Achondroplasia is a unique model of the effects of skeletal dysplasia and dwarfism on the respiratory system. We measured chest dimensions, spirometry, lung volumes, maximal expiratory flow volume curves, nasal and airways resistance, closing volume, maximal inspiratory/expiratory pressures, and tracheal area by acoustic reflection in 12 healthy subjects with achondroplasia. Anterior-posterior thoracic diameter was mildly reduced in men. Vital capacity for all subjects was 108 percent [+ or -] 18.6 percent (SD) of that predicted for achondroplastic subjects, but was reduced when compared with values for people of average stature that were predicted, based on either sitting height or thoracic height. The reduction was relatively greater in male than in female subjects. The RV/TLC and FRC/TLC ratios were normal. Other measurements were similar to those in average-statured adults. We conclude that achondroplasia results in a reduction in vital capacity out of proportion to what would be expected if these subjects had normal limb size. Although the lungs may be small, they are functionally normal, as are the airways.
Achondroplasia is the most common skeletal dysplasia resulting in short-limbed dwarfism. Respiratory complications occur frequently in achondroplastic infants and children under two years of age, and several factors appear to predispose to these complications, including chest wall deformity and neurologic problems at the level of the brain stem and upper cervical cord.[2-4] Chest wall involvement in achondroplasia is less severe than in other osteochondrodysplasias, but individuals with achondroplasia may have reduced chest measurements, pectus excavatum, accentuated thoracic kyphosis, or thoracic lordosis.[2,3]
In a spirometric survey of adults with achondroplasia, using height and age as predictors of vital capacity, we found that VC measurements appeared to be reduced. Several possibilities could explain this observation. First, the lungs of individuals with achondroplasia could be small relative to their trunk height or body size due to dysplastic changes in the rib cage. Second, the configuration of the chest wall could be such that VC was "reduced," but total lung capacity was normal. In that case, residual volume to total lung capacity ratios would be elevated. Third, lung volumes may, in fact, be appropriate to body size, but reference values for normal subjects, even after correcting for the short limbs in achondroplasia, are not appropriate to predict lung size in this disorder.
We performed detailed studies of lung function in individuals with achondroplasia in order to confirm our previous findings and to explore the possible mechanisms for "little lungs" in achondroplasia. In particular, we wished to determine total lung capacity in individuals with achondroplasia and to determine if the RV/TLC ratio was altered. A second aim was to detect any disparity between the indices of lung and airway size in this disorder. This study is the first detailed study of lung function in achondroplasia, a unique model of the effects of a skeletal dysplasia on lung and airway function.
All persons studied had classic heterozygous achondroplasia determined by clinical examination. They were attending a Little People of America (LPA) social convention in Boston, and selection was based on their willingness and availability for the study. Informed consent for participation in the study was obtained, as approved by the Committee on Clinical Investigation of the Children's Hospital, Boston, and the Clinical Trials Committee of St. Jude Children's Research Hospital, Memphis. The study was also approved by the Medical Advisory Board of the Little People of America.
Subjects completed a respiratory history and symptom questionnaire, and anthropometric measurements were made of standing height in stocking feet (H), sitting height (SH), and weight (W).
We also measured H, SH, and sitting height from the floor to the seventh cervical spinous process (SH-C7) in a separate group of 27 achondroplastic subjects at a second LPA convention, and in 70 normal-stature subjects.
Chest Wall Measurements: Transverse diameter at the levels of the axillae and xiphoid, of anterior-posterior (A-P) diameter at the same levels and of chest circumference were made during tidal breathing.[6,7]
Spirometry and Lung Volumes: Spirometry was performed with a 13-L chain compensated water-sealed spirometer. Forced expiratory volume, [FEV.sub.1], and FEF 25-75% were determined from the best of three spirometric tracings.
Total lung capacity was measured with a pressure-compensated, volume-displacement plethysmograph by the method of Dubois et al. The TLC was measured six times and averaged. Residual volume was calculated by subtracting VC from TLC.
