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A5641 - At the Opposite End of the Spectrum: Filamin A-Associated Interstitial Lung Disease
Author Block: M. Lu, B. A. Nelson, T. Kinane; Pediatric Pulmonary Medicine, Massachusetts General Hospital, Boston, MA, United States.
INTRODUCTION
Filamin A (FLNA) encodes an actin-cross-linking phosphoprotein crucial in guiding cellular migration. Loss-of-function mutations in FLNA account for the majority of familial periventricular nodular heterotopia (PVNH), which has a characteristic MRI finding due to arrest of neuronal migration. Extrapulmonary manifestations are well-described, encompassing bicuspid aortic valve (AV), aortic dilatation, atrial and ventricular septal defects (ASD, VSD), seizure disorder, and connective tissue anomalies. However, pulmonary involvement is not fully understood. We contrast the clinical features and course of an infant with interstitial lung disease (ILD) associated with FLNA mutation to the previously described course of her sibling with an identical mutation.
CASE
A 3-week-old female presented with two days of progressive tachypnea and respiratory distress associated with feeds. Notably, family history revealed PVNH across three generations of females, including a deceased sister with alveolar dysplasia, cardiac anomalies (bicuspid AV, aortic dilatation, VSD), and a pathogenic deletion in FLNA. In addition to PVNH, their mother had seizures, a small PDA, and joint hypermobility and maternal grandmother had seizures. This supported X-linked inheritance of FLNA-associated PVNH with the appearance of pulmonary findings in the sister suggesting increased disease penetrance. The sibling had respiratory distress since birth with demise at 5 months of age from respiratory failure.
Our patient demonstrated PVNH on head ultrasound and a large VSD, ASD, and PDA on echocardiogram. Chest radiograph showed bilateral patchy opacities. CT of chest demonstrated bibasilar atelectasis, axial interstitial thickening, scattered ground glass opacities, and air trapping. Due to congestive heart failure from volume overload, she underwent VSD and ASD closure with PDA ligation. Lung biopsy showed alveolar simplification. Genetic testing confirmed a FLNA mutation identical to that of her sibling. She remained on supplemental oxygen by low-flow nasal cannula for two months. At follow-up at 14 months of age, she was doing well without clinical evidence of pulmonary disease.
DISCUSSION
The limited literature available on pulmonary manifestations of FLNA mutations details variable presentations. Early onset of respiratory distress, prolonged supplemental oxygen dependence, radiographic findings of hyperinflation and basilar atelectasis, and lung histologic changes including emphysema and alveolar simplification are often highlighted. We present an infant with FLNA-associated ILD who was asymptomatic at follow-up at 14 months of age. In contrast, her sister with an identical mutation passed away at 5 months of age from respiratory decompensation. This case highlights the variable prognosis of childhood FLNA-associated ILD and the favorable end of the disease spectrum.