Introduction
Filamin A (FLNA) deficiency is an X-linked syndromic connective tissue disorder affecting multiple organ systems. One of the unique findings is periventricular nodular heterotopia (PVNH, OMIM #300049). Individuals affected by FLNA deficiency have shown neurological, cardiovascular, pulmonary, hematological, and musculoskeletal manifestations. We report a 27-year-old female diagnosed with FLNA deficiency following a diagnostic odyssey.

Case Presentation
The patient’s pediatric history included patent ductus arteriosus, spontaneous pneumothorax, and nephrocalcinosis. Brain MRI at age 14 revealed PVNH and a posteriorly truncated corpus callosum. Additional phenotypes included a platelet function defect, thrombocytopenia, and an echocardiogram showing mild aortic insufficiency, mitral valve prolapse, and dilated proximal abdominal aorta. At 24, she developed recurrent spontaneous pneumothoraces. Physical examination identified connective tissue features, such as joint hypermobility, pes planus, gingival recession, and scoliosis.

Diagnostic Workup
Chest CT imaging showed upper lobe emphysema with diffuse subpleural reticulations, while pulmonary function tests indicated a restrictive pattern. A lung biopsy showed significant hyperinflation and emphysematous changes in the lung parenchyma, interstitial lymphoid infiltrates, intra-alveolar cholesterol clefts, and smooth muscle hyperplasia; these suggested endogenous lipoid pneumonia-like changes. Sequencing and duplication/deletion analysis of the FLNA gene revealed a pathogenic c.7652del (p.Lys2551Argfs*9) variant, which was not maternally inherited. A next-generation sequencing panel for Hermansky-Pudlak syndrome and lysosomal storage disorders was negative.  

 

Treatment and Management
In our patient, she has had no seizures, a common symptom associated with PVNH. Due to the possibility of vasculopathy and aortopathy, it is imperative she have periodic echocardiography and imaging study of the aorta, carotids, and vasculature of the brain. Joint hypermobility and musculoskeletal symptoms can be managed by physical therapy. There is no specific treatment for the lung pathology, but pulmonologists should be involved in managing early-onset emphysema and pneumothorax.

 

Outcome and Follow-Up
Our patient was referred to vascular medicine for follow-up to evaluate the aorta, carotids, and vasculature of the brain. She was referred back to her pulmonologist with information regarding her diagnosis as well, with plans for pulmonary function testing

Discussion
Management of FLNA deficiency focusses on treating known complications and surveillance of organ systems. While hyperinflation and emphysematous changes are common findings, the lipoid pneumonia-like changes observed are, to the best of our knowledge, novel. We hypothesize that these changes may be linked to FLNA deficiency. Filamin A stabilizes actin filaments, which are essential for macrophage function. Defects in FLNA have been associated with impaired macrophage migration in lung tissues and disrupted lipid uptake, potentially contributing to the observed pathology.

Conclusion
The unique findings of PVNH should prompt analysis of the FLNA gene. Based on our patient’s lung histology, further research is needed to explore whether macrophage and lipid abnormalities contribute to lung disease in individuals with FLNA deficiency. Understanding this connection may lead to potential therapeutic developments.