Clinical Pearls & Morning Reports

By Carla Rothaus

Published September 11, 2019


What clinical findings may be associated with mutations in the gene encoding filamin A (FLNA)?

In recent years, a disorder similar to the Ehlers–Danlos syndrome that is caused by mutations in the gene encoding filamin A (FLNA) has been recognized. Read the latest Case Records of the Massachusetts General Hospital here.

Clinical Pearls

Q: Describe a role of the filamin A protein.

A: The filamin A protein is an important component of the cellular cytoskeleton. The filamin A protein links actin, which is essential to the regulation of cell shape and migration, to the cell surface. The filamin A protein is thought to be important in the maturation of alveoli in embryologic life, a process that affects lung growth and development.

Q: Does FLNA-related disease have a unique phenotype?

A:FLNA-related disease is an X-linked dominant condition that has highly variable phenotypic features. FLNA-related disease is frequently fatal in male patients. The cause of FLNA mutation seems to vary and has been linked to deletions, missense changes, duplications, and nonsense variants, all of which may have a role in the phenotypic outcome.

Morning Report Questions

Q: What clinical findings may be associated with mutations in the gene encoding filamin A (FLNA)?

A: 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 were first described in patients with periventricular heterotopia, which is an anomaly in which groups of neurons fail to migrate from the periventricular region to the cerebral cortex. Such patients usually present with seizures during the teenage years. Less commonly, microcephaly and developmental delays are seen. Since the mutations were first described, features such as dilatation of the aorta, cardiac valvular dysplasia, flexible joints, and fragile blood vessels have been increasingly recognized.

Q: What are some of the features of cases of FLNA mutation with pulmonary manifestations?

A: More recently, cases of FLNA mutation with pulmonary manifestations have been identified. The first case was identified in 2011. Since then, 17 additional case reports of lung disease have been described in the literature, but more cases are being recognized in the clinic, particularly in lung transplantation centers. Of the 18 patients, 15 were female, which suggests that males are more likely to be severely affected and are 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.

Browse more Clinical Pearls & Morning Reports »

NEJM Knowledge+