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The Spectrum of Filamin A Disease

Filamin A protein is an important component of the cellular cytoskeleton. Filamin A links actin to the cell membrane and is an important mediator of cell shape and migration. It plays an important role in the maturation of lung alveoli during embryologic life.

Filamin A is encoded by the FLNA gene. Mutations in FLNA result in a range of clinical syndromes. Gain-of-function mutations result in skeletal dysplasia with hearing loss (otopalatodigital syndrome types I and II and the Melnick–Needles syndrome). Loss-of-function mutations in FLNA cause periventricular heterotopia, in which groups of neurons fail to migrate from the periventricular region of the brain to the cerebral cortex. These patients usually present with seizures during the teenage years. Less commonly, microcephaly and developmental delays are seen. Other mutations have been reported to cause dilatation of the aorta, cardiac valvular dysplasia, flexible joints, and fragile blood vessels.

An X-linked dominant disorder similar to the Ehlers–Danlos syndrome is caused by mutations in FLNA gene. Phenotypic features vary widely depending on the type of mutation, but this disease is often fatal in males.

An FLNA mutation associated with pulmonary disease was reported in 2011. Since then, 17 additional case reports of lung disease have been published. Of the 18 patients, 15 were female, which suggests that males are more severely affected and less likely to survive to birth. All but 1 of these patients were born at full term. All had periventricular heterotopia. The onset of lung disease occurred during the first 3 months of life in all 18 patients. In 17 patients, CT scans showed areas with lung hyperinflation. In many of the patients, whole lobes were hyperinflated and lobar emphysema was noted. In total, 10 of the patients had a patent ductus arteriosus, and 4 had pulmonary hypertension. A total of 8 patients died or had lung transplantation. There was no apparent association between mutation type and outcome, but the number of cases is small.


Kenner TM et al. Case 28-2019: A 22-Year-Old Woman with Dyspnea and Chest Pain. N Engl J Med 2019;381:1059-1067

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