Klinefelter's Syndrome

Patients with Klinefelter's syndrome show a high incidence of restrictive lung defects, the pathogenesis of which is not clear yet. We investigated the respiratory muscle force (Pimax) and lung compliance in 13 patients with Klinefelter's syndrome who had not been receiving hormonal therapy for at least one year prior to being studied. Eleven were smokers and two were nonsmokers. None showed abnormalities of the chest wall. Five had normal lung volumes and eight showed a restrictive defect (TLC < 80 percent, VC <85 percent, [FEV.sub.1]FVC percent within normal values); DcosB and arterial blood gases were within normal limits. Pimax was similar in restricted (-115.9[+ or -]26.7 cm [H.sub.2]O) and not restricted patients (-115.4[+ or -]20.3 cm [H.sub.2]O), all within reference values. Lung compliance, however, was significantly decreased in the four patients studied (0.13[+ or-]0.08 cm [H.sub.2O.sup.-1]) compared with five normal control subjects (0.29[+ or -]0.05 cm H.sub.O.sup.-1]). We conclude that the likely cause of the lung restriction is a decrease of compliance of the lung matrix, probably related to the absence of testosterone.

Klinefelter's syndrome is a disorder in phenotypic men, characterized by the presence of two or more X chromosomes. The most frequent karyotype is XXY. The clinical picture of these individuals includes small and firm testes, decreased testosterone level, infertility, gynecomastia, and frequently eunuchoid aspect and mild mental retardation.

Pulmonary disease is known to be more prevalent in these patients than in the population at large.[1] A number of lung diseases have been associated with Klinefelter's syndrome: chronic bronchitis and emphysema, bronchiectasis, asthma, pectus excavatum, kyphoscoliosis, pulmonary cysts, sarcoidosis, and lung infections,[2] some of them probably unrelated to the phenotypic disorder (whether these patients smoke is usually important).

The few pulmonary function studies carried out to date show a high incidence of restrictive defects, far greater than obstructive defects,[2] despite heavy cigarette consumption. Restrictive lung defects have been attributed to chest wall abnormalities, bony deformities, increased chest wall compliance, decreased respiratory muscle strength, and occult parenchymal disease.[3] However, data supporting these theories have not been presented (to our knowledge). In any case, lung restriction has been reported in the absence of other demonstrable pulmonary disease or musculoskeletal abnormalities.[4]

In our investigation, we have examined the respiratory muscle force and the lung compliance of these patients to determine whether a decrease of respiratory muscle force or a decreased lung compliance could explain the observed restrictive lung defects.

METHODS

Subjects

We studied 13 individuals with Klinefelter's syndrome and no respiratory symptoms who were recruited from the registry of the andrology clinic of our hospital. The diagnosis had been confirmed by positive buccal smear. None had been receiving hormonal therapy for at least the year before entering the study. The mean age [+ or -] standard deviation of the group was 30.0 [+ or -]9.2 years (range, 19 to 46 years), their height was 176.2 [+ or -]10.5 cm, and weight was 80.8 [+ or -]7.3 kg (Table 1). Eleven were smokers and two were nonsmokers. None had been working in a setting known to cause lung disease. Chest inspection and thoracic roentgenographic examination did not disclose any abnormality of the thoracic cage.

Pulmonary Function Studies

Lung volumes, including the determination of the residual volume by the helium dilution method, and the forced expiratory spirogram were determined in a 10-L dry spirometer (Mijnhardt, Volugraph 2000). Reference values were those obtained in our laboratory from an autochthonous population of the same ethnic characteristics. The respiratory muscle force was assessed by measuring the maximum inspiratory pressure (PImax) in the sitting position, using a pressure transducer (Gould-Stratham P-23 ID; range, -50 to +300 mm Hg); the highest value obtained after the first second of five consecutive correct maneuvers was selected. Reference values were those of our laboratory.[5] Lung compliance was determined in four patients and five healthy control subjects by the flow interruption method, using a pneumotachograph (Jaeger, linear response 0.1 to 14 L/s) and integration of flow to obtain volume. Pressure was recorded 100 ms after closing the shutter. Reference values were those of five normal healthy volunteers of similar age. To complete our information on the pulmonary function status of our patients, single-breath CO lung diffusing capacity (DCOSB) and arterial blood gases were also determined.[6]

RESULTS

As can be seen in Table 2, of the 13 individuals with Klinefelter's syndrome investigated, five had normal lung volumes, with respect to reference controls (<30 years: TLC, 7.01 [+ or -] 1.17 [+ or -] L; VC, 5.48 [+ or -] 0.73 L;

[FVC.sub.1]/FVC,

84 percent; 30 to 39 years: TLC, 6.70 [+ or -] 1.11 L; VC, 4.99 [+ or -] 0.76 L; [FEV.sub.1]/FEV, 83 percent; 40 to 49 years: TLC, 6.98 [+ or -] 1.06 L; VC, 4.93 [+ or -] 0.67 L; [FEV.sub.1]FVC, 80 percent) and eight showed a restrictive defect, defined by a TLC <80 percent of predicted and VC <85 percent with an [FEV.sub.1]/FVC ratio within normal values. DCOSB and arterial blood gases were normal in all subjects.

