Abstract

Introduction

Cutis laxa syndromes are a group of inherited/acquired connective tissue disorders characterized by loose, redundant skin folds and defective elastic fiber assembly [1]. Elastic fibers are insoluble components of the extracellular matrix (ECM) that provide mechanical strength to the connective tissues of the lungs, skin, large arteries, ligaments, and cartilage [2]. While acquired cutis laxa results from inflammation triggered by infection, toxins, medications, and hematological malignancies, such as multiple myeloma [1] [3], inherited cutis laxa syndromes manifest heterogeneity with multiple genes responsible for elastic fiber assembly. The spectrum of inherited cutis laxa includes autosomal dominant cutis laxa (ADCL), autosomal recessive cutis laxa (ARCL), X-linked cutis laxa, and related disorders. ADCL arising from elastin gene variants generally present with less severity than ARCL [4], with most patients reaching an average lifespan [5].

While ADCL has been associated with diverse pulmonary complications including bronchiectasis [4], emphysema [6], and asthma [7], the specific etiology and radiological manifestations of pulmonary complications in ADCL remain elusive.

Recently, a modality of quantitative computed tomography (QCT), denoted as parametric response mapping (PRM), has been employed to assess the magnitude of functional small airways disease (fSAD) in individuals afflicted with chronic obstructive pulmonary disease (COPD). This study revealed that fSAD precedes the onset of emphysema in the progression of COPD [8].

We herein present a case of ADCL with a frameshift variant in exon 30 of the elastin gene (ELN), complicated by small airway disease, validated and investigated using QCT analysis.

Case presentation

The patient, a 36-year-old woman with recently diagnosed breast cancer, had been diagnosed with cutis laxa by skin biopsy at birth, undergoing skin reconstruction surgery as a child [9]. Her overall health remained robust until the breast cancer diagnosis, aside from episodes of childhood bronchitis, which did not require oxygen therapy. Upon presentation to our hospital, she reported no breathing difficulties or other subjective symptoms in daily life, demonstrating the ability to walk approximately 10 km on level ground. She was a never-smoker, with no history of noxious fume inhalation or oral pharmaceutical use, including dietary supplements. Thorough investigation revealed no significant history of occupational or environmental exposure. The patient was the fourth child of a consanguineous marriage between an uncle and a niece.

The physical examination revealed a body temperature of 36.1 °C, blood pressure of 137/85 mmHg, pulse of 76 beats per minute, respiratory rate of 16 breaths per minute, and oxygen saturation of 98% with ambient air. Dermatological examination revealed skin laxity (Fig. 1a) and a hooked nose (Fig. 1b).

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Fig. 1

The skin and facial view of our patient. Loose skin and wrinkles are observed in the upper arms (a). A hooked nose, one of the characteristic facial features of cutis laxa, is noted (b)

Preoperative respiratory function tests for breast cancer revealed an obstructive ventilatory defect (forced expiratory flow in 1 s (FEV1)/forced vital capacity (FVC) ratio [FEV1.0%=FEV₁/FVC]: 34.9%; %forced expiratory flow [FEV1]: 43.7%; %vital capacity [VC]: 104.7%; %residual volume [RV]: 186.5%; %total lung capacity [TLC]: 129.2%), small airway disease (FEF50%, FEF75% and FEF25–75% were 7.9%, 5.7%, and 6.8% of predicted, respectively), and diffusion impairment (%diffusion capacity of carbon monoxide/alveolar volume: 58.5%) (Table 1). Computed tomography (CT) showed the lack of normal increase in lung attenuation on expiratory CT scan, raising suspicion of small airway disease (Fig. 2a and b). In addition to these pulmonary findings, the chest CT scan revealed the presence of pectus excavatum.

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Fig. 2

The chest CT scans at the initial visit and after the 6- and 8-year follow-up. Inspiratory (a) and expiratory (b) chest computed tomography (CT) at the initial paired scans conducted at our clinic revealed a lack of normal increase in lung attenuation on expiratory CT scan (white arrow heads, b). Neither emphysema nor bronchial wall thickening, which is characteristic of bronchiolitis obliterans syndrome was present. In the inspiratory and expiratory chest CT after the 6- (inspiratory, c and expiratory, d) and 8- (inspiratory, e and expiratory, f) year follow-up periods, CT findings remained almost unchanged (white arrow heads, d and f)

Informed consent for molecular genetic analysis was obtained from the patient, with approval from the local institutional review board. Exome analysis was performed as previously reported [10], revealing a heterozygous variant: ELN (OMIM # 123,700) chr7:g.73477981delT (GRCh37), NM_001278939.1:c.2135del, p.(Leu712ProfsTer37), which was confirmed by Sanger sequencing (Fig. 3). This variant was scored as “pathogenic” (PVS1, PM1, PM2, and PS6) according to the American College of Medical Genetics and Genomics standards and guidelines for the interpretation of sequence variants [11].

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Fig. 3

DNA sequencing chromatogram from our patient. Genomic sequencing of exon 30 in ELN gene reveal a deletion of T at nucleotide position, chr7:g.73477981 in the patient, which causes frameshift variant

Over an 8-year outpatient follow-up period, a mild decline of 25.6 mL/year in FEV₁ and a marked increase in %RV were observed. Pulmonary function test parameters indicative of small airway disease demonstrated a progressive deterioration, with %FEF50%, %FEF75%, and %FEF25–75% decreasing from 7.9% to 7.0%, 5.7% to 4.6%, and 6.8% to 5.4%, respectively.