Maximal Expiratory Flow-Volume (MEFV) Curves: MEFV curves were obtained while the subjects were breathing room air and after the subjects had been breathing a mixture of 80 percent helium and 20 percent oxygen (He-[O.sub.2]) for 3 minutes. Expiration was performed into a balloon-box system. The flow was measured as airflow out of the box with a No. 4 Fleisch pneumotachometer; and volume was measured with the plethysmograph. Three curves from each subject were collected on a computer, the signals filtered, and an average curve was generated using two or more curves. Room air and He-[O.sub.2] curves were matched at TLC to determine the ratio of maximum flows on He-[O.sub.2] and on air at 50 percent VC and to determine the volume of isoflow (VisoV).
Airways Resistance (Raw): Raw was measured at functional residual capacity with a modification of the Dubois method. Specific conductance (SGaw) was calculated from resistance and simultaneously measured thoracic gas volume (Vtg), and the average of six separate determinations was recorded. [TABULAR DATA OMITTED]
Nasal Resistance: Measurements were made during inspiration and expiration through each nares separately using the anterior technique. Measurements were compared to values from ten normal subjects made using the same apparatus.
Cross-Sectioned Airway Geometry: Tracheal cross-sectional area 6 to 10 cm down from the glottis was calculated as an average of four determinations using the acoustic reflection technique as previously described.[13-15]
Single Breath Nitrogen Test: SBNT was performed by the method of Buist and Ross. Volume and nitrogen signals were digitized, and the slope of phase III and the closing volume were determined visually from the computer tracing.
Maximal Inspiratory and Expiratory Pressures: MIP/MEP were measured with a mouthpiece and pressure gauge.
Hemoglobin Saturation: Saturation was measured by pulse oximetry in both the sitting and supine position.
Statistical significance of differences between means was assessed by standard normal theory, with a significance level of 0.05. Multiple regression analyses for male and female normal-stature subjects were performed, with forced vital capacity as the response variable and sitting height to C-7 and age as the explanatory variables.
There were 12 subjects in this study (Table 1), eight male and four female subjects, with a median age of 29 years (range, 10 to 53 years).
Two subjects were smokers and one was a former smoker. Six gave a history of a prior pneumonia. One patient had a history of multiple laminectomies for spinal stenosis and one had spinal fusion for kyphoscoliosis. Nine had a history of loud nighttime snoring, but none had a history of obstructive sleep apnea.
Chest Wall Measurements: Measurements of chest wall for the 12 achondroplastic subjects are shown in Figure 1. In agreement with our previous findings in adults with achondroplasia, transverse chest wall dimensions were relatively normal in this group compared to normal stature subjects of similar age, but AP diameters were low in four of eight male subjects. Chest circumference was 90.7 [+ or -] 9.1 percent (SD) of that predicted for males and 95.7 [+ or -] 12.2 percent (SD) of that predicted for females.[6,7]
Anthropometric Measurements: Measurements for the 12 subjects are shown in Table 1. Mean standing height was higher in the male than female subjects (131.0 [+ or -] 4.0 cm vs 122.5 [+ or -] 5.8 cm, excluding the youngest subject, p = 0.02). Mean sitting height for the 11 older subjects was 82.7 [+ or -] 4.8 (SD) cm, and sitting height to standing height ratio was 0.65 [+ or -] 0.03 (SD). We also measured heights and sitting height to C-7 in a separate sample of 27 achondroplastic subjects (ten males, 17 females) and compared them with measurements in 70 average-stature subjects (30 males, 40 females). Both SH and SH-C7 were significantly reduced in the achondroplastic subjects. In both sexes, the ratio of SH-C7 to SH was also significantly smaller in achondroplast subjects compared to average-statured controls (0.68 vs 0.76 for females, 0.70 vs 0.73 for males), indicating that head size makes a larger contribution to SH in achondroplasia and that the proportion of SH that is attributable to trunk height is also reduced in achondroplasia. Relative body proportions in the normal stature and achondroplasia subjects are illustrated in Figure 2.
