Early‐Onset Progressive Pleuroparenchymal Fibroelastosis: Challenges in Genetic Diagnosis and Management

An 8-year-old female with otherwise unremarkable medical history until the age of seven, was admitted to our Pediatric Unit with dyspnea, pectus excavatum, deepened suprasternal notch and flattened chest. Although born to asymptomatic healthy parents, history of autoimmune disorders (i.e. vitiligo, Hashimoto thyroiditis), pectus excavatum, and malignancy (i.e. larynx carcinoma) was unveiled in the family. The patient was born at 38 weeks of gestation age from an elective caesarean section due to placenta previa. Perinatal and neonatal course was otherwise regular. A general well-being and development was described until the age of six when the patient experienced a growth arrest without evidence of any infectious cause contributing to increased morbidity. The child had not required hospital admissions except for cardiac evaluations in early childhood due to pectus excavatum (i.e. normal electrocardiography and cardiac ultrasound). At 6 years and 4 months of age, she experienced progressive asthenia and dry cough. In the following months, the clinical picture gradually worsened with palpitations and reduced tolerance to mild physical activity. Anemia and increased inflammatory markers were excluded as well as alterations of liver and kidney function. At admission, patient's weight, height and BMI were significantly below the range for age and sex (< 3°, 3°–5°and < 5° percentile, respectively). Oxygen saturation was 95% on room air without clubbing. Auscultation unveiled decreased breath sounds predominantly at the apex of the right lung, whereas pulmonary function tests (PFTs) (data expressed as % predicted, except for FEV1/FVC ratio, and z-score) demonstrated severe restrictive pattern (FVC = 29% pred, z-score = −6.3; FEV1 = 29% pred, z-score = −5.5 and FEV1/FVC ratio = 0.88). Chest radiograph showed areas of opacities predominantly in the right upper lobe along with diffuse bilateral interstitial-alveolar involvement and right trachea displacement. Chest computed tomography (CT) depicted bilateral pleural/subpleural fibrosis and multiple fibrocystic changes more prominent in the upper lobe of the right lung suggestive of pleuroparenchymal fibroelastosis (PPFE) (Figure 1A,B), a rare pulmonary disorder with unique clinical and radiological features [1, 2]. It has been suggested that acute or subacute lung injury causing interstitial inflammation may drive the pathological events leading to PPFE. However, to date the exact nature of putative triggers remains unknown [1]. The child's personal history was unremarkable for exposure to environmental factors [1] whereas potential PPFE infectious initiating factors (Table 1 in Ref. [1] and Material S1) were investigated and turned out negative (Material S1). Additional underlying infectious, immune, endocrine, nutritional, dermatological and cardiological disorders were investigated and ruled out, whereas associated liver fibrosis was excluded by FibroScan. Abdomen ultrasound was unremarkable while extrapulmonary involvement and abnormalities of the airways had been previously ruled out by whole body MRI and flexible bronchoscopy, respectively. At admission, nocturnal pulse-oximetry detected a pattern featured by mean SpO2 = 96%, minimum SpO2 = 92% with normal oxygen desaturation index (ODI = 0.5/h) and percentage of recording time spent with SpO2 ≤ 93% (T93) equal to 0.02%. Blood gas parameters were unremarkable, and hypercapnia was not detected by transcutaneous pCO2 monitoring. The distance covered in the 6-min Walk Test (248 m) was below the 3rd age- and gender-related reference percentile according to Vandoni et al [3]. Taken together, clinical features, lung functional profile and imaging (Figure 1A,B) were consistent with PPFE [1, 2]. After excluding potential infectious and environmental triggers [1] major known inherited causes [1, 4] of interstitial lung diseases (ILD), including PPFE, were investigated by next generation sequencing. Mutations of ABCA3, SFTPB, SFTPC, FOXF1, NKX2-1 were explored and ruled out whereas analysis of genes involved in telomere syndrome (i.e. TERC, TERT, MUC5B, TOLLIP) unveiled a homozygous TERT gene polymorphism (i.e. Chr5(GRCh37):g.1286516 C > A, c.1574-3777 G > T dbSNP: rs2736100), with variant present in one allele in both asymptomatic parents. The identified variant is classified as benign in ClinVar database but it has been associated with increased idiopathic pulmonary fibrosis (IPF) risk [4]. Given the complexity of ILD pathogenesis, genetic investigations were extended at immune-related and rarer ILD genes (Material S1) unveiling exclusively a heterozygous variant of unknown significance (c.331 A > Gp.