pulmonale, and alterations in growth and behavior (2, 8, 10, 22-25). Treatment in the form of adenoidectomy, tonsillectomy, or other surgical modalities corrects OSA in only 30–50% of cases (2, 3, 10, 11). This suggests that airway obstruction in subjects with Down syndrome may be the result of other factors, including other sites of obstruction, reduced airway size, or reduced muscle tone.

We used MRI to delineate the upper airway on the basis of our experience with adults (13-15). MRI provides accurate and reproducible measurements without ionizing radiation. MRI has excellent resolution for all tissues surrounding the airway including lymphoid, muscle, and bone. A disadvantage of MRI compared with CT scan is the relative long acquisition time and, therefore, its greater sensitivity to motion artifacts.

To minimize movement during MR scanning, light sedation is given routinely to all children younger than 8 yr of age in our institution. We are aware that sedation could have affected muscle tone, impacting on airway measurements in our subjects. We assume that because the same sedation protocol was used for both groups, airway measurements would be affected in a similar fashion. Sedation should not have affected the volumetric measurements of muscle, lymphoid, and bone tissues.

Children with Down syndrome are known to have linear growth retardation of 5–20% (26) with similar deficit noted in the size of the facial skeleton (6, 7, 27, 28). In our study, children with Down syndrome were 9% shorter than control subjects. The effect of this growth retardation on comparison of the midface and lower face measurements of the two groups requires consideration.

We looked at the mid- and lower face skeletal structure as a box limited by the maxilla, mandible, clivus, and anterior cervical spine, and having three orthogonal axes. The volume of this box will therefore be the product of these axes. However, it should not be assumed that these axes are proportionally reduced with body height (9%). In that case the box volume in subjects with Down syndrome would be 0.91 × 0.91 × 0.91 = 0.754 or 24% smaller than control subjects. A more accurate approach is to assess the length of each of these axes. We made three approximately orthogonal measurements: mental spine–clivus distance, intermandibular width, and hard palate length, and found in subjects with Down syndrome that these were −8, + 2.8, and −13.5%, with respect to control subjects. Therefore, the box volume of the subjects with Down syndrome was estimated to be 0.92 × 1.028 × 0.865 = 0.819 or 18% smaller on average.

We found that the total volume of tissues measured in subjects with Down syndrome and control subjects including adenoid, tonsils, tongue, and soft palate, together with the airway, added to 30.9 versus 38.1 cm3, demonstrating a 19% lower total volume in subjects with Down syndrome and close to the estimated 18% reduction. However, we did not find equal reduction in the volume of the individual tissues. The adenoids, tonsils, tongue, and soft palate were 55, 35, 8, and 16% smaller in subjects with Down syndrome, respectively. Because it occupies a large share of the box volume, the 8% lesser volume of the Down tongue is not compensated by the other smaller Down syndrome structures: adenoids, tonsils, and soft palate. The upper airway in subjects with Down syndrome is affected by this different volume distribution to the extent that it is only 60% of the volume in control subjects.

In contrast to the lower airway, which has an intrinsic cartilaginous and smooth muscle structure, the upper airway is formed by the impression of surrounding tissues within the midface and lower face. In our view, anatomical restrictive factors within the skeletal boundaries of the mid- and lower face box comprise the major cause for the smaller airway in the subjects with Down syndrome who do not have OSA. We noted a smaller midface and lower face skeleton, especially in the superior–inferior and anterior–posterior aspects. Previous studies assessing cephalometeric and facial anthropometric measurements in the general Down syndrome population have noted similar findings (6, 7, 27, 28). However, by using MRI, we were able to obtain soft tissue measurements within these skeletal boundaries. Although it was previously thought that macroglossia contributes to airway obstruction in Down syndrome, volumetric measurements in this study show that the tongue and soft palate volumes in both the Down syndrome and control groups were similar. Cross-sectional areas of the pterygoids and parapharyngeal fat pads were likewise similar. These findings suggest the crowding of relatively normal-sized tongue and soft palate within the midface and lower face skeleton and secondary airway volume loss.

Conflicting information exists about the size and physiological effects of the adenoid and tonsils as well as the benefit of surgical removal of these tissues in Down syndrome (2-5, 8, 10, 11). This study shows that children with Down syndrome without OSA do not have increased adenoid and tonsil volume. Adenoid and tonsil size in subjects with Down syndrome were 55 and 35% smaller than noted in control subjects, respectively. Our findings support the report of Strome (11), who noted relatively small amounts of adenoid and tonsil tissue removed in 16 children with Down syndrome with symptoms of sleep-disordered breathing. Strome concluded that adenoidectomy is not indicated in these children and tonsillectomy should be reserved only for selected patients. Because we studied children without OSA, it is difficult to infer from our results to the size of the adenoid and tonsils in children with airway obstruction. However, our findings suggest that in our subjects, reduced upper airway size is not due to increased adenoid and tonsil size. It is conceivable that reduced lymphoid tissue in the nasopharyngeal and oropharyngeal regions has an effect protecting this particular group from OSA. Thus, it may be that subjects with Down syndrome who do not develop OSA have particularly small tonsils and adenoids, offsetting the effects of the skeletal abnormalities that compromise airway size. This hypothesis, we believe, is worthy of further study. In addition, smaller lymphoid tissue volume may be related to an altered immune function found in subjects with Down syndrome (29, 30).

We believe that the significantly smaller upper airway found in our study of subjects with Down syndrome without OSA may predispose to sleep-disordered breathing in the general Down syndrome population. The upper airway has less capacity to remain patent in the face of lymphoid hyperplasia, inflammation, loss of tone, and variation in lower face skeleton growth.

A possible limitation of our study affecting our measurements is related to the fact that our control subjects were matched by age rather than by height to the subjects with Down syndrome. We chose to match by age because age is an independent variable that is strongly associated with developmental maturation of anatomical structures surrounding the airway (31). Moreover, we have noted that age correlated better to the volumetric measurements obtained in this study in comparison with height.

In summary, we have shown that children with Down syndrome with no evidence of OSA have a significantly smaller upper airway compared with control subjects. Reduced airway size could not be attributed to increased adenoid or tonsil size. Airway size was found to be restricted by soft tissue crowding within the boundaries of a smaller midface and lower face skeleton.

The authors thank the children and families who participated in the study, and Mark Batshaw, M.D., Elaine Zackai, M.D., and Donna McDonald-McGinn, M.S., clinical genetic councilor.

Supported by grants HL-62408, HL-60287, and HL-07713 from the National Institutes of Health.

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Correspondence and requests for reprints should be addressed to Raanan Arens, M.D., Division of Pulmonary Medicine, Children's Hospital of Philadelphia, 34th Street and Civic Center Blvd., Philadelphia, PA 19104-4399. E-mail:


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