The PImax was similar in restricted and nonrestricted groups and, in all instances, within reference values (Table 3). Lung compliance, however, was significantly decreased (p <0.001) in all four patients studied (0.13 [+ or -] 0.80 cm [H.sub.2O. [1]) with respect to five controls (0.29 [+ or -] 0.05 cm [H.sub.2O.sup-1]).

DISCUSSION

As previously found in other studies, [3] the incidence of restrictive lung defects in our series of patients with Klinefelter's syndrome was high: 8 (61 percent) of 13. None had airflow limitation. The fact that all of our patients were free of respiratory symptoms makes this group particularly appropriate to study the pathogenesis of the restriction in these patients. The cause of the restrictive defect in Klinefelter's syndrome has not yet been established. It is commonly attributed to chest wall abnormalities.[1] Deformities of the chest wall, such as kyphoscoliosis and pectus excavatum, have been reported in several patients,[2] but they are not frequent and cannot explain the majority of cases of restrictive defects. However, severe chest wall deformities may result in restrictive ventilatory defect. In our study, the absence of deformities of the chest wall and the presence of restrictive defects in most subjects do not support the theory that thoracic cage deformities are the cause of the observed restrictive ventilatory defects. [TABULAR DATA OMITTED]

Testosterone deficiency has also been implicated in the genesis of the restrictive defect seen in these patients;[7] testosterone deficiency may interfere with bony maturation and could result in either chest wall deformities or in an increase in the chest wall compliance resulting in an abnormal retraction of the chest wall due to the elastic recoil of the lung. Testosterone deficiency may also muscular weakness, thus theoretically leading to a restrictive defect. No direct proof has been presented to sustain this theory. On the contrary, our study does not support it; our patients had a normal chest wall configuration, both on inspection and on roentgenographic examination. All of our patients had normal respiratory muscle force assessed by measuring the PImax, despite the fact that none was receiving testosterone replacement therapy for at least one year. Nevertheless, maximal respiratory force bears a very weak relationship with restriction; ie, very severe weakness is needed to decrease lung volumes. Obesity, commonly found in patients with Klinefelter's syndrome, if important, may cause a certain degree of pulmonary restriction.[8] None of our patients was significantly overweight (Table 1). It has also been speculated that the lung restriction found in these individuals might be artifactual. These patients usually have disproportionately long limbs with respect to their trunk. Considering that prediction equations used to estimate lung volumes are based on height, they will tend to overestimate the predicted lung volumes for these individuals. However, if we correct the prediction values to a lower height, using the distance between the extended arms, restriction still is apparent.[3]

Attention has not been paid to the possibility of lung parenchymal abnormalities in Klinefelter's syndrome. Only the possibility of occult parenchymal disease has been raised with no further comment other than this was dismissed as a possibility in the series of Huseby and Petersen.[3] Although we cannot rule out the existence of occult parenchymal disease with certainty in our patients, none of them complained of respiratory symptoms. The physical examination of the chest and chest roentgenograms were unrevealing. Confirmation of the absence of parenchymal disease would require a lung biopsy specimen, but we deemed it not ethical to subject our patients to a thorcotomy. In our study, we also investigated whether a decrease of lung compliance due to parenchymal abnormalities rather than chest wall deformities might be responsible for the restrictive ventilatory defects in our patients. Having ruled out the presence of chest wall abnormalities, decreased respiratory muscle force, and parenchymal disease, a decrease of lung compliance would likely be due to decreased elasticity of the lung matrix. We examined this possibility in four patients with Klinefelter's syndrome and found a highly significant decrease of lung compliance compared with that of five healthy control subjects of similar age. We do not have a clear explanation for the decreased elasticity in absence of lung disease. One possibility could be the development of biochemical changes of the lung matrix, due to the absence of testosterone. However, the effect of the absence of testosterone on the human lung, to our knowledge, has not been reported.

From this study, we conclude that, as previously reported in other series, restrictive lung defects are frequent in patients with Klinefelter's syndrome (61 percent in our study). The likely cause of the restriction is a decrease of lung compliance due to diminished elasticity of the lung matrix. Chest wall abnormalities, when present, may contribute to the restrictive defect, but do not seem to be the main cause. The biochemical events leading to a decrease of elasticity of the lung matrix are not known, but they should be related to the absence of testosterone.

REFERENCES

[1] Rohde RA. Klinefelter's syndrome with pulmonary disease and other disorders. Lancet 1964; 2:149-50

[2] Daly JJ, Hunter H, Rickards DF. Klinefelter's syndrome and pulmonary disease. Am Rev Respir Dis 1968; 98:717-19

[3] Huseby JS, Petersen D. Pulmonary function in Klinefelter's syndrome. Chest 1981; 80:31-3

[4] Varkey B, Funahashi A. Restrictive defect in Klinefelter's syndrome. Chest 1982; 82:132

[5] Morales P, Diez JL, Marco V, Casan P, Sanchis J. Maximal static respiratory pressures: reference values for adults. Am Rev Respir Dis 1990; 141:717

[6] Cotes JE. Lung function: assessment and application in medicine. Oxford: Blackwell Scientific Publications 1979:369-70

[7] Gluck MC, Becker KL, Katz S. The pulmonary function of hypogonadal men before and after testosterone. Am Rev Respir Dis 1966; 144:676-80

[8] Domm BM, Vassallo ChL. Klinefelter's syndrome, obesity, and respiratory failure. Am Rev Respir Dis 1973; 107:123-26

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