Spirometry and Lung Volumes: Spirometric variables and lung volumes are shown in Table 2 and 3. Predicted values for vital capacity and other lung volume divisions were derived in several ways. We first used our regression formulae for spirometry which were based on a sample of 88 subjects with achondroplasia, and calculated that the mean vital capacity in these 12 subjects was 108 [+ or -] 18.6 percent of expected for achondroplastic subjects (Table 2). [TABULAR DATA OMITTED]
We previously derived predicted values for vital capacity in achondroplast subjects based on the observation that sitting height is less distorted in achondroplasia than is the lower limb length. We used the subjects' sitting heights to derive a "normalized" standing height, ie, their height if they did not have the short limbs of achondroplasia: predicted standing height = observed sitting height divided by sitting/standing height ratio for normal-stature subjects. When we used these "normalized" standing heights (mean 163 [+ or -] 12.5 cm for males and 152.5 [+ or -] 12.5 cm for the females in the present study, Table 1) in standard regression equations for VC, TLC, and other lung volumes, we observed that VC was 74 [+ or -] 11.7 percent, TLC was 70 [+ or -] 12.4 percent, and FRC was 74 [+ or -] 18.8 percent of predicted values[19,20] (Table 2).
Because predicting VC from sitting height (or derived standing height) is not valid if the proportion of sitting height that is thoracic height is not the same in normal subjects and those with achondroplasia, we determined whether use of thoracic height (SH-C7) rather than sitting height to predict vital capacity would result in normal values for vital capacity in achondroplasia. We derived equations for predicting FVC in normal stature adults (females [is greater than or equal to] 20 yr, males [is less than or equal to] 25 yr) based on SH-C7 height and age using spirometry in the 70 normal subjects. Although we did not have SH-C7 measurements for the achondroplastic subjects in this study or our previous study, we calculated SH-C7 from sitting height measurements using the mean SH-C7/SH ratio measured in the separate sample of 27 achondroplastic subjects. We then plotted FVC for 67 adult subjects with achondroplasia from both studies vs their calculated SH-C7 heights (Fig 3). The FVCs for females (n = 44) were still slightly reduced compared with the values for the normally proportioned adults (mean predicted 86 percent, p<0.001). The males (n = 23) also showed a reduction in FVC (mean predicted 70 percent, p<0.001) compared to the normal subjects. [TABULAR DATA OMITTED]
Thus, the apparent reduction in vital capacity seen in achondroplasia is, at least in part, real, and cannot be explained entirely by normalizing body proportions.
The RV/TLC and FRC/TLC ratios were normal in achondroplasia, compared with standards for average-stature subjects (Table 2).
Expiratory Flows: Flow volume curves in air were done in eight subjects and spirograms were done in all (Table 3). The [FEV.sub.1]/FVC% was 83.0 [+ or -] 6.0 (SD) percent, consistent with out previous observations in this population. The FEF 25-75%, V50 and V25 were 74.1 [+ or -] 27.6 (SD), 99 [+ or -] 21.8 (SD) percent and 89 [+ or -] 25.3 (SD) percent of predicted values, respectively, using calculated standing height in standard regression equations. When flow rates were expresseds as VC/s, flow rates in the anchondroplastic subjects were significantly increased compared with expected values (1.38 [+ or -] 0.26 (SD) vs 1.12 [+ or -] 0.10 (SD), p = 0.04) (Table 3). Flow rates in VC/s were higher in the female subjects than in the male subjects (1.58 [+ or -] 0.14 vs 1.17 [+ or -] 0.14, p = 0.02). Three patients who had MEFV curves in helium-oxygen showed a normal increase in flows (mean [[delta]V.sub.50] He-air: 1.40 [+ or -] .50 (SD) L/s) and Viso V (12, 13 and 22 percent).
Airway Resistance: Raw was slightly increased compared with normal-stature values (mean Raw 3.21 [+ or -] 1.32 cm [H.sub.2]O/L/s). This was somewhat suprising because Raw has been reported to be independent of height. When expressed as specific conductance, however, achondroplastic values were normal. This is consistent with measurements being made at low thoracic gas volumes (Vtg), where the high Raw is offset by the low Vtg resulting in a normal SGaw. The female subjects in this study had a higher SGaw than the male subjects (0.22 [+ or -] 0.05 vs 0.13 [+ or -] 0.03, p = 0.01).
Nasal Resistance Measurements: Nasal resistance data were compared with published values and with measurements made using the same apparatus in ten control subjects and were within the wide range of normal.
Cross-Sectional Airway Geometry: For five adults males (ages 17 to 53 years), the average tracheal area was 2.59 [+ or -] 0.67 (SD) [cm.sub.2], and for three females (ages 16 to 47 years), the average area was 2.67 [+ or -] 1.03 (SD) [cm.sub.2]. These results are within the limits obtained from normal men and women using the same technique.
