Nonidiopathic pleuroparenchymal fibroelastosis with a novel fibrillin-2 gene variant characterized by the expression of prenatal fibrillin-2 antigen and the aberrant proliferation of elastin and reticular fibers: a case report

doi:10.21203/rs.3.rs-2012080/v2

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Case Report

Nonidiopathic pleuroparenchymal fibroelastosis with a novel fibrillin-2 gene variant characterized by the expression of prenatal fibrillin-2 antigen and the aberrant proliferation of elastin and reticular fibers: a case report

https://doi.org/10.21203/rs.3.rs-2012080/v2

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Pleuroparenchymal fibroelastosis is a recently recognized clinical entity characterized by interstitial pneumonia that has pathological characteristics with proliferating elastin in the upper lung regions. Pleuroparenchymal fibroelastosis is categorized as idiopathic or nonidiopathicdepending on coexistent initiating factors; however, congenital contractural arachnodactyly, which is caused by abnormal production of elastin based on a mutation in the fibrillin-2 gene, rarely reports lung lesion especially features resembling pleuroparenchymal fibroelastosis. We present a case of nonidiopathicpleuroparenchymal fibroelastosis in a patient with a novel mutation in the fibrillin-2 gene, which encodes the prenatal fibrillin-2 protein as a scaffold for elastin.

Pathology

Pulmonology

pleuroparenchymal fibroelastosis

fibrillin-2

congenital contractural arachnodactyly

Marfan syndrome

elastic fiber

reticular fiber

case report

Amitani et al. reported that pleuroparenchymal fibroelastosis (PPFE) is sometimes complicated by lung cysts that develop into Aspergillus infection resulting from insufficiency of airway clearance at its advanced stage [1]. Here, we report that nonidiopathic PPFE and paraseptal emphysema developed into chronic necrotizing pulmonary aspergillosis (CNPA) in a patient suffering from severe micrognathia as a manifestation of congenital contractural arachnodactyly (CCA) carrying a novel fibrillin-2 (FBN2) gene variant known to be a responsible gene. We examined lung specimens from this autopsied case to explore the relationship between lung fibroelastosis and mutations in the FBN2 gene using an immunohistochemical (IHC) method and to evaluate the features and relative occupied areas of elastic fibers and reticular fibers using specific staining.

A 45-year-old patient who had severe micrognathia resulting in difficulty with mouth opening but no problems in birth and development in childhood was referred to us with a complaint of cough and fever. The patient had a history of smoking, with a Brinkman index of 250, and alcohol consumption. The patient’s mother had died of rectal cancer at age 45, and a maternal aunt had died of collagen disease at age 50 (Fig. 1).

The patient’s height was 160 cm, weight was 43 kg, and body mass index was 16.8. On physical examination, except for a slender and thin body habitus and micrognathia, there were no specific findings. However, chest imaging revealed paraseptal emphysema with subpleural bullae, pleural or subpleural fibrosis, mild elevation of the 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). With no evidence of Aspergillus infection according to negative galactomannan and precipitating antibody results and improvement on the images after the prescription of an antibiotic agent (moxifloxacin 400 mg once a day orally), a diagnosis of bacterial pneumonia superimposed on upper lung fibrosis and paraseptal emphysema was made. Two years later, after a second referral with a complaint of dyspnea, both upper lung lobes were reduced in volume on his chest images (Fig. 2B, 2E, 2H). Pulmonary function tests revealed mixed ventilatory impairment. Three years after the second referral, the patient was admitted to our hospital because of progressive respiratory insufficiency and recurrent pneumothorax. On physical examination, vital signs were almost normal, but oxygen saturation was 89% while the patient was breathing ambient air. Pitting edema was observed on both lower extremities, and breath sounds were decreased on both sides of the lung. The condition was not inconsistent with hypercapnic respiratory failure, cor pulmonale and CNPA based on the laboratory data, which revealed elevated partial pressure of arterial carbon dioxide, serum galactomannan antigen and Aspergillus precipitating antibody positivity, and right heart failure on transthoracic echocardiography. A computed tomography scan of the chest obtained during the final admission showed a platythorax with a marked reduction in the size of the upper lobes of both lungs and cavitary lesions (Fig. 2C, 2F, 2I).

