Researchers have identified a new mutation in the FLNA gene that was linked with pulmonary arterial hypertension (PAH) and congenital heart defects in a two-year-old girl.
This case, along with more than a dozen others, highlights the association between FLNA mutations and early onset PAH. Together, they support genetic testing in children with suspected PAH.
The case report study, “Where the congenital heart disease meets the pulmonary arterial hypertension, FLNA matters: a case report and literature review,” was published in the journal BMC Pediatrics.
While there are multiple similarities between childhood- and adult-onset PAH, “pediatric patients have higher prevalence of idiopathic [unknown cause] PAH, PAH associated with congenital heart disease (CHD), and pulmonary disorders,” the researchers wrote. Of note, a disease’s prevalence is the number of cases present in a particular population at a given time.
Several mutations have been identified in children with PAH associated with congenital heart disease, and a previous study suggested that de novo mutations — those that appear in a child without being inherited from the parents — may underlie about 19% of cases of childhood-onset idiopathic PAH.
Mutations in the FLNA gene, which contains instructions to produce a protein involved in maintaining the cell’s structure and molecule transport, have been linked to a broad range of diseases, from neurodevelopmental disorders to skeletal, gastrointestinal, and heart conditions. An increasing number of studies also support an association between FLNA mutations and lung diseases, including PAH.
To date, 18 cases of children and young infants with FLNA-associated early onset PAH have been reported in the literature.
All of the children had congenital heart disease and five (27.8%) had developmental delays. A total of 13 of the children (72.2%) had partial lung collapse or incomplete expansion of some areas in the lung, called atelectasis. Of note, when the lungs cannot fully expand and take in enough air, the blood may not receive enough oxygen, which can lead to serious complications and, eventually, to respiratory failure.
Nearly 40% of these children died. Lung transplant appeared to improve the children’s chances of survival, as only one of these young patients died after undergoing the procedure.
Researchers at Wuhan Asia Heart Hospital, in China, now described the case of a two-year-old girl with rapidly progressive PAH and congenital heart disease associated with a previously unidentified FLNA gene mutation.
The girl was first treated at the hospital when she was 8 months old for severe cough, shortness of breath, fatigue, and fever. She had an enlarged heart and had experienced repeated episodes of pneumonia since she was two months old.
Detailed examination revealed she had a cleft lip, cleft palate, mild developmental delay, and an atrial septal defect, or a hole in the wall that divides the heart’s two upper chambers. The child also had reduced oxygen levels in the blood, and a slightly high blood pressure in the arteries connecting the lungs to the heart (PAH).
Despite treatment for heart failure and supplemental oxygen use at home thereafter, the girl was re-hospitalized several times due to recurrent pneumonia and heart failure.
Additional analyses showed her blood oxygen levels continued to drop and her PAH to worsen. A chest computed tomography (CT) scan also showed she had enlargement of the main pulmonary artery and right heart atrium, and atelectasis.
Genetic testing identified a new, de novo, disease-causative FLNA mutation — specifically c.5417-1G>A — confirming the cause of her PAH diagnosis.
“FLNA mutation causes rare but progressive PAH in addition to a wide spectrum of congenital heart disease and other [simultaneous conditions] in pediatric patients,” the researchers wrote.
The investigators also recommended that genetic testing be considered in children with suspected PAH.
They noted that lung transplant may be a particularly effective therapeutic approach in children with FLNA-associated PAH.
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