Respiratory disease in WBS has not been previously reported. Our study suggests that significant obstructive lung disease, as assessed by spirometry, is not typically seen in adolescents and young adults with WBS. However, this does not preclude the possibility of significant subclinical pulmonary disease, as illustrated by the finding of substantial emphysema in a non-smoking WBS patient.
Haploinsufficiency at the elastin locus, a deletion shared by nearly all patients with WBS, may predispose subjects towards premature development of emphysema. Possible mechanisms for this increased susceptibility may involve increased sensitivity to oxidative and mechanical stress due to differences in elastin gene dosage. This hypothesis is supported by murine models employing mice with a heterozygous deletion of the elastin gene (Eln
+/-). While mice homozygous for the elastin gene deletion (Eln
-/-) develop extensive changes in baseline lung architecture, heterozygous mice (Eln
+/-) exhibit normal lung development and morphology despite having only approximately 45% of the lung elastin levels of wild type mice. However, when compared to wild type (Eln
+/+) mice, heterozygous mice exhibit an augmented inflammatory response and are more susceptible to developing emphysema when exposed to cigarette smoke [Shifren 2007
In the absence of a smoking history, other possible factors contributing to emphysema susceptibility may exist. In addition to increased sensitivity towards oxidative stress, reduced elastin levels in Eln
+/- mouse lungs alter the mechanical properties of the lung [Shifren 2007
]. Mechanical stress, in the absence of inflammation or oxidative stress, may contribute to the pathogenesis and propagation of emphysema [Brenner 1998
; Suki 2003
; West 1971
]. Patients with WBS have also been purported to exhibit accelerated signs of aging such as premature cataracts, gray hair, and presbycusis [Cherniske 2004
]. “Senile emphysema”, which is distinct from the normal aging lung [Verbeken 1992a
; Verbeken 1992b
], may be a part of the spectrum of premature aging in these individuals.
The lack of literature on pulmonary function and the development of emphysema in this population may reflect the general paucity of literature on adult WBS patients. Alternatively, because subjects with WBS often have other more salient systemic problems, pulmonary problems may not assume priority and may be underreported. Because many WBS patients have limited exercise capacity due to cognitive, musculoskeletal, or cardiovascular deficits [Giordano 2001
], their pulmonary reserve may be adequate to avoid respiratory symptoms in the course of their usual activities. When exertional dyspnea is reported, it may be difficult to discern cardiovascular etiologies from intrinsic pulmonary disease. Increased dyspnea in our WBS cohort is not unexpected and may be due in part to the higher incidence of comorbid cardiovascular disease in this population [Pober 2008
Besides dyspnea, a substantial proportion of our WBS patients reported respiratory complaints, such as wheezing and coughing, which have less salient overlap with possible cardiac etiologies. Although the differences between our WBS and reference populations did not reach statistical significance, this likely reflects low power due to our small sample sizes. Given the lack of obstructive pulmonary disease in our WBS patients, investigation into other lung impairments such as diffusion abnormalities or chronic bronchitis may represent an area that warrants further examination.
We acknowledge several additional limitations to this largely descriptive study. Our small cohort may be subject to self-selection bias with regards to participation. The diagnosis of WBS was previously confirmed by FISH analysis of the ELN gene deletion in the majority of our patients; the remaining minority may be subject to misclassification bias, though we feel this scenario is very unlikely in the setting of their typical WBS features. By using traditional spirometry to assess lung function, only subjects who were physically and mentally able to perform this test were included in the analysis; a possible alternative would be to utilize techniques which require limited subject participation similar to techniques employed for infants and young children. Longitudinal follow up and review of radiographic data in additional WBS subjects in the future would allow for improved detection of subclinical emphysema and lung disease. If emphysema is not a common finding among patients with WBS, more in-depth analysis of our case report subject may yield additional insights on the pathogenesis of non-smoking related emphysema.