Single-Breath Nitrogen Tests: Seven subjects had an average closing volume of 9.3 [+ or -] 4.0 (SD) percent of vital capacity and slope of phase III of 1.96 [+ or -] 1.39 (SD) percent [N.sub.2]/L, both well within the range of published values for normal subjects.
MIP/MEP: Maximal inspiratory pressures generated by the respiratory muscles in the achondroplastic subjects averaged - 132 cm [H.sub.2]O (SD, [+ or -] 48 cm [H.sub.2]O; range 45 to 200 cm [H.sub.2]O) and maximal expiratory pressures averaged + 182 cm [H.sub.2]O (SD, [+ or -] 81 cm [H.sub.2]O; range, 60 to 340 cm [H.sub.2]O).
Hemoglobin Saturation: Saturation was 93.4 [+ or -] 1.2 (SD) percent in the sitting position and 93.3 [+ or -] 1.5 (SD) percent in the supine position in 11 subjects.
Achondroplasia results from abnormal endochondral bone formation. The primary manifestations are short stature with proximal shortening of the limbs (rhizomelia; Fig 2), macrocepahly with prominent forehead and depressed nasal bridge, and narrowing of the spinal canal.
In a previous study in which we derived predicted values of spirometry in achondroplasia, it was unclear whether the abnormal skeletal growth that made standard prediction equations (based on standing height) unless for predicting lung size had any other direct effect on the lungs. In that study, we calculated what would have been the standing height for the subjects if they did not have the short lower body segment characteristic of achondroplasia. Calculations using age and this normalized standing height or sitting height indicated that there was a 25 to 30 percent reduction in vital capacity. One purpose of this study was to confirm this finding of "little lungs" and explore possible mechanisms for its occurrence.
Chest Wall Involvement
Involvement of the ribs and spine in achondroplasia is variable and is not as striking as the changes in the cranial and long bone. The chest may appear broad when viewed from the front but flattened in the anterior-posterior (A-P) dimension, an effect that is exaggerated by the prominent abdomen. The ribs may be foreshortened, and the curvature of the spine is frequently abnormal. Infants genrally have a lower thoracic-upper lumbar kyphosis when sitting, and older individuals have an exaggerated lumbar lordosis with a pelvic tilt. Reduced chest wall dimensions have been correlated with hypoxemia and respiratory complications in infants with achondroplasia.[2,3] In a previous study, we found AP chest diameters were reduced in some adults with achondroplasia, primarily male subjects, a finding similar to the results of this study.
Because of short limbs and truncal obesity, muscle mass often appears increased in achondroplasia, creating the impression of increased muscle strength. However, the trunk muscles could be at a mechanical disadvantage in an unusually shaped chest, contributing to a reduced VC. Muscle weakness and hypotonia are frequently seen in infants with achondroplasia, and their persistence could provide another explanation for reduced lung volumes. However, this study found normal to increased MIPs and MEPs in these adult subjects, indicating that muscle weakness was not a cause of lung restriction.
One possible explanation for the observation of reduced VC in our previous study is that the "normalized" standing heights that we derived from sitting height were excessive, leading to large predicted lung volumes. This does not appear to be the case, because sitting heights in persons with achondroplasia were decreased compared with normal subjects and the heights derived by assuming a normal body proportion indicate that these individuals would be small, even if they had normal limb lengths. The predictive equation used for spirometry has been validated for short subjects of normal proportions (in the range where these subjects would fall), but this is not true for predictive equations for other lung volumes.
The head is relatively large in achondroplasia and appears to contribute more to sitting height in persons with achondroplasia than in normal subjects. Therefore, at least part of the reason for the apparent reduction in VC (and presumably other lung volumes) is that extrapolation of sitting height overestimates trunk height in achondroplasia. However, when we used sitting height to C7 -- a more direct index of trunk height in achondroplasia. However, when we and normal subjects, the achondroplastic subjects continued to have significantly reduced FVC values. The reduction in lung volume presumably comes from the reduction in both chest diameter (primarily AP dimension) and thoracic height in achondroplasia. Men appeared to have both relatively smaller FVCs and AP chest diameters, suggesting that the effects of the skeletal deformity may be greater in men.
