A 45-year-old man was referred to us with a complaint of cough and fever. He had a smoking history of Brinkman index 250, and alcohol consumption. He worked as a barber. He had severe micrognathia and had been taking medication for difficulty with mouth-opening for several years. His mother had died of rectal cancer at age 45 and a maternal aunt had died of collagen disease at age 50. His other family members had no health problems (Fig. 1). To the best of his knowledge, his birth and childhood development had been normal. His height was 160 cm and his weight was 43 kg, body mass index was 16.8. On physical examination, there were no specific respiratory or musculoskeletal findings. However, imaging of the chest revealed paraseptal emphysema with subpleural bullae, pleural or subpleural fibrosis, mild elevation of hilum, and consolidation in the apical regions of both lungs, which were more marked on the right than on the left (Fig. 2A, 2D, 2G). Emphysema complicated by pneumonia was diagnosed, then an antibiotic (moxifloxacin 400 mg once a day orally) was prescribed. His symptoms and the consolidation on his chest image were improved thereafter. Two years later, he was referred to us again with a complaint of dyspnea. However, both upper lung lobes were reduced in volume on his chest images (Fig. 2B, 2E, 2H). His respiratory symptom was alleviated with respiratory physical therapy. Three years after the second referral, he was treated for recurrent pneumothorax, pneumonia, rupture of Achilles tendon, and acute heart failure with unknown etiology at his local primary care hospital and subsequently admitted to our hospital because of progressive respiratory insufficiency. On physical examination, the temperature was 36.6℃, the pulse 70/min, the systolic blood pressure 106 mm Hg, respiratory rate 22/min, the oxygen saturation 89% while he was breathing ambient air. The crackles was heard on his right upper lung region and pitting edema was observed on both lower extremities. He was diagnosed with hypercapnic respiratory failure, cor plumonale and chronic necrotizing aspergillosis, based on the laboratory data in which the elevation of the partial pressure of arterial carbon dioxide, the positive of serum galactomannan antigen and the Aspergillus precipitating antibody, and right heart failure on transthoracic echocardiography were observed. A computed tomography scan of the chest obtained during his final admission showed a platythorax with a marked reduction in the size of the upper lobes of both lungs and cavitary lesions (Figs. 2C, 2F, 2I). The respiratory condition was not improved following the administration of anti-fungal agent (micafungin sodium 75 mg once a daily intravenously), diuretics (furosemide 20mg once a daily, intravenously) and the initiation of non-invasive positive pressure ventilation, and then died on the fifth day of hospitalization. An autopsy was performed after informed consent was obtained from the next of kin. At the autopsy, extrapulmonary separation was impossible because of severe adhesions in the right thoracic cavity. The right upper lobe was consolidated and contained cavitary lesions. Histo-pathologically, subpleural atelectatic indurations composed of marked fibroelastosis with collapse was seen in the left upper lobe (Fig. 3A). The cavitations contained filamentous fungi with brown spores (Fig. 3B) and were surrounded by fibrosis (Fig. 3C). PPFE coexisting with chronic necrotizing aspergillosis was the most likely pathological diagnosis in this case. Moreover, the multiple subpleural bullae seen in chest images and the history of severe micrognathia suggested hereditary connective tissue disease such as Marfan syndrome (MFS). Therefore, genetic tests for hereditary connective tissue disease were performed at Shinshu University Hospital. A novel variant of FBN2 (NM_001999.3:c.3160C > A:p.Arg1054Ser), was identified by next-generation sequencing and confirmed by Sanger sequencing. Mutations of FBN2 are responsible for CCA, which share clinical phenotype with MFS caused by mutation of fibrillin-1 (FBN1) gene. The variant in our case was localized to a mutation hotspot in FBN2 that is not registered in any of the population databases or supported by any of the predictive in silico programs; therefore, it was classified as a variant of uncertain significance in accordance with the guideline published by the American College of Medical Genetics and Genomics and the Association for Molecular Pathology [3]. The variant was not found in a healthy younger brother, suggesting that it was pathogenic. The patient’s other family members were apparently healthy but did not consent to testing for mutation in FBN2 gene. As the expression of FBN2 antigen is reported to be limited to the prenatal period and disappeared at post-natal period [4], we carried out the immunohistochemical staining for the expression of FBN2 antigen in the autopsied lung referring to a previously reported method [5], using non-cancerous lung parenchymal tissue obtained at autopsy from a case of pancreatic cancer as a control. More intense expression of FBN2 antigen was identified in the lung parenchyma from this case with the FBN2 monoclonal antibody compared to the controlled lung tissues (Fig. 3D–3I). Furthermore, we compared the morphology of elastic fibers and that of reticular fibers consisting of collagen Ⅲ in the autopsied lung from this case with the control lung tissue, because not only elastic fibers but also aberrant collagen proliferations were reported in various organs in MFS [6]. Compared to the controlled lung tissue, the elastic fibers in the lung parenchyma from this case were seen on microscopy with resorcin-fuchsin staining to be thickened, wavy, frayed, and granular (Fig. 4A, 4B) and the reticular fibers were sparse and did not have a typical mesh-like structure on silver staining in the whole lung parenchyma (Fig. 4D, 4E). According to the method described before [7], analysis of images of the lung using ImageJ software (National Institutes of Health, Bethesda, MD, USA) showed a significant increase in the ratio of the total surface areas of elastic fibers to those of alveolar spaces (Fig. 4C, p = 0.049 < 0.05) and a significant decrease in the ratio of the total surface areas of reticular fibers to those of alveolar spaces when compared with the control lung tissue (Fig. 4F, p = 9.3E-13 < 0.01). Conclusively, PPFE coexisting with chronic necrotizing pulmonary aspergillosis occurred in the case with a novel FBN2 gene variant and exhibited the expression of FBN2 antigen along with the aberrant and imbalanced proliferations of elastic and reticular fibers in the lung parenchyma.