(Met111Val)) in NRAS which is involved in RASopathies, autoimmune lymphoproliferative syndrome, and cancer. To promote growth and weight gain, nutrition has been optimized by including oral supplementary foods with additional energy source. Oral hydroxychloroquine and cycles of azithromycin were initiated without clear evidence of clinical benefit as outlined by an increase, on serial nocturnal pulse-oximetry measurements, of the percentage of recording time with SpO2 ≤ 93% (T93), from 2.1% at 2 months to 8.2% at 4 months follow-up, respectively (Figure 1E). At the latter, PFTs showed progression to a more severe restrictive pattern (FVC = 21% pred, z-score = −7.1; FEV1 = 23% pred, z-score = −5.9 and FEV1/FVC ratio = 0.97). Hence, after obtaining local Ethics Committee (Comitato Etico Territoriale (C.E.T) delle Marche, Azienda Ospedaliero-Universitaria delle Marche) approval (C.E.T 2024-280) and parents' informed consent, nintedanib treatment [5] was initiated under compassionate use in the attempt to arrest fibrosis progression, along with nocturnal oxygen therapy. However, 2 months later, she presented with increased tachypnea and retractions, requiring oxygen supplementation (up to 2 L/min). A chest X-ray revealed spontaneous right pneumothorax requiring a chest-tube insertion with radiological resolution occurring after 2 months (Figure 1C,D). Despite medical interventions, recurrence of spontaneous bilateral pneumothorax occurred after 4 months, requiring prolonged placement of a chest tube on the left side. Given the progressive disease history and unfavorable prognosis, 1 year after establishing PPFE diagnosis, the patient underwent successful lung transplantation. The post-operative course was favorable. At present time, the patient is alive and in good clinical condition 2 months after transplantation. Progressive fibrotic ILDs including Idiopathic pulmonary fibrosis (IPF) are challenging entities featured by multifactorial etiology, severe clinical burden and unfavorable prognosis. Ongoing advances in ILDs/IPF pathogenesis and disease history have, indeed, suggested that genetic predisposition (i.e. rare genetic variant/risk loci or common SNPs), epigenetic modifying agents as well as environmental factors, contribute to the disease onset. This complexity, in turn, accounts for the extreme heterogeneity in phenotypic expression among patients with sporadic form as well as within family members carrying comparable genetic background. In conclusion, this child represents a clinical enigma that should rise awareness. While children presenting with PPFE have usually history of treated cancer [1, 4], we herein describe an unprecedented PPFE pediatric onset lacking an identified predisposing primary condition, and featured by rapidly aggressive disease history. The personal history and investigations carried out excluded exposure to putative environmental and infectious triggers (Material S1). The early onset is, indeed, evocative of underlying genetic cause although parents partly sharing patient's genetic background are so far asymptomatic. To date, the homozygous TERT gene variant appears to be the only identified potential disease driver in this child. However, this polymorphism has been variably linked to increase IPF risk [4] and supporting evidence is controversial. In addition to challenges in early diagnosis and therapeutic intervention, ethical issues concerning appropriate and time-manner genetic counselling in healthy parents and family members need to be addressed. Alessia Omenetti: conceptualization, writing – original draft, writing – review and editing, data curation, supervision, methodology, visualization. Vittorio Romagnoli: conceptualization, writing – review and editing, data curation, methodology, visualization. Bianca Lattanzi: data curation, conceptualization, visualization. Cecilia Lanza: data curation, visualization. Salvatore Cazzato: conceptualization, funding acquisition, methodology, writing – review and editing, supervision, data curation, visualization, project administration. We thank Alessandra Mihalich (Molecular Biology Laboratory, Istituto Auxologico Italiano IRCCS, Milan, Italy) and Roberta Bertelli (Laboratory of Human Genetics, Giannina Gaslini IRCCS, Genoa, Italy) for support interpretation of the identified genetic variants. The authors received no specific funding for this work. The authors declare no conflicts of interest. Written informed consent was obtained from the child's parents for publication of this case and any accompanying images. The data supporting the results of this study are available from the corresponding author upon reasonable request. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.