Although the present study shows that VC and other lung volume divisions were reduced, the ratios of RV/TLC and FRC/TLC were normal. This indicates that the developmental forces that set FRC and RV are relatively normal and argues against there being an overly "stiff" chest wall in which the chest wall pressure-volume relationship is altered out of proportion to the lung P-V relationship.
The upper airways is abnormal in younger subjects with achondroplasia and contributes to the development of nasal obstruction, frequent otitis medias, and obstructive sleep apnea. Obstructive sleep apnea has also been reported in some older individuals with achondroplasia. In the achondroplasia adults in this study, most of whom had a history of loud snoring, nasal resistance was normal.
Although airway resistance was slightly elevated in these subjects, specific conductance was normal. This we interpreted as consistent with additional evidence of reduced Vtg measurements in these subject. The acoustic area distance measurements give a noninvasive index of central airway size, which shows a close correlation with tracheal dimensions obtained by roentgenograms or computed axial tomography.[14,15] The measurements in achondroplasia are consistent with central airway sizes for normal adults.
When normalized for lung size by expressing expiratory flow rates as VC/s (or TLC/s), the flow rates in the achondroplastic subjects were significantly increased compared with the values expected for normal-stature subjects. There was also a trend toward gender differences in central airways, with male subjects having a lower SGaw, lower tracheal area and expiratory flow rates in VC/s, despite having larger absolute lung volumes. However, additional studies in achondroplastic subjects are needed to confirm these preliminary observations.
Hypoxemia is common in younger, symptomatic infant with achondroplastic.[2,3] This reflects the combined effects of low lung recoil in infants with low lung volume due to the chest wall deformity which leads to increased airway closure. Single-breath nitrogen studies and oximetry were normal in these adults subjects, indicating that the normal increase in lung recoil with age results in less airway closure during tidal breathing.
Lung Growth in Achondroplasia
There have been no careful morphometric studies of the lungs of patients with achondroplasia. In studies of infants with achondroplasia, reduced chest wall dimensions were found in some and appeared to be associated with increased risk of respiratory complications.[2,3] The reduced chest wall size in young achondroplastic infants presumably affects growth of lung parenchyma during the vulnerable period of alveolar growth, ie, the first 8 to 12 years of life. A similar effect on lung growth is seen in patients with kyphoscoliosis. On the other hand, the central conducting airways are well-formed at birth and their growth may not be as affected by the chest wall disorder. In adulthood, there is minimal reduction in external chest wall dimensions, perhaps due to catch-up growth of rib cartilage to replace the foreshortened bony portion of the ribs or simply due to the bulkiness of trunk muscle and fat.
Although there may be a reduction in lung volume the demands for gas exchange are also reduced in achondroplasia. The orthopedic complications of achondroplasia, including rhizomelia, genu varum, and flexion contractures of the hips, place limitations on gait and locomotion. It is, therefore, doubtful that a mild reduction on lung volume is physiologically significant, even with exercise. Lung size is directly related to body mass, and judging by the weight of these subjects (mean weight for males, 48.2 [+ or -] 8.5 kg), a 30 percent reduction in lung size compared with a 70 kg average-statured man would be appropriate if the general observation that scaling of lung size is directly proportional to body size in mammals applies.
We have made detailed pulmonary function studies in subjects with achondroplasia, a disorder which provides a unique "experiment of nature" on the effects of skeletal dysplasia on lung and airway growth. Although there are reductions in vital capacity (and other lung volume divisions) which appear disproportional to the expected values if these subjects had normal limb size, lung size is appropriate to body mass. The RV/TLC and FRC/TLC ratios are normal, and other studies of upper and lower airway size and function were comparable to results in normal subjects. Male achondroplastic subjects appear to have a relatively greater reduction in vital capacity, compared to normal stature subjects, and male achondroplastic subjects also have lower specific conductances, tracheal area by acoustic reflection, and expiratory flow rates in VC/s despite being taller and having larger absolute lung volumes compared to female achondroplastic subjects. Achondroplastic results in small, but functionally normal lungs, most likely as a result of the effects of the skeletal dysplasia on the developing lung and chest wall.
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