Pulmonary Manifestations in Pseudoxanthoma Elasticum: A Review of Current Literature

Pseudoxanthoma Elasticum (PXE) is an autosomal recessive disease involving the calcification of elastic fibers resulting in ophthalmic, cutaneous, and cardiovascular clinical symptoms and has an estimated prevalence of 1:160,000. The disorder is caused by an ABCC6 gene mutation that causes loss of function of the MRP6 protein, resulting in dysregulated tissue mineralization. Characteristic traits of the disease include the presence of angioid streaks on funduscopic examination, cutaneous yellow xanthomatous papules in ABSTRACT

Pseudoxanthoma Elasticum (PXE) is an autosomal recessive disease involving the calcification of elastic fibers resulting in ophthalmic, cutaneous, and cardiovascular clinical symptoms and has an estimated prevalence of 1:160,000. 1 The disorder is caused by an ABCC6 gene mutation that causes loss of function of the MRP6 protein, resulting in dysregulated tissue mineralization. 2 Characteristic traits of the disease include the presence of angioid streaks on funduscopic examination, cutaneous yellow xanthomatous papules in INTRODUCTION flexural regions, and various cardiovascular manifestations. Serious complications of the disease secondary to elastic calcification of the tunica media layer of both peripheral and central arteries include permanent loss of vision, early onset myocardial infarction, valvular abnormalities such as mitral valve prolapse, intermittent claudication, and gastrointestinal hemorrhage. In the lung, elastin is expressed by pleural mesothelial cells, smooth muscle cells in airways and blood vessels, endothelial cells, and interstitial fibroblasts. 3 As the lungs contain extensive networks of elastic laminae, calcification of this system with some clinical manifestations is expected, yet not often reported clinically or in the literature. The purpose of this review is to identify clinical, radiologic, and histologic pulmonary findings of PXE.
A PubMed search was conducted with the following terms, "PXE", "pulm*" and "lung", and investigation was limited to adult case reports and cohort studies appearing in the English-language literature as of December 2020. Articles wherein the full text was not available or of an irrelevant publication type such as literature reviews, conference abstracts, posters, and editorials were excluded. There was a total of four case studies and one cohort study included in this review of pulmonary manifestations in PXE patients.
The literature search yielded four case reports and one cohort study from four countries with a total of 15 cases of pulmonary manifestations of PXE. Publication years spanned from 1980-2020.
A summary of the patient characteristics and clinical manifestations from each report is provided in Table 1. All four case reports featured PXE patients who complained of progressive dyspnea on exertion and underwent investigative workup that revealed elastic fiber irregularity in two discrete locations: the pulmonary arteries and the alveolar septum. Histologic vascular changes included fragmentation of elastic laminae in the tunica medica along with intimal and perivascular fibrosis. 4 Radiologic lung findings in one patient were limited to calcification and stenosis of the pulmonary artery that led to pulmonary hypertension. 5 One patient was found to only have discrete calcified nodules scattered diffusely across the alveolar septum without vascular changes. 6 A lung biopsy in a patient with severe dyspnea revealed calcified deposits within thickened alveolar lumina and septa, widespread irregularities in elastic laminae, This literature review demonstrates that elastic fiber calcification of the pulmonary arteries and alveolar septa can be a rare manifestation of PXE. All four patients who complained of progressive exertional dyspnea had radiologic and/or histologic evidence of pulmonary calcification. Theoretically, the significantly decreased TLC and DLCO values in PXE patients is consistent with decreased perfusion and a restrictive pattern of lung disease. One possible explanation for this is how PXE induced calcification in pulmonary arteries can result in stenosis and thus perfusion defects without effect on ventilation. Calcification and decreased elasticity of in alveolar septum can manifest as subclinical interstitial lung disease with decreased TLC. Continual calcification of these two regions over time could explain the insidious onset of progressive exertional dyspnea reported. However, spirometry abnormalities in PXE patients did not correlate with the presence of pulmonary symptoms. Long term observation for the development of dyspnea in the PXE cohort could be helpful in determining whether spirometry could be used as a screening tool for asymptomatic patients. In addition, while calcification of small arteries in the ocular, gastrointestinal,

DISCUSSION
and rarely cerebrovascular systems can result in bleeding complications of these areas, there were no reported cases of pulmonary hemorrhage. 9 Currently, there is no standard of care for PXE or its pulmonary manifestations. Due to the exceedingly rare nature of clinically significant symptoms, screening and referral to pulmonary specialists for monitoring is not recommended. Even in the presence of progressive exertional dyspnea, the impact of diagnostic imaging on overall management in PXE patients is minimal. Although uncommon, physicians might consider PXE as a diagnosis of exclusion for unexplained progressive exertional dyspnea if found in conjunction with classic cutaneous lesions or ocular findings. Further research must be conducted to evaluate the long-term clinical impact of pulmonary manifestations on PXE patients and possible response to experimental systemic therapies currently in development.