Treatment with antifungal agents (micafungin sodium 75 mg once daily intravenously) and diuretics (furosemide 20 mg once daily intravenously) and the initiation of noninvasive positive pressure ventilation failed, and the patient died on the fifth day of hospitalization. Juvenile pulmonary paraseptal emphysema and a history of severe micrognathia suggested a hereditary connective tissue disease, such as Marfan syndrome (MFS). Therefore, genetic tests for hereditary connective tissue diseases 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 in FBN2 are responsible for CCA, which shares a clinical phenotype with MFS caused by mutation of the 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 guidelines published by the American College of Medical Genetics and Genomics and the Association for Molecular Pathology [2]. The variant was not found in the patient’s healthy younger brother, suggesting that it was pathogenic. The patient’s other family members were apparently healthy but did not consent to testing for mutations in the FBN2 gene. An autopsy was performed after informed consent was obtained from the next of kin. At autopsy, the right upper lobe was consolidated, including cavitary lesions, and impossible to separate from the thorax because of severe adhesion. Histopathologically, subpleural atelectatic indurations composed of marked fibroelastosis with collapse were 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 CNPA was the most likely pathological diagnosis in this case. The FBN2 antigen is known to be detectable in the lung epithelial region in the mesenchyme of the fetal lung and disappears in the postnatal period [3]. By IHC staining for the FBN2 antigen with an FBN2 antibody according to a previous report [4], the FBN2 antigen was intensely identified in this case of autopsied lung parenchyma compared to the control noncancerous lung tissues from an autopsied case of pancreatic cancer. Additionally, the appearances and quantities of elastic and reticular fibers by specific staining were different between the lungs of the patient and the control. In detail, compared to the control lung, elastic fibers were seen on microscopy with resorcin-fuchsin staining to be thickened, wavy, frayed, and granular (Fig. 4A, 4B), and a significant increase in the ratio of the total surface area of elastic fibers to that of alveolar spaces (Fig. 4C, p= 0.049<0.05) was observed by analysis of images of the lung using ImageJ software (National Institutes of Health, Bethesda, MD, USA) according to the method described previously [5]. The reticular fibers were sparse and did not have a typical mesh-like structure as observed by silver staining in the whole lung parenchyma (Fig. 4D, 4E) and had a significant decrease in the ratio of the total surface area (Fig. 4F, p=9.3E-13<0.01) using the same methods described above.

Clinical discussion

CCA (also known as Beals syndrome or distal arthrogryposis type 9, OMIM #121050) is a rare autosomal dominant disorder of connective tissue caused by mutation in FBN2, which encodes the FBN2 protein and is located at 5q23-31 [6]. Fibrillin is necessary for the assembly of elastin and its scaffold and contributes to tissue elasticity and resilience [7]. The skeletal features shared with MFS such as joint contracture and crumpled-looking ears in CCA are known to improve in the postnatal period [6]. The rarity of skeletal manifestations in adult onset sometimes makes it difficult to define a clinical diagnosis of CCA, and the diagnosis of CCA is established with suggestive findings and heterozygous FBN2 pathogenic variants identified by molecular testing.Our case had fewer characteristic features than classical CCA, except for micrognathia, which is a known craniofacial manifestation of CCA [6]. Respiratory insufficiency resulting from tracheomalacia and lung infection, including Nontuberculous mycobacterium infection, has been reported in patients with CCA [6, 8]; however, it is uncertain whether the apical lung fibrosis and aspergillosis caused by pulmonary emphysema found in MFS also occur in CCA [9]. PPFE is classified as a rare idiopathic interstitial pneumonia in the American Thoracic Society/European Respiratory Society classification in 2013 [10], but initiating and underlying factors including genetic disorders such as short telomere length,are also reported [11]. Reddy et al. suggested that repeated inflammatory damage due to recurrent infection, including aspergillosis, in predisposed individuals leads to PPFE [12]. We observed no laboratory data with evidence of Aspergillus infection until the advanced stage of PPFE and emphysema, supporting the hypothesis that preceding PPFE complicated by pulmonary cysts might be a predisposing condition for the onset of Aspergillus infection, as previously reported.

Imaging discussion

It has been reported that findings other than emphysema, such as upper lung fibrosis, recurrent infection, aspergillosis, and pneumothorax, occur in the lungs of patients with MFS [9, 13-14]. Paraseptal emphysema and blebs caused by fragile collagen and elastic fibers are some of the pathological manifestations of MFS [15] but are not specific to MFS, and their presence is cause to suspect hereditary connective tissue disease. Platythorax occurs commonly in cases of PPFE, but progression to extensive fibrosis as a result of simple chronic Aspergillus infection has not been reported in a previous report [11, 16]. In the pathogenesis of MFS, defective microfibrils are unable to keep transforming growth factor beta (TGF-β) sequestered, leading to increased free TGF-βand increased degradation of collagen and elastin [14].However, it remains unclear that dysregulated TGF-β also involve with pathogenesis of CCA.

