Lung disease associated with filamin A gene mutation: a case report

Abstract

BackgroundMutations in the gene encoding filamin A (FLNA) lead to diseases with high phenotypic diversity including periventricular nodular heterotopia, skeletal dysplasia, otopalatodigital spectrum disorders, cardiovascular abnormalities, and coagulopathy. FLNA mutations were recently found to be associated with lung disease. In this study, we report a novel FLNA gene associated with significant lung disease and unique angiogenesis.Case presentationHere, we describe a 1-year-old Saudi female child with respiratory distress at birth. The child then had recurrent lower respiratory tract infections, bilateral lung emphysema with basal atelectasis, bronchospasm, pulmonary artery hypertension, and oxygen and mechanical ventilation dependency. Molecular testing showed a new pathogenic variant of one copy of c.3153dupC in exon 21 in the FLNA gene.ConclusionsOur data support previous reports in the literature that associate FLNA gene mutation and lung disease.

Filamin A (FLNA) mutation—A newcomer to the childhood interstitial lung disease (ChILD) classification

“…With regards to the cardiac co‐morbidities, two of our patients were found to have a patent ductus arteriosis, which was also seen in five previously reported FLNA associated lung disease cases and was the second commonest associated cardiac abnormality within 17.6% (six patients) of patients with FLNA associated PVNH (second only to aortic valvular insufficiency) . This illustrates the importance of echocardiographic findings in this cohort of patients and the need for future extended medical surveillance from a cardiovascular standpoint.…”

“…Filamin A is an actin‐binding protein expressed ubiquitously within the body with multiple roles both in cell signaling and maintenance of cell shape and motility . A well‐known association already exists between this mutation and disorders of neuronal migration, vascular function, connective tissue integrity, and skeletal development; however, pulmonary manifestations are only just being described with four published case reports to date and a further five patients altogether reported within two separate poster abstract publications…”

“…Pathology obtained from lung biopsy or resection have revealed a combination of alveolar simplification, emphysematous changes, and pulmonary arteriopathy suggesting that mutations of FLNA appear to result in alveolar growth abnormality and thus reflect another causal etiology within the referenced classifications . In nearly all cases treatment has involved either lobar resection or lung transplantation with only one case reported where supportive therapy was successful …”

Lung Transplantation for FLNA -Associated Progressive Lung Disease

“…Additional cases of lung disease associated with pathogenic variants in FLNA have been subsequently reported (Table 5, Online) 3, 4, 7, 12, 13, 17–19, 28, 29 . The association of pulmonary pathology with pathogenic variants in FLNA is further supported by a mouse model 30 .…”

“…Additional phenotypes that have been observed in a subset of patients with X-linked PVNH and FLNA pathogenic variants include Ehlers-Danlos syndrome–like features 3–6 , cardiovascular anomalies 4, 5, 7–9 , and intestinal pseudo-obstruction 4, 10, 11 . Moreover, pulmonary complications of varying severity have been associated with this disorder 3–5, 12–16 , and a few patients with progressive obstructive pulmonary disease in early childhood leading to respiratory failure have been described 12, 13, 17–19 . In the present report, we describe the largest published cohort of patients with heterozygous pathogenic variants in FLNA and progressive lung disease leading to respiratory failure in infancy and delineate the first use of lung transplantation to promote survival in patients with severe pulmonary complications in this disorder.…”