This study details a case of ADCL with small airway disease confirmed using QCT analysis. Despite a childhood cutis laxa diagnosis, the patient maintained good health until the onset of breast cancer. Preoperative pulmonary function tests revealed severe obstructive ventilatory impairment, prompting genetic testing that identified ADCL attributable to a frameshift variant in exon 30 of the ELN gene.
ADCL is associated various lung diseases, including bronchiectasis (4), emphysema (6), and asthma (7). Graul-Neumann et al. described a case of ADCL complicated by congenital emphysema, where the patient developed respiratory distress syndrome and pneumothorax immediately after birth (12). Corbett et al. reported two cases, a mother and daughter, both diagnosed with ADCL and having risk factors (smoking and heterozygosity for alpha-1-antitrypsin deficiency) leading to early onset emphysema (6). Urban et al. provided clinical information about a patient with ADCL who, after a history of repeated chest infections in childhood, was later diagnosed with bronchiectasis using bronchography (13). Previously reported ADCL cases exhibited frameshift variants in exon 30 (14) or 32 (15) of ELN, resulting in the production of abnormal elastic fibers. A previous study suggested that a defect in the ELN gene is an independent risk factor for developing COPD (13).
In this case, exome sequencing detected frameshift variants in exon 30 of the ELN gene (Figure 3). Functional mapping studies have pinpointed crucial domains in the C-terminal region of the tropoelastin protein encoded by exons 30 and 36, which are critical for tropoelastin self-association and interaction with cells and accessory assembly proteins (16).
To our knowledge, no reports have documented ADCL with lung disease that include a comprehensive longitudinal follow-up of QCT and pulmonary function test findings. This case report not only validates the existence of small airway disease but also reveals the longitudinal change in fSAD% on CT, contributing to our understanding of the pathogenesis of cutis laxa. Additionally, we utilized state-of-the-art QCT techniques beyond PRM to thoroughly evaluate the extent of small airway disease associated with cutis laxa.
QCT for lung diseases has rapidly advanced over the past few decades and now has diverse applications, from evaluating the extent of emphysema (17) to assessing the severity of interstitial lung disease (18). COPD is one of the most studied lung diseases using QCT. COPD is characterized by three constituent elements: inflammation of the small airways (bronchiolitis), destruction of lung parenchyma (emphysema), and gross airway disease (19). The principal components, fSAD and emphysema, collectively contribute to disease progression in a heterogeneous combination unique to each patient. PRM was developed to assess this combination of COPD and identify the severity of fSAD and emphysema (8).
Within the framework of PRM, emphysema severity is quantified as the ratio of image voxels registering below –950 Hounsfield Units (HU) to the total lung volume in the inspiratory CT scan. Conversely, fSAD is defined as the percentage of image voxels with normal attenuation (–950 to –650 HU) in inspiratory CT scans and reduced attenuation (<–856 HU) in expiratory CT scans, indicating air trapping (8). According to PRM analysis in healthy populations, fSAD% was 20% ± 8% (95% confidence interval [CI]: 16–25%) and emphPRM% was 1% ± 1% (95% CI: 1–2%) (20).
In the PRM analysis of this case, fSAD% increased from 37.84% to 46.61% over the 8-year follow-up, whereas there was no deterioration in emphPRM% (from 22.73% to 19.17%) during the same period (Figure 4a and 4b). Despite the change in fSAD%, there were no noteworthy alterations in the visual CT findings.
Although no visual CT findings indicated emphysema, emphPRM% in this case was significantly elevated. This seemingly contradictory results of CT visual findings and QCT can be explained by emphysema-like lesions not caused by parenchymal destruction. Emphysema-like lesions, homogeneously distributed in low-attenuation areas on CT, are caused by increased collateral ventilation, hypoxic vasoconstriction, and impaired lung development (21).
The CT total airway count (TAC) serves as a surrogate biomarker for early small airway changes below CT resolution in COPD patients and is associated with a decline in longitudinal lung function (22).
The human bronchial tree demonstrates geometric attributes of self-repetition across various scales, termed fractals (23). The airway fractal dimension (AFD) increases proportionally with the heightened intricacy of bronchial tree geometry, consequently diminishing in cases of airway narrowing and loss. AFD has been shown to be significantly associated with clinical parameters of COPD severity, such as the frequency of exacerbations, 6-minute walking distance, FEV1 and FEV1/FVC in patients with COPD (24).
The bronchial wall area percentage (WA% = 100 × wall area/total bronchial cross-sectional area) represents the standard CT measure for central airway abnormalities. Statistically significant associations between WA% and FEV1% are reported in both smokers and never-smokers (25).
The longitudinal changes in TAC, AFD, and WA% ranged from 114 to 111, 1.56 to 1.69, and 68.8% to 66.6%, respectively (Figure 5), indicating no significant deterioration.
Over the 8-year follow-up period from the initial visit, a decrease of 25.6 mL/year in FEV1 was observed. Comparatively, in nonsmoking Japanese women, the average decrease in FEV1 was 19.6 mL/year (26), underscoring a higher rate of FEV1 decline in our case compared to the average.
A decrease in FEV1 reflects relatively large airway dysfunction, whereas forced expiratory flow (FEF) is a sensitive indicator of small airway disease. When two of the three indicators of FEF50%, FEF75% and FEF25–75% (alternatively recognized as maximum mid expiratory flow) fall short of the threshold of 65%, it is now generally accepted that small airway dysfunction is present (27). During the initial consultation at our hospital, the %FEF50%, %FEF75%, and %FEF25–75% were 7.9%, 5.7%, and 6.8% of predicted, respectively, significantly below the established threshold of 65% (Table 1).
Following an 8-year longitudinal assessment from the initial visit, the pulmonary function test parameters reflecting small airway disease exhibited a progressive decline (%FEF50%, %FEF75%, and %FEF25–75% transitioning from 7.9% to 7.0%, 5.7% to 4.6%, and 6.8% to 5.4%, respectively).
This is the first reported case of ADCL with an in-depth quantitative CT analysis revealing a longitudinal fSAD% increase alongside an above-average reduction in FEV1.
Although the specific etiology and clinical course of lung involvement in cutis laxa are not fully understood, it is possible that small airway disease precedes emphysematous changes, paralleling the pattern observed in COPD. We advocate for meticulous monitoring with pulmonary function tests and CT scans, even in cases of cutis laxa with minimal CT evidence of emphysematous changes. Early identification of small airway diseases presents a substantial challenge, and addressing this condition through treatment involves additional complexities, primarily attributed to difficulties in drug delivery to the small airways (28). Further investigations into small airway diseases associated with connective tissue diseases are imperative to elucidate the pathogenesis of the disease and devise more efficacious therapeutic interventions.