The lack of normal increase in lung attenuation on expiratory CT scan remained constant over the same period. Additionally, no significant visual CT findings were observed during the follow-up (Fig. 2c, d, e and f). However, a PRM analysis revealed that fSAD% increased from 37.84% to 47.67% over the 6-year follow-up and remained elevated during the subsequent 2-year follow-up,

Another PRM parameter, emphPRM%, did not exhibit significant deterioration over the same timeframe (Fig. 4a–c). A longitudinal QCT analysis was conducted, revealing no significant alterations in the CT total airway count (TAC), the airway fractal dimension (AFD), and the bronchial wall area percentage (WA%=100×wall area/total bronchial cross-sectional area) (Fig. 5). Pharmacological intervention was withheld due to the absence of respiratory manifestations and the lack of evidence.

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Fig. 4

PRM analysis at the initial visit and after the 6- and 8-year follow-up. At the initial computed tomography (CT) assessment conducted at our clinic, fSAD% and emphPRM% were recorded at 37.84% and 22.73%, respectively (a). After a 6-year follow-up period, fSAD% increased to 47.67%, whereas emphPRM% did not exhibit a significant change (b). After an additional 2-year follow-up, the fSAD% remained elevated, with no significant worsening in emphPRM% (c). emphPRM%, extent of emphysema; fSAD%, extent of functional small airway disease

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Fig. 5

QCT analysis except for PRM at the initial visit and after the 8-year follow-up. In the initial CT assessment conducted at our clinic, TAC, AFD, and WA% were 114, 1.56 and 68.8%, respectively (a). No significant changes in these parameters were observed during the 8-year follow-up duration (b). CT, computed tomography; TAC, total airway count; AFD, airway fractal dimension; WA%, bronchial wall area percentage. AFD, airway fractal dimension; TAC, CT total airway count; WA%, bronchial wall area percent

Conclusion and discussion

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. 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 predominantly caused by pathogenic variants in the elastin gene (ELN). In rare instances, mutations in FBLN5 (encoding fibulin-5) and ALDH18A1 can also lead to ADCL [1]. ADCL is associated with 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 heterozygous frameshift variants in exon 30 [14] or 32 [15] of ELN, resulting in the production of abnormally sparse and fragmented elastic fibers [1]. 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 (Fig. 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].

The patient was the offspring of a consanguineous marriage, which elevates the likelihood of autosomal recessive disorders. However, the genetic etiology in this case was autosomal dominant. Consequently, consanguinity did not contribute substantially to the development of ADCL in our patient.

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 pulmonary involvement in 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, which is one of the most studied lung diseases using QCT 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 of COPD. 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, fSAD% increased from 37.84% to 47.67% over the 6-year follow-up and remained elevated during the following 2 years. However, there was no significant deterioration in emphPRM% over the same timeframe (Fig. 4a–c). Despite the change in fSAD%, there were no noteworthy alterations in the visual CT findings (Fig. 2a, b, c, d, e and f).

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]. A limitation of this study is that there are only three data points in the PRM analysis. Data from both 6 and 8 years post-initial visit demonstrated an increase in fSAD% without progression in emphPRM%, which substantiates our assertion that there was only a deterioration of small airway disease without exacerbation of emphysema in this patient. However, accurately assessing the temporal changes in fSAD% in small airway disease associated with cutis laxa remains challenging when relying on only three data points.

The 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 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-min walking distance, FEV₁ and FEV₁/FVC in patients with COPD [24].

The WA% 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 (Fig. 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).

Cutis laxa is a known cause of pectus excavatum [28], and there is evidence that FVC, FEV1, and FEF25–75% are significantly lower in patients with relatively severe pectus excavatum [29]. In the present case, pectus excavatum was not severe enough to require treatment. In addition, there was no significant worsening of pectus excavatum during the follow-up period, and it was considered an unlikely cause of worsening respiratory function during the follow-up period.

ADCL is an exceptionally rare disease, with only 50 cases reported to date [30]. In a case report and literature review by Duz et al., 10 of 39 patients (28%) with ADCL (including 38 with pathogenic variants in ELN and one with a mutation in FBLN5) had emphysema [31]. 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.

In emphysematous COPD, fSAD can progress to emphysema; however, some reports suggest that fSAD does not advance to emphysema in cases of bronchiolitis obliterans [32]. Further research is required to elucidate the pathogenesis and mechanisms underlying small airway disease in cutis laxa. 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 [33]. A successful case of bilateral lung transplantation for juvenile emphysema associated with cutis laxa has been documented. In cases of severe respiratory function decline, lung transplantation may be a viable treatment option [34]. 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.

Acknowledgements

Abbreviations

Authors’ contributions

NH conceived of the presented idea. MK and HN wrote the main manuscript text. T.U., H.S., M.Y., and K.K. analyzed the genetic data of the patient. All authors discussed the results and contributed to the final manuscript.

Funding

This work was supported by AMED [Grant Number JP23ak0101206, JP23ek0109549, JP23tm0524008, JP22fk0108621, JP24ek0109682, JP23tm0524008, JP21lk1403044, JP22wm0325044], JST PRESTO [Grant Number JPMJPR21R7], and KAKENHI [Grant Number 23H02952, 21K15667].

Availability of data and materials

The datasets generated during and/or analyzed during the current study are not publicly available, but are available from the corresponding author on reasonable request.

Declarations

Footnotes

References