Pathological discussion

PPFE is defined by intra-alveolar fibrosis with collapse and septal elastosis with pleural fibrosis in the upper lung region and is radiologically defined by pleural thickening with associated subpleural fibrosis concentrated in the upper lobes [11]. Pathological findings consistent with those of PPFE were present in our case and were predominantly located in the lingula of the left lung; they were presumed to also be present in the right upper lobe but could not be examined because of severe pleural adhesions and insufficient separation of the lung. Although the association between Aspergillus infection or MFS and PPFE-like features has been discussed previously [9, 12-14], there are few reports revealing the pathological relationships. Some authors reported abnormal elastic fibers in lung specimens from patients with MFS or PPFE that were similar to those seen in our case [16, 17]. However, these findings might not be unique to MFS lungs because the same features were reported in lung specimens from patients with idiopathic pulmonary fibrosis [18]. Kinoshita et al. reported increased elastin production in PPFE, which was not inconsistent with the results of our case [4]. We identified the aberrant lung elastogenesis and the expression of fetal FBN2 antigen in the lung specimens of the patient carrying a novel FBN2 gene variant, which might be indicative of a role for prenatal FBN2 antigen in profibrotic lung conditions. In addition, reticular fibers composed of collagen Ⅲ, which is the second most abundant collagen subtype in normal lungs after collagen Ⅰ, showed a decreased and disorganized composition. Aberrant proliferation of both fibers might play a part in the devastating fibroelastosis in the case described in this report.

Brief review of literature

PPFE was first described by Amitani et al. in 1992 as the entity of idiopathic pulmonary upper lobe fibrosis [1]; subsequently, Frankel et al. termed it PPFE in 2004 [19].

The former reported a slender body habitus with a low body mass index and suggested the predisposing factor in its pathogenesis, as well as MFS and its related disorder. Both entities have specific body habitus characteristics and a pathogenesis of aberrant elastin production, but the association has rarely been reported. This case is valuable because it is the first report in which nonidiopathic PPFE identified aberrant elastin and reticular fibers production involving a fibrillin gene mutation.

Nonidiopathic PPFE and paraseptal emphysema occurred in the lungs of a patient carrying a novel FBN2 gene variant who exhibited aberrant proliferation of elastic and reticular fibers along with the expression of prenatal FBN2 antigen.

pleuroparenchymal fibroelastosis: PPFE

congenital contracture arachnodactyly: CCA

fibrillin-2: FBN2

chronic necrotizing pulmonary aspergillosis :CNPA

fibrillin-1: FBN1

Marfan syndrome: MFS

transforming growth factor-β: TGF-β

hematoxylin-eosin: HE

immunohistochemical: IHC

Ethics approval and consent to participate: All procedures performed in this case report were approved by the Ethics Committee of Kokura Medical Center (No. 248) and in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Written informed consent was obtained from the patient’s next of kin for inclusion in this case report, as the patient was deceased.

Consent for publication: Written informed consent was obtained from the patient’s next of kin for publication of this case report and accompanying images, as the patient was deceased.

Availability of data and material: All data generated or analyzed during this case report are included in this published article.

Declaration of interests: None.

Funding: This research did not receive any specific grants from funding agencies in the public, commercial, or not-for-profit sectors.

Author contributions: HK is the corresponding author and contributed to the collection and analysis of clinical data and writing the manuscript, IT contributed to the histological and imaging analysis and to the preparation of figures, KT and YT contributed to the genetic analysis and diagnosis, KY contributed to the pathological diagnosis and preparation of figures, IS participated in the histological analysis as a cytotechnologist, IY participated in the discussion as a dentist, and SS participated in the discussion of the pathological diagnosis. All authors have critically read the manuscript and given final approval for its submission.

Acknowledgment: We thank Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript.

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[4]. Brinckmann J, Hunzelmann N, Kahle B, et al. Enhanced fibrillin-2 expression is a general feature of wound healing and sclerosis: potential alteration of cell attachment and storage of TGF-β. Lab Invest. 2010;90:739-52. doi:10.1038/labinvest.2010.49;

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[6]. Callewaert B. Congenital Contractural Arachnodactyly. (Updated 2019 Oct 21) In: Adam MP, Ardinger HH, Pagon RA, et al., editors. Gene Reviews(Internet).Seattle(WA); University of Washington, Seattle;1993-2021, http://www.ncbi.nlm.nih.gov/books/

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Nonidiopathic pleuroparenchymal fibroelastosis with a novel fibrillin-2 gene variant characterized by the expression of prenatal fibrillin-2 antigen and the aberrant proliferation of elastin and reticular fibers: a case report

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Abstract

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Introduction

Case Presentation

Discussion

Conclusion

Abbreviations

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References

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