Journal Article

The first Japanese case of autosomal dominant cutis laxa with a frameshift mutation in exon 30 of the elastin gene complicated by small airway disease with 8 years of follow-up

Haraguchi Hashiguchi, Mizuha, Ouchi, Takeshi, Uehara, Tomoko, Tsuji, Atsutoshi, Fukunaga, Koichi, Kaji, Masanori, Chubachi, Shotaro, Kosaki, Kenjiro, Asakura, Takanori, Hasegawa, Naoki, Suzuki, Hisato, Yamada, Yoshitake, Tanaka, Hiromu, Nozaki, Taiki, Yamada, Mamiko, Namkoong, Ho, Tanabe, Naoya

2024

Overview

Background Cutis laxa constitutes a diverse group of connective tissue diseases, both inherited and acquired, characterized by loose skin and varying systemic involvement, including pulmonary lesions. While cutis laxa has been linked to conditions like emphysema, asthma, and bronchiectasis, the specific pathological and radiological characteristics underlying pulmonary complications related to cutis laxa remain unclear. Case presentation A 36-year-old woman, diagnosed with cutis laxa at birth, presented to our outpatient clinic with severe obstructive ventilatory impairment, evident in pulmonary function tests (expiratory volume in one second (FEV 1 )/forced vital capacity (FVC): 34.85%; %residual volume [RV]: 186.5%; %total lung capacity [TLC]: 129.2%). Pulmonary function tests also indicated small airway disease (%FEF50%, 7.9%; %FEF75%, 5.7%; and %FEF25–75%, 6.8%). Computed tomography (CT) revealed the lack of normal increase in lung attenuation on expiratory CT scan, with no discernible emphysematous changes. Exome sequencing was performed to confirm the association between the pulmonary lesions and cutis laxa, revealing a frameshift variant in exon 30 of the elastin gene ( ELN ). Further analysis employing a parametric response map revealed a longitudinal increase in the percentage of functional small airway disease (fSAD) from 37.84% to 46.61% over the 8-year follow-up, despite the absence of overt changes in CT findings, specifically the lack of normal increase in lung attenuation on expiratory CT scan. Over the same follow-up interval, there was a modest reduction of 25.6 mL/year in FEV 1 coupled with a significant increase in %RV. Pulmonary function test metrics, reflective of small airway disease, exhibited a continual decline; specifically, %FEF50%, %FEF75%, and %FEF25–75% diminished from 7.9% to 7.0%, 5.7% to 4.6%, and 6.8% to 5.4%, respectively. Conclusions This case highlighted an instance of autosomal dominant cutis laxa arising from a frameshift variant in exon 30 of ELN , accompanied by small airway disease. Comprehensive investigation, utilizing quantitative CT analysis, revealed a longitudinal increase in fSAD percentage with a mild reduction in FEV 1 . These findings indicate that elastin deficiency may not only diminish elastic fibers in the skin but also be implicated in small airway disease by impacting components of the extracellular matrix in the lungs.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Adult / Allergic diseases / Analysis / Asthma / Breast cancer / Bronchiectasis / Care and treatment / Case Report / Chronic obstructive pulmonary disease / Computed tomography / Connective tissue diseases / Critical Care Medicine / Cutis laxa / Cutis Laxa - genetics / Diagnosis / East Asian People / Elastin / Elastin - genetics / Emphysema / Exons / Extracellular matrix / Female / Follow-Up Studies / Frameshift Mutation / Gene mutations / Genetic aspects / Health aspects / Humans / Intensive / Internal Medicine / Japan / Lung - diagnostic imaging / Lung - physiopathology / Lung diseases / Medical imaging / Medicine / Medicine & Public Health / Obstructive lung disease / Parametric Response Map (PRM) / Pneumology/Respiratory System / Pulmonary function tests / Pulmonary lesions / Respiratory function / Respiratory Function Tests / Respiratory tract diseases / Skin / Skin diseases / Small airway disease / Tomography / Tomography, X-Ray Computed / Whole genome sequencing